Regioselective Aziridination of Silyl Allenes and Application for the Synthesis of New Heterocycles

Science.gov (United States)

Burke, Eileen Grace

Rhodium catalyzed aziridination of homoallenic sulfamates has proven to be a successful first step in the synthesis of a diverse array of complex nitrogenated motifs. Previously, however, the resultant methyleneaziridine was limited to the exocyclic isomer. In this work, a reliable direction strategy for the formation of the endocyclic isomer was identified. Placement of a silicon group on the allene so that its C - Si bond is co-planar to the distal pi-bond allowed for stabilization of the developing positive charge during aziridination, and therefore selective activation to form the endocyclic methyleneaziridine. This strategy proved robust, and endocyclic methyleneaziridines were formed in high yields with exclusive formation of the desired isomer regardless of the substitution of the allene. With the endocyclic isomer now readily available, its reactivity could be explored. First, the endocyclic methyleneaziridine was applied to the synthesis of densely functionalized, nitrogen containing motifs. In comparison with their exocyclic counterparts, the endocyclic methyleneaziridines were found to have differing reactivity. The olefin could be epoxidized using meta-chloroperoxybenzoic acid (mCPBA), and the resulting spirocyclic intermediate rapidly rearranged to an azetidin-3-one. This synthesis of the highly substituted fourmembered heterocycle represented a novel approach to these motifs, and was found to be both flexible, and to selectively form a single diastereomer. Additional derivatization of these scaffolds gave a diverse array of complex products. Further use of the endocyclic methyleneaziridine focused not on the complexity of the product motif but rather on its utility. The remaining silyl group could be eliminated upon reaction with a fluoride source, triggering the formation of an alkyne and resultant opening of the aziridine. This strained heterocyclic alkyne and its synthesis represent a new addition to the field of strained alkyne synthesis. Uniquely

Asymmetric Synthesis of Fluoroamines from Chiral Aziridines

Energy Technology Data Exchange (ETDEWEB)

Park, Hyeonjeong; Yoon, Dooha; Ha, Hyunjoon [Hankuk Univ. of Foreign Studies, Yongin (Korea, Republic of); Son, Se In; Lee, Won Koo [Sogang Univ., Seoul (Korea, Republic of)

2014-03-15

We described an efficient preparation of fluoroamines by the ring-opening reactions of chiral aziridines with Et{sub 3}N·3HF. At most cases both regioisomers were obtained from the ring openings at C2 and C3 positions depending on the substituents at C2 of the starting substrates.The fluorinated organic molecules have attracted great attentions from synthetic and medicinal chemists with wide use of various agrochemicals and pharmaceuticals. Their uniqueness is originated from its electronic characteristics and the small size without altering the molecular conformations of non-fluorinated compounds. The fluorine is the second most widely used atom in the commercial drugs following the amine. Thereby, the elaboration of fluoro-amines bearing two most widely used atoms in drugs is one of the most challenging problems in drug synthesis and its development.

Stereocontrolled Syntheses of Seven-Membered Carbocycles by Tandem Allene Aziridination/[4+3] Reaction.

Science.gov (United States)

Gerstner, Nels C; Adams, Christopher S; Tretbar, Maik; Schomaker, Jennifer M

2016-10-10

A tandem allene aziridination/[4+3]/reduction sequence converts simple homoallenic sulfamates into densely functionalized aminated cycloheptenes, where the relative stereochemistry at five contiguous asymmetric centers can be controlled through the choice of the solvent and the reductant. The products resulting from this chemistry can be readily transformed into complex molecular scaffolds which contain up to seven contiguous stereocenters. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

Directory of Open Access Journals (Sweden)

Hongnan Sun

2015-04-01

Full Text Available The metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an SN2-type ring opening followed by cyclization of the resulting haloalkoxy amine.

Copper-Catalyzed Trifluoromethylazidation of Alkynes: Efficient Access to CF3-Substituted Azirines and Aziridines.

Science.gov (United States)

Wang, Fei; Zhu, Na; Chen, Pinhong; Ye, Jinxing; Liu, Guosheng

2015-08-03

A novel method for convenient access to CF3-containing azirines has been developed, and involves a copper-catalyzed trifluoromethylazidation of alkynes and a photocatalyzed rearrangement. Both terminal and internal alkynes are compatible with the mild reaction conditions, thus delivering the CF3-containing azirines in moderate to good yields. The azirines can be converted into various CF3-substituted aziridines. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Short and Efficient Synthesis of Optically Active N-Tosyl Aziridines from 2-Amino Alcohols

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Maria C. F. de Araújo

2002-12-01

Full Text Available Two alternative and complementary one-pot procedures for the direct transformation of 2-amino alcohols to N-tosyl aziridines are presented. The unsubstituted parent compound and its less hindered homologues can be obtained in high yields by tosylation and in situ cyclisation effected by potassium hydroxide in water/dichloromethane. Higher substituted amino alcohols give better yields using potassium carbonate in acetonitrile. Both procedures use simple inorganic bases and produce only inorganic salts as byproducts.

2-[2-(Aziridin-1-ylethyl]-5,5-dimethyl-2,5-dihydro-4H-benzo [e]isoindol-4-one (Cytotoxic Oxonaphthalene-Pyrroles, Part IV

Directory of Open Access Journals (Sweden)

Helmut Spreitzer

2012-10-01

Full Text Available An aziridine-containing side chain is attached to an oxonaphthalene-annelated pyrrole in expectation of DNA alkylating properties. The cytotoxicity is evaluated against two cell lines, KB-31 and KB-8511, respectively.

Fluorescence method for the determination of carcinogenic N-nitrosamines using N-(8-methoxy-5-quinolinesulfonyl)-aziridine

International Nuclear Information System (INIS)

Gracheva, I.N.; Kovel'man, I.R.; Pimenova, V.V.; Tochilkin, A.I.; Zhukova, G.F.

1986-01-01

The determination of carcinogenic N-nitrosamines (NA) in the environment and particularly in food products is, according to the authors, extremely important. The objective of the present work is the development of an easily accessible and highly sensitive method for the determination of NA. NA, isolated from food products, are denitrosated to their corresponding amines, which are then determined in the form of fluorescent derivatives by reaction with N-(8-methoxy-5-quinolinesulfonyl) aziridine. The validity of the results of NA analysis from food product was confirmed by gas-liquid chromatography using a thermoluminescent detector TEA-502. The limit of detection is 1x10 -10 mole of N-nitrosamine. The possibility of separating and determining the new fluorescent derivatives III(a-f) on silufol plates, which are easily obtained and widely used in analytical practice, was examined

Diastereomerically and enantiomerically pure 2,3-disubstituted pyrrolidines from 2,3-aziridin-1-ols using a sulfoxonium ylide: a one-carbon homologative relay ring expansion.

Science.gov (United States)

Schomaker, Jennifer M; Bhattacharjee, Somnath; Yan, Jun; Borhan, Babak

2007-02-21

An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring-closure yields the desired pyrrolidine, thus completing the relay of the three-membered to the five-membered nitrogen-containing ring system. This process takes place with complete transfer of stereochemical fidelity and can be applied to sterically hindered aziridinols.

An unusual methylene aziridine refined in P2(1)/c and the nonstandard setting P2(1)/n.

Science.gov (United States)

Feast, George C; Haestier, James; Page, Lee W; Robertson, Jeremy; Thompson, Amber L; Watkin, David J

2009-12-01

The unusual methylene aziridine 6-tert-butyl-3-oxa-2-thia-1-azabicyclo[5.1.0]oct-6-ene 2,2-dioxide, C(9)H(15)NO(3)S, was found to crystallize with two molecules in the asymmetric unit. The structure was solved in both the approximately orthogonal and the oblique settings of space group No. 14, viz. P2(1)/n and P2(1)/c, respectively. A comparison of these results clearly displayed an increase in the correlation between coordinates in the ac plane for the oblique cell. The increase in the corresponding covariances makes a significant contribution to the standard uncertainties of derived parameters, e.g. bond lengths. Since there is yet no CIF definition for the full variance-covariance matrix, there are clear advantages to reporting the structure in the nonstandard space-group setting.

Reusable radiation monitor

International Nuclear Information System (INIS)

Fanselow, D.L.; Ersfeld, D.A.

1978-01-01

An integrating, reusable device for monitoring exposure to actinic radiation is disclosed. The device comprises a substrate having deposited thereon at least one photochromic aziridine compound which is sealed in an oxygen barrier to stabilize the color developed by the aziridine compound in response to actinic radiation. The device includes a spectral response shaping filter to transmit only actinic radiation of the type being monitored. A color standard is also provided with which to compare the color developed by the aziridine compound

Diastereo- and regioselective addition of thioamide dianions to imines and aziridines: synthesis of N-thioacyl-1,2-diamines and N-thioacyl-1,3-diamines.

Science.gov (United States)

Shibahara, Fumitoshi; Kobayashi, Shun-ichiro; Maruyama, Toshifumi; Murai, Toshiaki

2013-01-02

Addition reactions of thioamide dianions that were derived from N-arylmethyl thioamides to imines and aziridines were carried out. The reactions of imines gave the addition products of N-thioacyl-1,2-diamines in a highly diastereoselective manner in good-to-excellent yields. The diastereomeric purity of these N-thioacyl-1,2-diamines could be enriched by simple recrystallization. The reduction of N-thioacyl-1,2-diamines with LiAlH(4) gave their corresponding 1,2-diamines in moderate-to-good yields with retention of their stereochemistry. The oxidative-desulfurization/cyclization of an N-thioacyl-1,2-diamine in CuCl(2)/O(2) and I(2)/pyridine systems gave the cyclized product in moderate yield and the trans isomer was obtained as the sole product. On the other hand, a similar cyclization reaction with antiformin (aq. NaClO) as an oxidant gave the cis isomer as the major product. The reactions of N-tosylaziridines gave the addition products of N-thioacyl-1,3-diamines with low diastereoselectivity but high regioselectivity and in good-to-excellent yields. The use of AlMe(3) as an additive improved the efficiency and regioselectivity of the reaction. The stereochemistry of the obtained products was determined by X-ray diffraction. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Expedite Protocol for Construction of Chiral Regioselectively N-Protected Monosubstituted Piperazine, 1,4-Diazepane, and 1,4-Diazocane Building Blocks

DEFF Research Database (Denmark)

Crestey, François; Witt, Matthias; Jaroszewski, Jerzy W.

2009-01-01

This paper describes the first study of solution-phase synthesis of chiral monosubstituted piperazine building blocks from nosylamide-activated aziridines. The protocol, involving aminolysis of the starting aziridines with ω-amino alcohols and subsequent Fukuyama−Mitsunobu cyclization, offers the...

NMR Investigation of the complexation of (S-2-isopropyl- 1-(o-nitrophenylsulfonylaziridine with -cyclodextrin

Directory of Open Access Journals (Sweden)

Mohamed Z. Sliman

2014-07-01

Full Text Available Aziridines are known to undergo hydrolysis in the presence of cyclodextrins, whereas the latter are largely investigated as potential vectors of biologically active compounds. Despite this easy cyclodextrin-induced cleavage of aziridines in aqueous medium, it was of interest to find out a model aziridine derivative that would be sufficiently water-stable and form a stable complex with b-cyclodextrin in aqueous medium, so that it could be used as a reference in future formulations or vectorization work. Among compounds we have investigated, we found out that only (S-2-isopropyl-1-(o-nitrophenylsulfonylaziridine complied with the above-mentioned solubility and stability requirements. NMR studies of the inclusion complex of this derivative with b-cyclodextrin provided useful parameters related to the stoichiometry of the complex and the association constant Ka. The geometry of the complex was assessed by 2D-ROESY experiments, suggesting a deep insertion of the aziridine into the cavity of b-cyclodextrin.

The Determination of Rate-Limiting Steps during Soot Formation

Science.gov (United States)

1990-06-08

and a CH3N precursor of acetonitrile such as 2H-aziridine although other intermediates of lower energy such as ketenimine have been identified on the...precursor of acetonitrile such as 2H-aziridine or ketenimine . Experimentally it was found that the overall rate of disappearance of pyrrole is first order

Metodologia AGOA: a modelagem de clusters de hidratação no complexo aziridina···ácido fluorídrico AGOA methodology: modeling the hydration clusters for the aziridine···hydrofluoric complex

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Boaz G. Oliveira

2009-01-01

Full Text Available We present a theoretical study of solvent effect on C2H5N···HF hydrogen-bonded complex through the application of the AGOA methodology. By using the TIP4P model to orientate the configuration of water molecules, the hydration clusters generated by AGOA were obtained through the analysis of the molecular electrostatic potential (MEP of solute (C2H5N···HF. Thereby, it was calculated the hydration energies on positive and negative MEP fields, which are maxima (PEMmax and minima (PEMmin when represent the -CH2- methylene groups and hydrofluoric acid, respectively. By taking into account the higher and lower hydration energy values of -370.6 kJ mol-1 and -74.3 kJ mol-1 for PEMmax and PEMmin of the C2H5N···HF, our analysis shows that these results corroborate the open ring reaction of aziridine, in which the preferential attack of water molecules occurs at the methylene groups of this heterocyclic.

Reactions of ethyl diazoacetate catalyzed by methylrhenium trioxide

Energy Technology Data Exchange (ETDEWEB)

Zhu, Z.; Espenson, H. [Iowa State Univ., Ames, IA (United States)

1995-11-03

Methylrhenium trioxide (CH{sub 3}ReO{sub 3} or MTO) has found wise use in catalysis, including the epoxidation and metathesis of olefins, aldehyde olefination, and oxygen transfer. Extensive reports have now appeared in the area of MTO-catalyzed substrate oxidations with hydrogen peroxide. Certain catalytic applications of MTO for organic reactions that do not utilize peroxide have now been realized. In particular, a catalytic amount of MTO with ethyl diazoacetate (EDA) will convert aromatic imines to aziridines and convert aldehydes and ketones to epoxides. The aziridine preparation proceeds in high yields under anaerobic conditions more conveniently than with existing methods. Compounds with a three-membered heterocyclic ring can be obtained with the EDA/MTO catalytic system. Aromatic imines undergo cycloaddition reactions to give aziridines under mild conditions.

Aminolysis of resin-bound N-nosylaziridine-2-carboxylic acids

DEFF Research Database (Denmark)

Olsen, Christian A; Christensen, Caspar; Nielsen, Birgitte

2006-01-01

[Structure: see text] Solid-phase synthesis is a rapidly developing area of organic chemistry, of particular importance for medicinal chemistry and chemical biology. Aziridines have previously only rarely been applied in solid-phase synthesis. In the present work, aminolysis of resin-bound, sprin......-loaded N-nitrobenzenesulfonyl-activated aziridine-2-carboxylic acids has been optimized and employed in the synthesis of a number of open-chain and heterocyclic scaffolds, including enantiopure products....

Photosensitive interaction of RSU 1069 with DNA

Energy Technology Data Exchange (ETDEWEB)

Edwards, D.I.; Knox, R.J.; Skolimowski, I.M.; Zahoor, A.; Knight, R.C.

1984-08-01

RSU 1069 is a 2-nitroimidazole radiosensitizer with an aziridine-containing side chain. In light (360 nm) the absorbance maximum of the nitro group at 325 nm disappears, which is accompanied by expulsion of the nitro group as the nitrite ion. This photosensitive effect was used to determine separately the damage of DNA induced by the reduced nitro group and the alkylating property of the aziridine. The aziridine-induced DNA damage is maximized in the dark when the nitro group is either absent (electrolytically reduced prior to the addition of DNA) or non functional (unreduced). In the light, damage is reduced. Typical DNA damage includes helix disruption leading to single strand breaks and the release of thymidine. Alkaline filter elution studies show evidence only for strand breakage and none for cross-linking indicating the drug is capable of mono-functional alkylation only.

Photosensitive interaction of RSU 1069 with DNA

International Nuclear Information System (INIS)

Edwards, D.I.; Knox, R.J.; Skolimowski, I.M.; Zahoor, A.; Knight, R.C.

1984-01-01

RSU 1069 is a 2-nitroimidazole radiosensitizer with an aziridine-containing side chain. In light (360 nm) the absorbance maximum of the nitro group at 325 nm disappears, which is accompanied by expulsion of the nitro group as the nitrite ion. This photosensitive effect was used to determine separately the damage of DNA induced by the reduced nitro group and the alkylating property of the aziridine. The aziridine-induced DNA damage is maximized in the dark when the nitro group is either absent (electrolytically reduced prior to the addition of DNA) or non functional (unreduced). In the light, damage is reduced. Typical DNA damage includes helix disruption leading to single strand breaks and the release of thymidine. Alkaline filter elution studies show evidence only for strand breakage and none for cross-linking indicating the drug is capable of mono-functional alkylation only

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

Directory of Open Access Journals (Sweden)

Karl Hemming

2014-10-01

Full Text Available The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs, pyrrolo[1,2,5]benzothiadiazepines (PBTDs, and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics.

An Approach to Preparation of trans-DHQs via Ring-Opening of meso-N-Sulfonylaziridines

DEFF Research Database (Denmark)

Nolsøe, Jens Mortansson Jelstrup; Riegert, David; Müller, Paul

2011-01-01

As an approach to the enantioselective synthesis of trans-decahydroquinolines (DHQs), desymmetrization of meso-aziridine (5) with various carbon nucleophiles under catalytic conditions was investigated. By applying TMSCN in the presence of YbCl3 and chiral nonracemic ligands, nitrile 13 was obtai......As an approach to the enantioselective synthesis of trans-decahydroquinolines (DHQs), desymmetrization of meso-aziridine (5) with various carbon nucleophiles under catalytic conditions was investigated. By applying TMSCN in the presence of YbCl3 and chiral nonracemic ligands, nitrile 13...

A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines.

Science.gov (United States)

Schmid, Steven C; Guzei, Ilia A; Schomaker, Jennifer M

2017-09-25

The reaction of rhodium-bound carbenes with strained bicyclic methylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio- and stereoselectivity. The reaction appears to proceed through an ylide-type mechanism, where the unique strain and structure of the methylene aziridine promotes a ring-opening/ring-closing cascade that efficiently transfers chirality from substrate to product. The resultant products can be elaborated into new azetidine scaffolds containing vicinal tertiary-quaternary and even quaternary-quaternary stereocenters. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reduction of 2-chloro-N-phenylpropanamide and 2-methyl-N-phenylaziridine with lithium aluminium hydride

DEFF Research Database (Denmark)

Vilhelmsen, Mie Højer; Østergaard, Lars Frøsig; Nielsen, Mogens Brøndsted

2008-01-01

in the reduction and can be isolated from reactions with less LiAlH4. Reduction of 2-methyl-N-phenylaziridine itself proceeds non-regioselectively to provide a mixture of propyl- and isopropylanilines. Formation of the amines by reduction of the aziridine is much slower than formation by reduction of the 2......-chloropropanamide, which indicates that Lewis acid catalysis (by aluminium chlorohydrides) facilitates the reduction of the aziridine. In addition, Lewis acid catalysis increases the relative yield of the propylamine product. The reduction of 2-chloro-N-phenylpropanamide furnishes 2-phenylamino-1-propanol as a by...

Studies on the toxicity of RSU-1069

International Nuclear Information System (INIS)

Whitmore, G.F.; Gulyas, S.

1986-01-01

RSU-1069 combines an aziridine function with a 2-nitroimidazole and has been reported to exhibit extraordinary radiosensitization both in vitro and in vivo. Such sensitization appears to be at variance with the electron affinity of the compound. In addition, recent experiments suggest that the compound is highly toxic to hypoxic tumor cells in vivo. On the assumption that the observed radiosensitizing ability may be a manifestation of toxicity and because of the high in vivo toxicity, we have investigated aerobic and hypoxic toxicity, both in wild type CHO cells and in mutants sensitive to a variety of DNA damaging agents. With wild type cells under aerobic conditions, the compound is approximately 50 times as toxic as misonidazole and under hypoxic conditions, approximately 250 times as toxic. The ratio of hypoxic to aerobic toxicity is approximately 80 times. Under aerobic conditions, repair-deficient mutants are 10 times as sensitive to RSU-1069 as wild type cells and approximately 100 times as sensitive under hypoxic conditions. The ratio of hypoxic to aerobic toxicity for the mutant cells is approximately 900. Based on these observations, we suggest that under aerobic conditions the aziridine function is primarily responsible for toxicity, whereas, under hypoxic conditions, the aziridine moiety combined with a reduced 2-nitroimidazole moiety produces a bifunctional agent

Syntheses and Post-Polymerization Modifications of Well-Defined Styrenic Polymers Containing Three-Membered Heterocyclic Functionalities

Science.gov (United States)

McLeod, David Charles

compositions, architectures, and thermal stabilities of the resulting ?-hydroxy ether-functionalized homopolymers were evaluated using NMR and FTIR spectroscopy, size exclusion chromatography, and thermal gravimetric analysis. Aziridines and thiiranes (saturated, three-membered heterocycles containing either a single nitrogen or sulfur atom, respectively) are also susceptible to nucleophilic ring-opening reactions, and functional materials derived from aziridine- or thiirane-containing polymers could potentially have many interesting properties as a result of their high amine or thiol content, such as the ability to form pH- or redox-responsive structures. The synthesis of polymers containing aziridines that are activated towards nucleophilic ring-opening by C-aryl and/or N-sulfonyl substituents is unprecedented in the literature. Efficient methods for synthesizing styrenic monomers that contain these highly-reactive functionalities, namely 2-(4-vinylphenyl)aziridine (VPA) and its sulfonyl-activated derivative, N-mesyl-2-(4-vinylphenyl)aziridine (NMVPA), were developed utilizing 4VPO as a starting material. VPA was polymerized under LCC ATRP and RAFT conditions, but these methods were ineffective at producing well-defined polymers due to side reactions between the aziridine groups and the polymerization mediating compounds. Nitroxide-mediated radical polymerization (NMRP) produced well-defined polyVPA at low to moderate conversions of monomer, but cross-linking side reactions were evident at higher monomer conversions. Nearly all undesirable side reactions were prevented by attaching a mesyl group to the aziridine nitrogen atom, and well-defined polyNMVPA was realized under RAFT and NMRP conditions. Under ATRP conditions, reactions between the aziridine groups and catalyst still occurred, so the polymerization of NMVPA was not controlled using this technique. The synthesis of thiirane-containing styrenic polymers from either 2-(4-vinylphenyl)thiirane (VPT) or 2

Oligonucleotides as probes for studying polymerization reactions in dilute aqueous solution

Science.gov (United States)

Kolb, V.; Orgel, L. E.; Miller, S. L. (Principal Investigator)

1994-01-01

We have prepared a [32P]-labled oligonucleotide probe carrying a free primary amine at its 3'-terminus. This probe is used to initiate polymerization of aziridine (ethyleneimine) in aqueous solution. The nature of the oligomeric products and the kinetics of their formation are then monitored by gel electrophoresis. Our results are generally consistent with those obtained using conventional techniques. We have also investigated the effect of polyanionic templates on the rate of oligomerization of aziridine. We find that water-soluble polyanions generally accelerate the polymerization. The sodium salt of polymethacrylic acid is the most effective of the templates that we studied. The methods introduced in this paper should be applicable to a variety of polymerization reactions in aqueous solution. They should greatly simplify the screening of potentially prebiotic polymerization reactions.

Chemistry of phosphorus ylides 31: Reaction of azidocoumarin with ...

Indian Academy of Sciences (India)

5, 11, and moreover, aziridine 6 was produced via nitrogen extrusion from the triazoline 3, followed by ring expansion to the ... triphenylphosphine (m.p. and mixed m.p. 78. ◦. C). ..... degradation31 of compound 4 afforded the triazepine.

Journal of Chemical Sciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

Uncatalyzed thermal gas phase aziridination of alkenes by organic azides. ..... fluorescence spectroscopic investigation of TMU/water binary mixtures ... and its application in solid phase extraction of heavy metals from environmental samples ...... Synthesis, crystal structure and characterization of new biologically active ...

Total Synthesis of balanol, Part 2

DEFF Research Database (Denmark)

Tanner, David Ackland; Kelly, Nicholas; Tedenborg, Lars

1997-01-01

A convergent enantioselective total synthesis of the natural product (-)-balanol (1) is described. In addition to benzophenone fragment 8, key intermediates are chiral bicyclic aziridine 3 and the corresponding epoxide 4, both of which undergo highly regio- and stereoselective nucleophilic ring...

A new class of analogues of the bifunctional radiosensitizer alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069): The cycloalkylaziridines

International Nuclear Information System (INIS)

Suto, M.J.; Stier, M.A.; Werbel, L.M.; Arundel-Suto, C.M.; Leopold, W.R.; Elliott, W.E.; Sebolt-Leopold, J.S.

1991-01-01

A series of compounds related to alpha-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol (RSU 1069, 1) were synthesized and evaluated as selective hypoxic cell cytotoxic agents and as radiosensitizers. The aziridine moiety was replaced with a number of other potential alkylating groups including cycloalkylaziridines and azetidines. The data indicated that modification of the aziridine of 1 resulted in a substantial decrease in the ability of the compounds to selectively kill hypoxic cells. However, these modifications did not affect the compounds' in vitro radiosensitizing activity since many of the derivatives were as potent as 1. All of the compounds that were evaluated in vivo were less toxic than 1, and several members of this series had significant activity. The best compound was trans-alpha-[[(4-bromotetrahydro-2H-pyran-3-yl) amino]methyl]-2-nitro-1H-imidazole-1-ethanol (18), which, due to its activity and log P value, is a candidate for additional in vivo studies

Fulltext PDF

Indian Academy of Sciences (India)

with Ac2O-Pyr on the C3 carbon side of aziridine.10. On the other ... hydrated acid-activated clays with N-acyl-2,2-dimethy- laziridines 1. ... 10% NaOH to neutral pH, and the aqueous mixture was ..... influence in the progress of these reactions.

Journal of Chemical Sciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

Home; Journals; Journal of Chemical Sciences. R H DUNCAN LYNGDOH. Articles written in Journal of Chemical Sciences. Volume 128 Issue 5 May 2016 pp 681-693 Regular Articles. Uncatalyzed thermal gas phase aziridination of alkenes by organic azides. Part I: Mechanisms with discrete nitrene species · S PREMILA ...

Synthesis and evaluation of alpha-[[(2-haloethyl)amino]methyl]-2- nitro-1H-imidazole-1-ethanols as prodrugs of alpha-[(1-aziridinyl)methyl]-2- nitro-1H-imidazole-1-ethanol (RSU-1069) and its analogues which are radiosensitizers and bioreductively activated cytotoxins

International Nuclear Information System (INIS)

Jenkins, T.C.; Naylor, M.A.; O'Neill, P.; Threadgill, M.D.; Cole, S.; Stratford, I.J.; Adams, G.E.; Fielden, E.M.; Suto, M.J.; Stier, M.A.

1990-01-01

alpha-[(1-Aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanols, of general formula ImCH2CH(OH)CH2NCR1R2CR3R4, where Im = 2-nitroimidazole and R1, R2, R3, R4 = H, Me, are radiosensitizers and selective bioreductively activated cytotoxins toward hypoxic tumor cells in vitro and in vivo. Treatment of the aziridines with hydrogen halide in acetone or aqueous acetone gave the corresponding 2-haloethylamines of general formula ImCH2CH(OH)CH2(+)-NH2CR1R2CR3R4X X-, where R1, R2, R3, R4 = H, Me, and X = F, Cl, Br, I. These 2-haloethylamines were evaluated as prodrugs of the parent aziridines. The rates of ring closure in aqueous solution at pH approximately 6 were found to increase with increasing methyl substitution and to depend on the nature of the leaving group (I approximately Br greater than Cl much greater than F). A competing reaction of ImCH2CH(OH)CH2+NH2CH2CH2X X- (X = Cl, Br) with aqueous HCO3- ions gives 3-[2-hyroxy-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone. The activities of these prodrugs as radiosensitizers or as bioreductively activated cytotoxins were consistent with the proportion converted to the parent aziridine during the course of the experiment. alpha-[[(2-Bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1- ethanol (RB 6145, 10), the prodrug of alpha-[(1-aziridinyl)methyl]-2-nitro-1H-imidazole-1-ethanol (RSU-1069, 3), is identified as the most useful compound in terms of biological activity and rate of ring closure under physiological conditions

Enantioselective Synthesis of Aminodiols by Sequential Rhodium-Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine-Based Catalysis.

Science.gov (United States)

Guasch, Joan; Giménez-Nueno, Irene; Funes-Ardoiz, Ignacio; Bernús, Miguel; Matheu, M Isabel; Maseras, Feliu; Castillón, Sergio; Díaz, Yolanda

2018-03-26

Regio- and stereoselective oxyamination of dienes through a tandem rhodium-catalysed aziridination-nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process with amidine-based catalysts (ABCs) to achieve s values of up to 117. This protocol was applied to the enantioselective synthesis of sphingosine. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

1,4-Diazaspiro[2.2]pentanes as a flexible platform for the synthesis of diamine-bearing stereotriads.

Science.gov (United States)

Rigoli, Jared W; Boralsky, Luke A; Hershberger, John C; Marston, Dagmara; Meis, Alan R; Guzei, Ilia A; Schomaker, Jennifer M

2012-03-02

Nitrogen-containing stereotriads occur in a number of biologically active compounds, but general and flexible methods to access these compounds are limited mainly to the manipulation of chiral olefins. An alternative approach is to employ a highly chemo-, regio-, and stereocontrolled allene oxidation that can install a new carbon-heteroatom bond at each of the three original allene carbons. In this paper, an intramolecular/intermolecular allene bis-aziridination is described that offers the potential to serve as a key step for the construction of stereotriads containing vicinal diaminated motifs. The resultant 1,4-diazaspiro[2.2]pentane (DASP) scaffolds contain two electronically differentiated aziridines that undergo highly regioselective ring openings at C1 with a variety of heteroatom nucleophiles to give chiral N,N-aminals. Alternatively, the same DASP intermediate can be induced to undergo a double ring-opening reaction at both C1 and C3 to yield vicinal diaminated products corresponding to formal ring opening at C3. The chirality of a propargyl alcohol is easily transferred to the DASP with good fidelity, providing a new paradigm for the construction of enantioenriched nitrogen-containing stereotriads.

Synthesis and mechanistic studies of phosphoraziridines as radiation sensitizers

International Nuclear Information System (INIS)

Perlman, M.E.

1982-01-01

Ethyl bis(2,2-dimethyl-1-aziridinyl)phosphinyl carbamate (AB-132) and ethyl bis(2,2-dimethyl-1-aziridinyl)phosphinate (AB-163) are potent antitumor agents which have also been demonstrated to be radiation sensitizers in experimental and clinical studies. Monophenyl aziridines and various isomers of diphenylaziridines were utilized. Optically active 2-phenyl aziridine was also employed in order to prepare diastereomerically homogeneous compounds. Para-substituted phenylaziridines were prepared as well and converted to the corresponding phosphoraziridines in order to probe electronic effects of such substituents on biological activity and chemical reactivity. The hydrolysis of 2,2-dimethylaziridine-type compounds including AB-132 and AB-163 was studied by NMR in order to gain further insight into the hydrolytic intermediates which may be responsible for the known cholinesterase inhibition and the suspected phosphorylation of radiation-damaged DNA. Comparative reactivities of the compounds prepared in this study with p-nitrobenzylpyridine were investigated so as to provide some indication of potential alkylating activity, in the hope of obtaining a correlation with biological activity. Electron spin resonance was utilized to study the effects of radiation on phosphoraziridine crystals

A stereodivergent strategy to both product enantiomers from the same enantiomer of a stereoinducing catalyst: agelastatin A.

Science.gov (United States)

Trost, Barry M; Dong, Guangbin

2009-07-13

In this article, we report a full account of our recent development of pyrroles and N-alkoxyamides as new classes of nucleophiles for palladium-catalyzed AAA reactions, along with application of these methodologies in the total synthesis of agelastatin A, a marine natural product with exceptional anticancer activity and other biological properties. Our method allows for access to either regioisomer of the pyrrolopiperazinones (6 and 19) with high efficiency and enantioselectivity. Note that isomer 19 was obtained via a cascade reaction through a double allylic alkylation pathway. From regioisomer 6, the total synthesis of (+)-agelastatin A was completed in a very short fashion (four steps from 6), during the course of which we developed a new copper catalyst for aziridination and an In(OTf)(3)/DMSO system to oxidatively open an N-tosyl aziridine. Starting with the other pyrrolopiperazinone 19, a five-step sequence has been developed to furnish a formal total synthesis of (-)-agelastatin A. A unique feature of our syntheses is the use of two rather different strategies for the total syntheses of both enantiomers of agelastatin A using the same enantiomer of a chiral palladium catalyst.

Heterocyclization reaction of 4-(2-Methylaziridin-1-yl)-3-ureidobenzotrifluorides under appel's conditions

International Nuclear Information System (INIS)

Cho, Hyun In; Lee, Kee Jung

2003-01-01

The reaction of 4-(2-Methylaziridin-1-yl)-3-ureidobenzotrifluorides 4 with triphenylphosphine, carbon tetrachloride, and triethylamine (Appel's condition) led to the corresponding carbodiimides 5, which underwent intramolecular cycloaddition reaction with aziridine under the reaction condition to give the benzimidazole-fused heterocycles, 2.3-dihydro-1H-imidazo(1,2-a)benzimidazoles 8 and 12,13-dihydro-5H-benzimidazo(2,3-b)(1,3)benzodizzepines 9

Iron(II)-catalyzed intramolecular aminohydroxylation of olefins with functionalized hydroxylamines.

Science.gov (United States)

Liu, Guan-Sai; Zhang, Yong-Qiang; Yuan, Yong-An; Xu, Hao

2013-03-06

A diastereoselective aminohydroxylation of olefins with a functionalized hydroxylamine is catalyzed by new iron(II) complexes. This efficient intramolecular process readily affords synthetically useful amino alcohols with excellent selectivity (dr up to > 20:1). Asymmetric catalysis with chiral iron(II) complexes and preliminary mechanistic studies reveal an iron nitrenoid is a possible intermediate that can undergo either aminohydroxylation or aziridination, and the selectivity can be controlled by careful selection of counteranion/ligand combinations.

Facile and Green Synthesis of Saturated Cyclic Amines

Directory of Open Access Journals (Sweden)

Arruje Hameed

2017-10-01

Full Text Available Single-nitrogen containing saturated cyclic amines are an important part of both natural and synthetic bioactive compounds. A number of methodologies have been developed for the synthesis of aziridines, azetidines, pyrrolidines, piperidines, azepanes and azocanes. This review highlights some facile and green synthetic routes for the synthesis of unsubstituted, multisubstituted and highly functionalized saturated cyclic amines including one-pot, microwave assisted, metal-free, solvent-free and in aqueous media.

Synthesis of Functionalized Arylaziridines as Potential Antimicrobial Agents

Directory of Open Access Journals (Sweden)

Arianna Giovine

2014-08-01

Full Text Available By using the Suzuki-Miyaura protocol, a simple straightforward synthesis of functionalized 2-arylaziridines has been developed. By means of this synthetic strategy from readily available ortho-, meta- and para-bromophenylaziridines and aryl- or heteroarylboronic acids, new aziridines could be obtained. The cross-coupling reactions occurred without ring opening of the three membered ring. Preliminary results on the antimicrobial activity of the heterosubstituted biaryl compounds have been also included.

Pulse radiolysis study of the reduction mechanism of an antitumor antibiotic, mitomycin C

International Nuclear Information System (INIS)

Machtalere, G.; Houee-Levin, C.; Gardes-Albert, M.; Ferradini, C.; Hickel, B.

1988-01-01

Mitomycin C is a quinonic antitumor metabolized in vivo by one-electron reduction. We have studied the mechanism of the one-electron reduction of this drug by pulse radiolysis using C00 .- free radicals as reductants. Semiquinonic and hydroquinonic intermediates are formed. The hydroquinonic form undergoes a methanol elimination leading to a transient which can disappear in one of two ways: by either internal redox reaction or hydrolysis of the aziridine. 17 refs [fr

Nitrogen Atom Transfer From High Valent Iron Nitrides

Energy Technology Data Exchange (ETDEWEB)

Johnson, Michael D. [New Mexico State Univ., Las Cruces, NM (United States); Smith, Jeremy M. [Indiana Univ., Bloomington, IN (United States)

2015-10-14

This report describes the synthesis and reactions of high valent iron nitrides. Organonitrogen compounds such as aziridines are useful species for organic synthesis, but there are few efficient methods for their synthesis. Using iron nitrides to catalytically access these species may allow for their synthesis in an energy-and atom-efficient manner. We have developed a new ligand framework to achieve these goals as well as providing a method for inducing previously unknown reactivity.

Highly dispersive ion exchangers in the analytical chemistry of uranium, particularly regarding separation methods

International Nuclear Information System (INIS)

Schoening, R.

1975-01-01

The reaction of water-insoluble polyvinyl pyrrolidon with uranium VI was investigated and a determination method for uranium was worked out in which the polyvinyl pyrrolidon was used as specific exchanger. Good separations of uranium from numerous transition metal ions were achieved here. The application of this exchanger for a fast and simple elution and determination method was of particular importance. A possible sorption mechanism was suggested based on the capacity curve of uranium with polyvinyl pyrrolidon and nitrogen and chloride content at maximum load. The sorption occurs by coordination of the carbonyl oxygen of single pyrrolidon rings with the protons of the complex acides and uranium. This assumption is supported by IR investigations. The sorbability of other inorganic acids was also investigated and possible structures were formulated for the sorption mechanism. In addition to this, ion exchangers were prepared based on cellulose by converting cellulose powder with aziridine and tris-1-aziridinyl-phosphine oxide. A polyethylene imine cellulose of high capacity was obtained in the conversion of cellulose powder with aziridine. This exchanger absorbs cobalt III very strongly. The exchanger loaded with cobalt III was used to separate the uranium as cyanato complex. The exchanger obtained in converting chlorated cellulose with tris-1-aziridinyl phosphine oxide also absorbs uranium VI very strongly. Thus a separation method of high specifity and selectivity was developed. (orig.) [de

Dual-function radiation sensitizers and bioreductive drugs: factors affecting cellular uptake and sensitizing efficiency in analogues of RSU 1069

International Nuclear Information System (INIS)

Walling, J.; Stratford, I.J.; Adams, G.E.; Stephens, M.A.

1988-01-01

Alkyl aziridine analogues of the hypoxic cell radiosensitizer RSU 1069 have been synthesized and one, RB 7040, containing tetramethyl substituted aziridine, is a more efficient sensitizer in vitro than RSU 1069 (Ahmed et al., 1986). The extent to which variation in drug uptake can influence the sensitizing efficiency of RSU 1069 and its analogues has been investigated by determining cellular uptake as a function of pH of extracellular medium (pHsub(e)) over the range 5.4-8.4. Following exposure of V79 cells for 1 h at room temperature, the ratio of intra-to extracellular concentration (Ci/Ce) was near unity at pH 5.4. Increasing pHsub(e) to 8.4 resulted in no change in the ratio Ci/Ce for RSU 1069 (pKsub(a) = 6.04). Values of Ci/Ce increased three-fold for RSU 1165 (pKsub(a) 7.38) and eleven-fold for RB 7040 (pKsub(a) = 8.45). Radiosensitization by RSU 1069 showed little dependence on pHsub(e) whereas increasing pH caused an apparent increase in sensitizing efficiency of both RSU 1165 and RB 7040. When enhancement ratios for sensitization were normalized to take account of the effect of extracellular pH on drug uptake, efficiency of sensitization was independent of pHsub(e). (author)

Effect of support structure on CO2 adsorption properties of pore-expanded hyperbranched aminosilicas

KAUST Repository

Drese, Jeffrey H.; Choi, Sunho; Didas, Stephanie A.; Bollini, Praveen; Gray, McMahan L.; Jones, Christopher W.

2012-01-01

Hyperbranched aminosilica (HAS) CO 2 adsorbents are prepared by the ring-opening polymerization of aziridine from SBA-15 mesoporous silica, as in the original synthesis of HAS materials, as well as over an array of new support materials with substantially larger average pore diameters to elucidate the effect of support porosity on final adsorbent properties. Pore-expanded hyperbranched aminosilica (PEHAS) CO 2 adsorbents are prepared from several different pore-expanded, ordered mesoporous silicas including pore-expanded SBA-15, mesocellular foam, and a large-pore commercial silica. The effect of the nature of the silica support is determined by examining the degree of aziridine polymerization and the CO 2 adsorption kinetics and capacities of the resulting organic/inorganic hybrid materials. Comparisons are made to non-pore-expanded SBA-15 based HAS adsorbents, reported previously, where pores become blocked at higher amine loadings. The PEHAS materials unexpectedly possess lower amine loadings than the previously reported HAS materials and do not exhibit pore blocking. The use of acetic acid as a catalyst during PEHAS synthesis only marginally increases amine loading. The adsorption kinetics of PEHAS adsorbents are similar to HAS adsorbents with low amine loadings and do not show the detrimental effects of pore-blocking. However, the inability to synthesize PEHAS adsorbents with high amine loadings via this approach limits the total amount of CO 2 captured per gram of material, compared to HAS adsorbents with high amine loadings. © 2011 Elsevier Inc. All rights reserved.

Effect of support structure on CO2 adsorption properties of pore-expanded hyperbranched aminosilicas

KAUST Repository

Drese, Jeffrey H.

2012-03-01

Hyperbranched aminosilica (HAS) CO 2 adsorbents are prepared by the ring-opening polymerization of aziridine from SBA-15 mesoporous silica, as in the original synthesis of HAS materials, as well as over an array of new support materials with substantially larger average pore diameters to elucidate the effect of support porosity on final adsorbent properties. Pore-expanded hyperbranched aminosilica (PEHAS) CO 2 adsorbents are prepared from several different pore-expanded, ordered mesoporous silicas including pore-expanded SBA-15, mesocellular foam, and a large-pore commercial silica. The effect of the nature of the silica support is determined by examining the degree of aziridine polymerization and the CO 2 adsorption kinetics and capacities of the resulting organic/inorganic hybrid materials. Comparisons are made to non-pore-expanded SBA-15 based HAS adsorbents, reported previously, where pores become blocked at higher amine loadings. The PEHAS materials unexpectedly possess lower amine loadings than the previously reported HAS materials and do not exhibit pore blocking. The use of acetic acid as a catalyst during PEHAS synthesis only marginally increases amine loading. The adsorption kinetics of PEHAS adsorbents are similar to HAS adsorbents with low amine loadings and do not show the detrimental effects of pore-blocking. However, the inability to synthesize PEHAS adsorbents with high amine loadings via this approach limits the total amount of CO 2 captured per gram of material, compared to HAS adsorbents with high amine loadings. © 2011 Elsevier Inc. All rights reserved.

Self-optimisation and model-based design of experiments for developing a C–H activation flow process

Directory of Open Access Journals (Sweden)

Alexander Echtermeyer

2017-01-01

Full Text Available A recently described C(sp3–H activation reaction to synthesise aziridines was used as a model reaction to demonstrate the methodology of developing a process model using model-based design of experiments (MBDoE and self-optimisation approaches in flow. The two approaches are compared in terms of experimental efficiency. The self-optimisation approach required the least number of experiments to reach the specified objectives of cost and product yield, whereas the MBDoE approach enabled a rapid generation of a process model.

Synthesis of 1,3-diaminated stereotriads via rearrangement of 1,4-diazaspiro[2.2]pentanes.

Science.gov (United States)

Weatherly, Cale D; Rigoli, Jared W; Schomaker, Jennifer M

2012-04-06

The synthesis of 1,3-diaminated stereotriads via the bis-aziridination of allenes is reported. The reactive 1,4-diazaspiro[2.2]pentane intermediates undergo a mild Brønsted acid-promoted rearrangement to yield 1,3-diaminated ketones in good yields with excellent stereocontrol. Directed reduction of the ketone can be achieved to yield a C-N/C-O/C-N stereotriad in high dr. The ability to transfer the axial chirality of the substrates to the products allows for the facile preparation of enantioenriched stereotriads from allenes in two simple steps.

Modular functionalization of allenes to aminated stereotriads.

Science.gov (United States)

Adams, Christopher S; Boralsky, Luke A; Guzei, Ilia A; Schomaker, Jennifer M

2012-07-04

Nitrogen-containing stereotriads, compounds with three adjacent stereodefined carbons, are commonly found in biologically important molecules. However, the preparation of molecules bearing these motifs can be challenging. Herein, we describe a modular oxidation protocol which converts a substituted allene to a triply functionalized amine of the form C-X/C-N/C-Y. The key step employs a Rh-catalyzed intramolecular conversion of the allene to a strained bicyclic methylene aziridine. This reactive intermediate is further elaborated to the target products, often in one reaction vessel and with effective transfer of the axial chirality of the allene to point chirality in the stereotriad.

Tunable, chemoselective amination via silver catalysis.

Science.gov (United States)

Rigoli, Jared W; Weatherly, Cale D; Alderson, Juliet M; Vo, Brian T; Schomaker, Jennifer M

2013-11-20

Organic N-containing compounds, including amines, are essential components of many biologically and pharmaceutically important molecules. One strategy for introducing nitrogen into substrates with multiple reactive bonds is to insert a monovalent N fragment (nitrene or nitrenoid) into a C-H bond or add it directly to a C═C bond. However, it has been challenging to develop well-defined catalysts capable of promoting predictable and chemoselective aminations solely through reagent control. Herein, we report remarkable chemoselective aminations that employ a single metal (Ag) and a single ligand (phenanthroline) to promote either aziridination or C-H insertion by manipulating the coordination geometry of the active catalysts.

Chemoselective construction of novel steroid derivatives.

Science.gov (United States)

Troisi, Luigino; Florio, Saverio; Granito, Catia

2002-07-01

Alpha-halo-alpha-heteroarylalkyllithiums, generated by deprotonation of the corresponding halides, when added promptly to steroids with C=O or C=NR groups, lead to epoxides and aziridines. The reactions are regio- and stereoselective; in fact, in the presence of more than one C=O group, the oxido or aziridino functions are formed uniquely at the C=O of C-17 (or C-20 depending on its position in the starting molecule), and the C-20(R) stereoisomer is often the only product isolated. Protection of the hydroxyl group present on several considered steroids was required, and it was accomplished through derivatization in acetyl, ether, or lactone.

Sulfonyl azide-mediated norbornene aziridination for orthogonal peptide and protein labeling

Czech Academy of Sciences Publication Activity Database

Gattner, M. J.; Ehrlich, M.; Vrábel, Milan

2014-01-01

Roč. 50, č. 83 (2014), s. 12568-12571 ISSN 1359-7345 Institutional support: RVO:61388963 Keywords : Diels- Adler reactions * transfer RNA synthetase * free click chemistry Subject RIV: CC - Organic Chemistry Impact factor: 6.834, year: 2014

Oxidative allene amination for the synthesis of azetidin-3-ones.

Science.gov (United States)

Burke, Eileen G; Schomaker, Jennifer M

2015-10-05

Regioselectivity in the aziridination of silyl-substituted homoallenic sulfamates is readily diverted to the distal double bond of the allene to yield endocyclic bicyclic methyleneaziridines with excellent stereocontrol. Subsequent reaction with electrophilic oxygen sources initiates facile rearrangement to densely functionalized, fused azetidin-3-ones in excellent d.r., effectively transferring the axial chirality of the allene to central chirality in the products. The steric nature of the silyl group dictates which of the two rings of the fused azetidin-3-one will undergo further functionalization, providing an additional element of diversity for the preparation of enantioenriched azetidine scaffolds with potential biological activity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Regioselective Nucleophilic Ring Opening of Epoxides and Aziridines derived from Homoallylic Alcohols

DEFF Research Database (Denmark)

Tanner, David Ackland; Groth, Thomas

1997-01-01

The regioselectivity of nucleophilic ring opening of some 3,4-epoxy and 3,4-aziridino alcohols has been studied. The nucleophiles chosen were complex hydrides (LiAlH4, Red-Al and DIBAL) and Lipshutz- or Gilman-type organocuprate reagents. The C-4 substituent in the substrates was varied in order...... to study steric and electronic effects on the ring opening reactions. For alkyl substituents at C-4, most of the results can be explained on the basis of intramolecular delivery of the nucleophile to C-3 via a six-membered transition state, leading to 1,4-diols or 1,4-amino alcohol derivatives. In general......, the epoxy alcohols gave poorer regioselectivity than the N-tosyl aziridino alcohols, for which selectivities of >95:5 were routinely obtained. The activating effect of a phenyl group at C-4 led to a switch in regiochemistry, with the 1,3-diol or 1,3-amino alcohol derivative as the major product. (C) 1997...

(Z-N-[1-(Aziridin-1-yl-2,2,2-trifluoroethylidene]-4-bromoaniline

Directory of Open Access Journals (Sweden)

Alexander S. Bunev

2014-05-01

Full Text Available The title compound, C10H8BrF3N2, crystallizes with two independent molecules in the asymmetric unit, which can be considered as being related by a pseudo-inversion center, so their conformations are different; the corresponding N=C—N—C torsion angles are 54.6 (5 and −50.5 (5°. In the crystal, molecules related by translation in [001] interact through short intermolecular Br...F contacts [3.276 (2 and 3.284 (2 Å], thus forming two types of crystallographically independent chains.

Catalyst-Controlled and Tunable, Chemoselective Silver-Catalyzed Intermolecular Nitrene Transfer: Experimental and Computational Studies.

Science.gov (United States)

Dolan, Nicholas S; Scamp, Ryan J; Yang, Tzuhsiung; Berry, John F; Schomaker, Jennifer M

2016-11-09

The development of new catalysts for selective nitrene transfer is a continuing area of interest. In particular, the ability to control the chemoselectivity of intermolecular reactions in the presence of multiple reactive sites has been a long-standing challenge in the field. In this paper, we demonstrate examples of silver-catalyzed, nondirected, intermolecular nitrene transfer reactions that are both chemoselective and flexible for aziridination or C-H insertion, depending on the choice of ligand. Experimental probes present a puzzling picture of the mechanistic details of the pathways mediated by [( t Bu 3 tpy)AgOTf] 2 and (tpa)AgOTf. Computational studies elucidate these subtleties and provide guidance for the future development of new catalysts exhibiting improved tunability in group transfer reactions.

Selectively N-protected enantiopure 2,5-disubstituted piperazines

DEFF Research Database (Denmark)

Ottesen, Lars Korsgaard; Olsen, Christian Adam; Witt, Matthias

2009-01-01

An efficient solid-phase route to ring-substituted piperazines from O-linked resin-bound (S)-aziridine-2-methanol is described. Regioselective microwave-assisted aminolysis followed by intramolecular Fukuyama-Mitsunobu cyclization constitute the key features of the protocol. Simple piperazines...... and diazepanes were readily obtained without preceding N-protection of the acyclic intermediate, whereas attempts to extend this protocol to chiral 2,5-disubstituted piperazines failed. Modifications encompassing N-carbamoylation prior to ring-closure were therefore investigated. However, standard carbamoylating...... on the bulk of the side chain and type of N-protecting group. This protocol readily provided novel cis- and trans-2,5-disubstituted piperazines displaying a variety of N-protecting group patterns after further on-resin manipulations. Also, unexpected by-products obtained during these optimization studies were...

Solid-phase route to Fmoc-protected cationic amino acid building blocks

DEFF Research Database (Denmark)

Clausen, Jacob Dahlqvist; Linderoth, Lars; Nielsen, Hanne Mørck

2012-01-01

Diamino acids are commonly found in bioactive compounds, yet only few are commercially available as building blocks for solid-phase peptide synthesis. In the present work a convenient, inexpensive route to multiple-charged amino acid building blocks with varying degree of hydrophobicity...... was developed. A versatile solid-phase protocol leading to selectively protected amino alcohol intermediates was followed by oxidation to yield the desired di- or polycationic amino acid building blocks in gram-scale amounts. The synthetic sequence comprises loading of (S)-1-(p-nosyl)aziridine-2-methanol onto...... of simple neutral amino acids as well as analogs displaying high bulkiness or polycationic side chains was prepared. Two building blocks were incorporated into peptide sequences using microwave-assisted solid-phase peptide synthesis confirming their general utility....

Sequence selectivity of azinomycin B in DNA alkylation and cross-linking: a QM/MM study.

Science.gov (United States)

Senthilnathan, Dhurairajan; Kalaiselvan, Anbarasan; Venuvanalingam, Ponnambalam

2013-01-01

Azinomycin B--a well-known antitumor drug--forms cross-links with DNA through alkylation of purine bases and blocks tumor cell growth. This reaction has been modeled using the ONIOM (B3LYP/6-31+g(d):UFF) method to understand the mechanism and sequence selectivity. ONIOM results have been checked for reliability by comparing them with full quantum mechanics calculations for selected paths. Calculations reveal that, among the purine bases, guanine is more reactive and is alkylated by aziridine ring through the C10 position, followed by alkylation of the epoxide ring through the C21 position of Azinomycin B. While the mono alkylation is controlled kinetically, bis-alkylation is controlled thermodynamically. Solvent effects were included using polarized-continuum-model calculations and no significant change from gas phase results was observed.

A New Approach to Non-Coordinating Anions: Lewis Acid Enhancement of Porphyrin Metal Centers in a Zwitterionic Metal$-$Organic Framework

Energy Technology Data Exchange (ETDEWEB)

Johnson, Jacob A. [Univ. of Nebraska, Lincoln, NE (United States). Dept. of Chemistry; Petersen, Brenna M. [Univ. of Nebraska, Lincoln, NE (United States). Dept. of Chemistry; Kormos, Attila [Hungarian Academy of Sciences, Budapest (Hungary); Echeverría, Elena [Univ. of Nebraska, Lincoln, NE (United States). Dept. of Physics and Astronomy; Chen, Yu-Sheng [Univ. of Chicago, Argonne, IL (United States). ChemMatCARS, Center for Advanced Radiation Sources; Zhang, Jian [Univ. of Nebraska, Lincoln, NE (United States). Dept. of Chemistry

2017-02-28

Here, we describe a new strategy to generate non-coordinating anions using zwitterionic metal–organic frameworks (MOFs). By assembly of anionic inorganic secondary building blocks (SBUs) ([In(CO₂)₄]^$-$) with cationic metalloporphyrin-based organic linkers, we prepared zwitterionic MOFs in which the complete internal charge separation effectively prevents the potential binding of the counteranion to the cationic metal center. We demonstrate the enhanced Lewis acidity of Mn^III- and Fe^III-porphyrins in the zwitterionic MOFs in three representative electrocyclization reactions: [2 + 1] cycloisomerization of enynes, [3 + 2] cycloaddition of aziridines and alkenes, and [4 + 2] hetero-Diels–Alder cycloaddition of aldehydes with dienes. Lastly, this work paves a new way to design functional MOFs for tunable chemical catalysis.

Fulleropyrrolidine end-capped molecular wires for molecular electronics--synthesis, spectroscopic, electrochemical, and theoretical characterization

DEFF Research Database (Denmark)

Sørensen, Jakob Kryger; Fock, Jeppe; Pedersen, Anders Holmen

2011-01-01

In continuation of previous studies showing promising metal-molecule contact properties a variety of C(60) end-capped "molecular wires" for molecular electronics were prepared by variants of the Prato 1,3-dipolar cycloaddition reaction. Either benzene or fluorene was chosen as the central wire...... state. However, the fluorescence of C(60) was quenched by charge transfer from the wire to C(60). Quantum chemical calculations predict and explain the collapse of coherent electronic transmission through one of the fulleropyrrolidine-terminated molecular wires......., and synthetic protocols for derivatives terminated with one or two fullero[c]pyrrolidine "electrode anchoring" groups were developed. An aryl-substituted aziridine could in some cases be employed directly as the azomethine ylide precursor for the Prato reaction without the need of having an electron...

Diastereoselective Synthesis of the Aminocyclitol Core of Jogyamycin via an Allene Aziridination Strategy.

Science.gov (United States)

Gerstner, Nels C; Adams, Christopher S; Grigg, R David; Tretbar, Maik; Rigoli, Jared W; Schomaker, Jennifer M

2016-01-15

Oxidative allene amination provides rapid access to densely functionalized amine-containing stereotriads through highly reactive bicyclic methyleneaziridine intermediates. This strategy has been demonstrated as a viable approach for the construction of the densely functionalized aminocyclitol core of jogyamycin, a natural product with potent antiprotozoal activity. Importantly, the flexibility of oxidative allene amination will enable the syntheses of modified aminocyclitol analogues of the jogyamycin core.

Mono- and Di-Alkylation Processes of DNA Bases by Nitrogen Mustard Mechlorethamine.

Science.gov (United States)

Larrañaga, Olatz; de Cózar, Abel; Cossío, Fernando P

2017-12-06

The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono- (G-mec and A-mec) and dialkylated (AA-mec, GG-mec and AG-mec) adducts has been studied using density functional theory (DFT). To gain a complete overview of DNA-alkylation processes, direct chloride substitution and formation through activated aziridinium species were considered as possible reaction paths for adduct formation. Our results confirm that DNA alkylation by mec occurs via aziridine intermediates instead of direct substitution. Consideration of explicit water molecules in conjunction with polarizable continuum model (PCM) was shown as an adequate computational method for a proper representation of the system. Moreover, Runge-Kutta numerical kinetic simulations including the possible bisadducts have been performed. These simulations predicted a product ratio of 83:17 of GG-mec and AG-mec diadducts, respectively. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of potential Schistosomicides: new 2-(alkylamino)-1-octometiosulfuric acids

International Nuclear Information System (INIS)

Oliveira Penido, M.L. de; Nelson, D.L.; Pilo-Veloso, D.

1990-01-01

Four new 2-(alkylamino)-1-octanethiosulfuric acids (1) were synthesized from 1-octene. 1-Octene was epoxidized with MCPBA or with a two-phase system composed of H 2 O 2 , sodium tungstate, phosphoric acid, 1-octene and a phase transfer agent. Reaction of the 1,2-epoxyoetane with primary amines furnished 1-(alkylamino)-2octanols which were converted to the respective N-alkyl-2-bromo-1-octanamine hydrobromides by reaction with hydrobromic acid, followed by phosphorus tribromide. Finally, substitution of the bromide ion with sodium thiosulfate was accompanied by rearrangement via an aziridine intermediate, resulting in formation of the product. 1. The intermediates and the final products were screened for activity against infection by Schistosoma mansoni, only the final products in which the N-alkyl group was sec-butyl or isopropyl exhibited activity. Nuclear magnetic resonance and infrared and mass spectroscopy analysis are presented. (author) [pt

4-[4-(4-Fluorophenyl-2-methyl-5-oxo-2,5-dihydroisoxazol-3-yl]-1-methylpyridinium iodide–4-[3-(4-fluorophenyl-2-methyl-5-oxo-2,5-dihydroisoxazol-4-yl]-1-methylpyridinium iodide (0.6/0.4

Directory of Open Access Journals (Sweden)

Simona Margutti

2008-01-01

Full Text Available The crystal structure of the title compound, C16H16FN2O2+·I−, was determined as part of a study of the biological activity of isoxazolone derivatives as p38 mitogen-activated protein kinase (MAPK inhibitors. The X-ray crystal structure of 4-[4-(4-fluorophenyl-2-methyl-5-oxo-2,5-dihydroisoxazol-3-yl]-1-methylpyridinium iodide showed the presence of the regioisomer 4-[3-(4-fluorophenyl-2-methyl-5-oxo-2,5-dihydroisoxazol-4-yl]-1-methylpyridinium iodide. The synthesis of the former compound was achieved by reacting 4-(4-fluorophenyl-3-(4-pyridylisoxazol-5(2H-one after treatment with Et3N in dimethylformamide, with iodomethane. The unexpected formation of the regioisomer could be explained by a rearrangement occurring via aziridine of the isoxazolone compound. The regioisomers have site occupancies of 0.632 (4/0.368 (4. The two six members rings make a dihedral angle of 66.8 (2°.

Mn-Catalyzed Highly Efficient Aerobic Oxidative Hydroxyazidation of Olefins: A Direct Approach to β-Azido Alcohols.

Science.gov (United States)

Sun, Xiang; Li, Xinyao; Song, Song; Zhu, Yuchao; Liang, Yu-Feng; Jiao, Ning

2015-05-13

An efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for synthesis of β-azido alcohols has been developed. The aerobic oxidative generation of azido radical employing air as the terminal oxidant is disclosed as the key process for this transformation. The reaction is appreciated by its broad substrate scope, inexpensive Mn-catalyst, high efficiency, easy operation under air, and mild conditions at room temperature. This chemistry provides a novel approach to high value-added β-azido alcohols, which are useful precursors of aziridines, β-amino alcohols, and other important N- and O-containing heterocyclic compounds. This chemistry also provides an unexpected approach to azido substituted cyclic peroxy alcohol esters. A DFT calculation indicates that Mn catalyst plays key dual roles as an efficient catalyst for the generation of azido radical and a stabilizer for peroxyl radical intermediate. Further calculation reasonably explains the proposed mechanism for the control of C-C bond cleavage or for the formation of β-azido alcohols.

Biotransformation and bioactivation reactions of alicyclic amines in drug molecules.

Science.gov (United States)

Bolleddula, Jayaprakasam; DeMent, Kevin; Driscoll, James P; Worboys, Philip; Brassil, Patrick J; Bourdet, David L

2014-08-01

Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines. The most common biotransformations include N-oxidation, N-conjugation, oxidative N-dealkylation, ring oxidation, and ring opening. In some instances, the metabolic pathways generate electrophilic reactive intermediates and cause bioactivation. However, potential bioactivation related adverse events can be attenuated by structural modifications. Hence it is important to understand the biotransformation pathways to design stable drug candidates that are devoid of metabolic liabilities early in the discovery stage. The current review provides a comprehensive summary of biotransformation and bioactivation pathways of aliphatic nitrogen containing heterocycles and strategies to mitigate metabolic liabilities.

A structural insight into the P1S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

Energy Technology Data Exchange (ETDEWEB)

Węglarz-Tomczak, Ewelina; Berlicki, Łukasz; Pawełczak, Małgorzata; Nocek, Bogusław; Joachimiak, Andrzej; Mucha, Artur

2016-07-01

N0 -substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki ¼ 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2- diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.

Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: three-membered ring opening vs 1,5-cyclization

Directory of Open Access Journals (Sweden)

Nikolai V. Rostovskii

2015-03-01

Full Text Available Strained azirinium ylides derived from 2H-azirines and α-diazoketones under Rh(II-catalysis can undergo either irreversible ring opening across the N–C2 bond to 2-azabuta-1,3-dienes that further cyclize to 2H-1,4-oxazines or reversibly undergo a 1,5-cyclization to dihydroazireno[2,1-b]oxazoles. Dihydroazireno[2,1-b]oxazoles derived from 3-aryl-2H-azirines and 3-diazoacetylacetone or ethyl diazoacetoacetate are able to cycloadd to acetyl(methylketene generated from 3-diazoacetylacetone under Rh(II catalysis to give 4,6-dioxa-1-azabicyclo[3.2.1]oct-2-ene and/or 5,7-dioxa-1-azabicyclo[4.3.1]deca-3,8-diene-2-one derivatives. According to DFT calculations (B3LYP/6-31+G(d,p, the cycloaddition can involve two modes of nucleophilic attack of the dihydroazireno[2,1-b]oxazole intermediate on acetyl(methylketene followed by aziridine ring opening into atropoisomeric oxazolium betaines and cyclization. Azirinium ylides generated from 2,3-di- and 2,2,3-triaryl-substituted azirines give rise to only 2-azabuta-1,3-dienes and/or 2H-1,4-oxazines.

Peptidomic Identification of Cysteine-Rich Peptides from Plants.

Science.gov (United States)

Hemu, Xinya; Serra, Aida; Darwis, Dina A; Cornvik, Tobias; Sze, Siu Kwan; Tam, James P

2018-01-01

Plant cysteine-rich peptides (CRPs) constitute a majority of plant-derived peptides with high molecular diversity. This protocol describes a rapid and efficient peptidomic approach to identify a whole spectrum of CRPs in a plant extract and decipher their molecular diversity and bioprocessing mechanism. Cyclotides from C. ternatea are used as the model CRPs to demonstrate our methodology. Cyclotides exist naturally in both cyclic and linear forms, although the linear forms (acyclotide) are generally present at much lower concentrations. Both cyclotides and acyclotides require linearization of their backbone prior to fragmentation and sequencing. A novel and practical three-step chemoenzymatic treatment was developed to linearize and distinguish both forms: (1) N-terminal acetylation that pre-labels the acyclotides; (2) conversion of Cys into pseudo-Lys through aziridine-mediated S-alkylation to reduce disulfide bonds and to increase the net charge of peptides; and (3) opening of cyclic backbones by the novel asparaginyl endopeptidase butelase 2 that cleaves at the native bioprocessing site. The treated peptides are subsequently analyzed by liquid chromatography coupled to mass spectrometry using electron transfer dissociation fragmentation and sequences are identified by matching the MS/MS spectra directly with the transcriptomic database.

Bonding and structure of copper nitrenes.

Science.gov (United States)

Cundari, Thomas R; Dinescu, Adriana; Kazi, Abul B

2008-11-03

Copper nitrenes are of interest as intermediates in the catalytic aziridination of olefins and the amination of C-H bonds. However, despite advances in the isolation and study of late-transition-metal multiply bonded complexes, a bona fide structurally characterized example of a terminal copper nitrene has, to our knowledge, not been reported. In anticipation of such a report, terminal copper nitrenes are studied from a computational perspective. The nitrene complexes studied here are of the form (beta-diketiminate)Cu(NPh). Density functional theory (DFT), complete active space self-consistent-field (CASSCF) electronic structure techniques, and hybrid quantum mechanical/molecular mechanical (QM/MM) methods are employed to study such species. While DFT methods indicate that a triplet (S = 1) is the ground state, CASSCF calculations indicate that a singlet (S = 0) is the ground state, with only a small energy gap between the singlet and triplet. Moreover, the ground-state (open-shell) singlet copper nitrene is found to be highly multiconfigurational (i.e., biradical) and to possess a bent geometry about the nitrene nitrogen, contrasting with the linear nitrene geometry of the triplet copper nitrenes. CASSCF calculations also reveal the existence of a closed-shell singlet state with some degree of multiple bonding character for the copper-nitrene bond.

Chromosome aberration assays in barley (Hordeum vulgare)

Energy Technology Data Exchange (ETDEWEB)

Constantin, M J [Univ. of Tennessee, Knoxville; Nilan, R A

1982-01-01

Barley is an exceellent organism for studies of induced chromosome aberrations because of its few (2n = 2x = 14) relatively large chromosomes. Root-tip and shoot-tip cells have been used extensively for the study of ionizing radiation-induced chromosome aberrations. The general procedures are well known, the technology is simple and easy to learn, and the assays are relatively quick and inexpensive. Both root tips and shoot tips can be used for the study of chemical mutagens as well as ionizing radiations. Pollen mother cells are well suited for studying the effects of mutagens on meiotic chromosomes. The literature review for the Gene-Tox Program reported on 61 chemicals tested for their effects on barley chromosomes. Of these, 90% were reported to be either positive or positive dose-related, while 7% were negative and 3% were questionable. Barley assays based on chromosomal aberrations are useful to detect the clastogenic potency of chemicals under laboratory conditions. Indications are that the data from barley can be used to corroborate data obtained from other organisms. Among the classes of chemicals assayed were: alcohols and phenols; alkaloids; epoxides; alkyl sulfates; amides and sulfonamides; aromatic amines; aryl halides; aziridines; alkenes; carbamates; hydroazides; nitroaromatics; nitrosamides; nitrosources; phenothiazines; and polycyclic aromatic hydrocarbons.

Computer-Assisted Design and Synthetic Applications of Chiral Enol Borinates: Novel, Highly Enantioselective Aldol Reagents

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Gennari Cesare

1998-01-01

Full Text Available We have recently described the development of a quantitative transition state model for the prediction of stereoselectivity in the boron-mediated aldol reaction. This model provides qualitative insights into the factors contributing to the stereochemical outcome of a variety of reactions of synthetic importance. The force field model was used to assist the design and preparation of new chiral boron ligands derived from menthone. The chiral boron enolates were employed in various stereoselective processes, including the addition to chiral aldehydes and the reagent-controlled total synthesis of (3S,4S-statine. The chiral enolates derived from alpha-halo and alpha-oxysubstituted thioacetates were added to aldehydes and imines. Addition to imines leads to the enantioselective synthesis of chiral aziridines, a formal total synthesis of (+-thiamphenicol, and a new highly efficient synthesis of the paclitaxel (taxol® C-13 side-chain and taxol semisynthesis from baccatin III. The stereochemical outcome of the addition to imines was rationalised with the aid of computational studies. Enantioselective addition reactions of the chiral boron enolate derived from thioacetate have successfully been applied to solid phase bound aldehydes to give aldol products in comparable yields and enantioselectivities to the usual solution conditions.

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro

Science.gov (United States)

Teng, Geling; Ju, Yuanrong; Yang, Yepeng; Hua, Hu; Chi, Jingyu; Mu, Xiuan

2016-01-01

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ-rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ-rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ-rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ-ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma. PMID:27840931

Combined antitumor activity of the nitroreductase/CB1954 suicide gene system and γ-rays in HeLa cells in vitro.

Science.gov (United States)

Teng, Geling; Ju, Yuanrong; Yang, Yepeng; Hua, Hu; Chi, Jingyu; Mu, Xiuan

2016-12-01

Escherichia coli nitroreductase (NTR) may convert the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent, which may lead to DNA crosslinks and the apoptosis of cancer cells. NTR/CB1954 has been demonstrated to be an effective gene therapy in cancer cells. The present study examined whether the NTR/CB1954 suicide gene system had cytotoxic effects on HeLa cells and may improve the radiosensitivity of HeLa cells to γ‑rays. It was observed that the NTR/CB1954 suicide gene system exerted marked cytotoxic effects on HeLa cells. The combined therapeutic effects of NTR/CB1954 and γ‑rays on HeLa cells demonstrated a synergistic effect. CB1954 at concentrations of 12.5 and 25 µmol/l increased the sensitization enhancement ratio of HeLa cells to 1.54 and 1.66, respectively. Therefore, when compared with monotherapy, the combined therapy of NTR/CB1954 and γ‑rays may increase the apoptotic rate and enhance the radiosensitivity of HeLa cells. The combined therapy of γ‑ray radiation and the NTR/CB1954 suicide gene system may be a novel and potent therapeutic method for the treatment of cervical carcinoma.

Cycloaddition of CO 2 to challenging N -tosyl aziridines using a halogen-free niobium complex: Catalytic activity and mechanistic insights

KAUST Repository

Arayachukiat, Sunatda

2017-11-06

An efficient and facile approach to the regioselective synthesis of N-tosyloxazolidinones from the corresponding N-tosylaziridines and CO2 was developed using dual catalytic systems involving an early transition metal coordination compound as a Lewis acid and a nucleophilic cocatalyst. Among the screened Lewis acids, halogen-free niobium pentaethoxide (Nb(OEt)5) displayed the best catalytic activity when used in the presence of tetrabutylammonium iodide (TBAI). Systematic DFT calculations, supported by catalytic experiments, demonstrate that CO2 insertion is the rate determining step for this process and it is highly dependent on the steric hindrance at the niobium center.

Cycloaddition of CO 2 to challenging N -tosyl aziridines using a halogen-free niobium complex: Catalytic activity and mechanistic insights

KAUST Repository

Arayachukiat, Sunatda; Yingcharoen, Prapussorn; Vummaleti, Sai V. C.; Cavallo, Luigi; Poater, Albert; D’ Elia, Valerio

2017-01-01

An efficient and facile approach to the regioselective synthesis of N-tosyloxazolidinones from the corresponding N-tosylaziridines and CO2 was developed using dual catalytic systems involving an early transition metal coordination compound as a Lewis acid and a nucleophilic cocatalyst. Among the screened Lewis acids, halogen-free niobium pentaethoxide (Nb(OEt)5) displayed the best catalytic activity when used in the presence of tetrabutylammonium iodide (TBAI). Systematic DFT calculations, supported by catalytic experiments, demonstrate that CO2 insertion is the rate determining step for this process and it is highly dependent on the steric hindrance at the niobium center.

(Z)-N-[1-(Aziridin-1-yl)-2,2,2-tri­fluoro­ethyl­idene]-4-bromo­aniline

OpenAIRE

Bunev, Alexander S.; Vasiliev, Maksim A.; Ostapenko, Gennady I.; Peregudov, Alexander S.; Khrustalev, Victor N.

2014-01-01

The title compound, C10H8BrF3N2, crystallizes with two independent mol­ecules in the asymmetric unit, which can be considered as being related by a pseudo-inversion center, so their conformations are different; the corresponding N=C—N—C torsion angles are 54.6 (5) and −50.5 (5)°. In the crystal, mol­ecules related by translation in [001] inter­act through short inter­molecular Br⋯F contacts [3.276 (2) and 3.284 (2) Å], thus forming two types of crystallographically independent chains....

Effect of constitutive androstane receptor on radiosensitization of mictomycin C and its homologoue-629

International Nuclear Information System (INIS)

Zhang Jianghong; Jin Yizun

2008-01-01

The object of this work is to evaluate radiosensitization of MMC and its analogue 5-(aziridin-l-yl)-3- hydroxymethyl-1-methylindole-4,7-dione(629) and how transfection of constitutive androstane receptor (CAR) affect their biological effects. The expressions of CAR mRNA and CYP2B6 mRNA in HepG2 cells and g2car cells were detected by RT-PCR. The radiosensitization of MMC and 629 in vitro were evaluated in HepG2 cells and g2car cells by colony formation under anaerobic and aerobic condition. The effect of 629 on cell cycle and apoptosis of HepG2 cells and g2car cells were assayed by flow cytometry. It was found that plasmid mCAR1/pCR3 was transfected into g2car cells successfully and target CYP2B6 was transactivated by CAR. To compare with aerobic and anaerobic, the radiosensitization of MMC and 629 to HepG2 cells and g2car cells had significantly enhanced, the radiosensitization of 629 was stronger than its parent compound-MMC under aerobic and anaerobic condition, and transfect CAR gene could improve the radiosensitization of MMC and 629. Furthermore, CYP2B6 is one master enzyme for the metabolism of MMC and 629. Transfection of CAR can increase expression of CYP2B6 mRNA in HepG2 cells, and can affect radiosensitization of MMC and 629. (authors)

Synthesis and Antitumor Evaluation of Novel Bis-Triaziquone Derivatives

Directory of Open Access Journals (Sweden)

Yuh-Ling Lin

2009-06-01

Full Text Available Aziridine-containing compounds have been of interest as anticancer agents since late 1970s. The design, synthesis and study of triaziquone (TZQ analogues with the aim of obtaining compounds with enhanced efficacy and reduced toxicity are an ongoing research effort in our group. A series of bis-type TZQ derivatives has been prepared and their cytotoxic activities were investigated. The cytotoxicity of these bis-type TZQ derivatives were tested on three cancer lines, including breast cancer (BC-M1, oral cancer (OEC-M1, larynx epidermal cancer (Hep2 and one normal skin fibroblast (SF. Most of these synthetic derivatives displayed significant cytotoxic activities against human carcinoma cell lines, but weak activities against SF. Among tested analogues the bis-type TZQ derivative 1a showed lethal effects on larynx epidermal carcinoma cells (Hep2, with an LC50 value of 2.02 mM, and also weak cytotoxic activity against SF cells with an LC50 value over 10 mM for 24 hr treatment. Comparing the viability of normal fibroblast cells treated with compound 1a and TZQ, the LC50 value of the latter was 2.52 mM, indicating more toxicity than compound 1a. This significantly decreased cytotoxicity of compound 1a towards normal SF cells, while still maintaining the anticancer activity towards Hep2 cells is an interesting feature. Among the seven compounds synthesized, compound 1c has similar toxicity effects on the three cancer cell lines and SF normal cells as the TZQ monomer.

Highly selective sulfur ylide mediated asymmetric epoxidations and aziridinations using an inexpensive chiral sulfide and applications to the synthesis of quinine and quinidine (abstract)

International Nuclear Information System (INIS)

Arshad, M.; Illa, O.; Mcgarrigle, E.M.

2011-01-01

Asymmetric sulfur ylide mediated epoxidation, which is considered a complimentary method to asymmetric epoxidation of alkene has been utilized as a key step in the asymmetric total synthesis of complex cinchona alkaloids quinine and quinidine. Isothiocineole 1, which was readily available in one step from very inexpensive starting materials, is employed as a chiral sulfide to prepare the desired sulfonium salt 2. The semi-stabilised ylide derived from this salt on epoxidation with meroquinene aldehyde 3, afforded the required epoxide 4 in 81% yield and 89:11 diastereoselectivity (trans/cis). The epoxide was converted to the target quinine 5 in 73% yield over four steps in one pot. Similarly, the opposite enantiomer of isothiocineole was used to synthesise the corresponding sulfonium salt, which on reaction with meroquinene aldehyde gave epoxide in 73% yield and 84:16 diastereoselectivity (trans/cis). This epoxide was transformed to the target quinidine in 78% yield over four steps in one pot. The epoxidation reactions proceeded under reagent control with high trans selectivity. The effect of sulfide and ylide substituents on the stereochemical outcome of the epoxidation reaction is also prescribed. (author)

A phase I study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer.

Science.gov (United States)

Cohen, Steven J; Zalupski, Mark M; Modiano, Manuel R; Conkling, Paul; Patt, Yehuda Z; Davis, Peg; Dorr, Robert T; Boytim, Michelle L; Hersh, Evan M

2010-07-01

Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m(2) intravenously (IV) over 30 min days 1-5, 15-19 and gemcitabine 800 or 1,000 mg/m(2) IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m(2) IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m(2) IV over 30 min on days 1, 8, and 15 every 28 days). One hundred five patients received 340 treatment cycles (median 2, range 1-16). median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. The recommended phase II dose of imexon is 875 mg/m(2) with gemcitabine 1,000 mg/m(2). DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

Exploring rearrangements along the fragmentation pathways of diuron anion: A combined experimental and computational investigation

Science.gov (United States)

Kanawati, Basem; Harir, Mourad; Schmitt-Kopplin, Philippe

2009-12-01

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea), a common herbicide from phenyl urea class, was investigated by studying the formation of several negative ions [M-H]- in the gas phase and the fragmentation behaviour of the thermodynamically most probably formed isomeric anions upon linear ion acceleration/collision experiments. The collision induced dissociation experiments (CID) were carried out in a hexapole-quadrupole-hexapole hybrid system coupled to 12 T magnet with infinity ICR cell for high resolution measurements. Two distinctive main pathways were observed in the MS/MS spectrum. Sustained off-resonance irradiation (SORI) experiments inside the ICR cell reinforce the fragmentation channels obtained from linear ion acceleration experiments. The fragmentation pathways were also completely investigated by the use of B3LYP/6-311+G(2d,p)//B3LYP/6-31+G(d) level of theory. Elimination of dimethylamine takes place in a two-step process, by which two successive 1,3 proton shifts occur. The second 1,3 proton shift is concerted with the departure of dimethylamine. The driving force for the (CH3)2NH elimination is the formation of isocyanate group. The formed primary product ion can further decompose to release HCl through a new transition state. A stable new aromatic product ion is formed with 10[pi] electrons. Loss of C3H5NO neutral from another anionic isomer of the precursor ion was also observed and is characteristic for the amide terminal of the diamide functional group. A concerted mechanism is proposed, by which N-C bond breakage and cyclization of the eliminated neutral fragment C3H5NO takes place simultaneously to form 1-methyl-aziridin-2-one.

Identification of novel nitroreductases from Bacillus cereus and their interaction with the CB1954 prodrug.

Science.gov (United States)

Gwenin, Vanessa V; Poornima, Paramasivan; Halliwell, Jennifer; Ball, Patrick; Robinson, George; Gwenin, Chris D

2015-12-01

Directed enzyme prodrug therapy is a form of cancer chemotherapy in which bacterial prodrug-activating enzymes, or their encoding genes, are directed to the tumour before administration of a prodrug. The prodrug can then be activated into a toxic drug at the tumour site, reducing off-target effects. The bacterial nitroreductases are a class of enzymes used in this therapeutic approach and although very promising, the low turnover rate of prodrug by the most studied nitroreductase enzyme, NfnB from Escherichia coli (NfnB_Ec), is a major limit to this technology. There is a continual search for enzymes with greater efficiency, and as part of the search for more efficient bacterial nitroreductase enzymes, two novel enzymes from Bacillus cereus (strain ATCC 14579) have been identified and shown to reduce the CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) prodrug to its respective 2'-and 4'-hydroxylamine products. Both enzymes shared features characteristic of the nitro-FMN-reductase superfamily including non-covalently associated FMN, requirement for the NAD(P)H cofactor, homodimeric, could be inhibited by Dicoumarol (3,3'-methylenebis(4-hydroxy-2H-chromen-2-one)), and displayed ping pong bi bi kinetics. Based on the biochemical characteristics and nucleotide alignment with other nitroreductase enzymes, one enzyme was named YdgI_Bc and the other YfkO_Bc. Both B. cereus enzymes had greater turnover for the CB1954 prodrug compared with NfnB_Ec, and in the presence of added NADPH cofactor, YfkO_Bc had superior cell killing ability, and produced mainly the 4'-hydroxylamine product at low prodrug concentration. The YfkO_Bc was identified as a promising candidate for future enzyme prodrug therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Synthesis, biological evaluation and SAR analysis of novel poly-heterocyclic compounds containing pyridylpyrazole group.

Science.gov (United States)

Wang, Bao-Lei; Zhu, Hong-Wei; Li, Zheng-Ming; Wang, Li-Zhong; Zhang, Xiao; Xiong, Li-Xia; Song, Hai-Bin

2018-03-01

In recent years, pyridylpyrazole derivatives, such as pyridylpyrazole-containing anthranilic diamide have attracted much attention by virtue of their useful insecticidal properties and unique action mode. Moreover, some pyridylpyrazole-containing compounds have also been found to possess significant fungicidal activities. With the aim of discovering new bioactive agrochemicals for crop protection, a series of poly-heterocyclic compounds containing pyridylpyrazole and aziridine, or β-lactam, or thiazolinone moieties were synthesized. A series of pyridylpyrazole-containing poly-heterocyclic compounds were obtained, and confirmed through IR, 1 H NMR, 13 C NMR, HRMS and elemental analysis. The crystalline structure of 4-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-3-chloro-1-mesitylazetidin-2-one (compound 13f) was determined to further illustrate a trans- configuration of the β-lactam motif. In addition, bioassays showed that most of these new compounds exhibited modest insecticidal activity towards Mythimna separate Walker at 200 µg mL -1 . Some of the compounds displayed excellent fungicidal activity towards some plant fungi, including Cercospora arachidicola (13j: EC 50 = 14.5 µg mL -1 ), Physalospora piricola (12d and 13d: EC 50 = 10.5 and 9.70 µg mL -1 ), Alternaria solani Sorauer (13j: EC 50 = 7.29 µg mL -1 ), Puccinia sorghi Schw. (13d: control efficacy 99.0 ± 2.1% at 200 µg mL -1 ) and Erysiphe graminis (14d: control efficacy 95.0 ± 1.4% at 200 µg mL -1 ). Compounds 12b-12e, 13a, 13d, 13f, 13j, 13 k and 14d could be considered potential fungicidal lead compounds to do further structural optimization. The structure-activity relationship analysis in this study brings some new understanding to the biological activities of N-pyridylpyrazole-containing compounds, and provides important information for the research and development of novel agricultural fungicides with poly-heterocyclic structures. © 2017 Society of Chemical Industry. © 2017 Society

Cytotoxicity and Radiosensitising Activity of Synthesized Dinitrophenyl Derivatives of 5-Fluorouracil

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Khosrou Abdi

2012-07-01

Full Text Available Background and the purpose of the study: Dual functional agents in which nitroaromatic or nitroheterocyclic compounds are attached through a linker unit to mustards and aziridines have shown higher cytotoxicities than the corresponding counterparts to both aerobic and hypoxic cells and enhanced radiosensitizing activity. In thepresent investigation cytotoxicity and radiosensitizing activity of 2,4-dinitrobenzyl, 2,4-dinitrobenzoyl, and 2,4-dinitrophenacetyl derivatives of 5-fluorouracil which was assumed to release cytotoxic active quinone methidide,and 5-fluorouracil under hypoxic conditions on HT-29 cell line under both aerobic and hypoxic conditions wasinvestigated.Methods: 5-fluorouracil derivative X-XIII were prepared by the reaction of the corresponding di-nitro substitutedbenzyl, benzoyl and phenacetyl halides with 5-fluorouracil protected at N-1 with di-t-butoxydicarbonate (BOC in dimethyl formamide (DMF in the presence of the potassium carbonate followed by hydrolysis of the blocking,group by potassium carbonate in methanol. Cytotoxicity of fluorouracil VIII and tested compounds X-XIII against HT-29cell line under both aerobic and hypoxic conditions after 48 hrs incubation were measured by determination of the percent of the survival cells using 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and percent of the dead cells using propidium iodide(PI-digitonine assay and results were used to calculate the corresponding IC50 values. Radiosensitization experiments were carried out by irradiation of the incubations with a 60Co source and clonogenic assay was performed to determine the cell viabilities following treatment with the tested compounds and/or radiation. Sensitization Enhancement Ratio (SER of each tested compound was obtained from the radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively.Results and major conclusion: Findings of the present study showed that

Cytotoxicity and radiosensitising activity of synthesized dinitrophenyl derivatives of 5-fluorouracil

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Khoshayand Mohammad

2012-07-01

Full Text Available Abstract Background and the purpose of the study Dual functional agents in which nitroaromatic or nitroheterocyclic compounds are attached through a linker unit to mustards and aziridines have shown higher cytotoxicities than the corresponding counterparts to both aerobic and hypoxic cells and enhanced radiosensitizing activity. In the present investigation cytotoxicity and radiosensitizing activity of 2,4-dinitrobenzyl, 2,4-dinitrobenzoyl, and 2,4-dinitrophenacetyl derivatives of 5-fluorouracil which was assumed to release cytotoxic active quinone methidide and 5-fluorouracil under hypoxic conditions on HT-29 cell line under both aerobic and hypoxic conditions was investigated. Methods 5-fluorouracil derivative X-XIII were prepared by the reaction of the corresponding di-nitro substituted benzyl, benzoyl and phenacetyl halides with 5-fluorouracil protected at N-1 with di-t-butoxydicarbonate (BOC in dimethyl formamide (DMF in the presence of the potassium carbonate followed by hydrolysis of the blocking group by potassium carbonate in methanol. Cytotoxicity of fluorouracil VIII and tested compounds X-XIII against HT-29 cell line under both aerobic and hypoxic conditions after 48 hrs incubation were measured by determination of the percent of the survival cells using 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and percent of the dead cells using propidium iodide(PI-digitonine assay and results were used to calculate the corresponding IC50 values. Radiosensitization experiments were carried out by irradiation of the incubations with a 60Co source and clonogenic assay was performed to determine the cell viabilities following treatment with the tested compounds and/or radiation. Sensitization Enhancement Ratio (SER of each tested compound was obtained from the radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results and major conclusion Findings of the present study

Tunable, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts.

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Alderson, Juliet M; Corbin, Joshua R; Schomaker, Jennifer M

2017-09-19

Carbon-nitrogen (C-N) bonds are ubiquitous in pharmaceuticals, agrochemicals, diverse bioactive natural products, and ligands for transition metal catalysts. An effective strategy for introducing a new C-N bond into a molecule is through transition metal-catalyzed nitrene transfer chemistry. In these reactions, a metal-supported nitrene can either add across a C═C bond to form an aziridine or insert into a C-H bond to furnish the corresponding amine. Typical catalysts for nitrene transfer include Rh 2 L n and Ru 2 L n complexes supported by bridging carboxylate and related ligands, as well as complexes based on Cu, Co, Ir, Fe, and Mn supported by porphyrins and related ligands. A limitation of metal-catalyzed nitrene transfer is the ability to predictably select which specific site will undergo amination in the presence of multiple reactive groups; thus, many reactions rely primarily on substrate control. Achieving true catalyst-control over nitrene transfer would open up exciting possibilities for flexible installation of new C-N bonds into hydrocarbons, natural product-inspired scaffolds, existing pharmaceuticals or biorenewable building blocks. Silver-catalyzed nitrene transfer enables flexible control over the position at which a new C-N bond is introduced. Ag(I) supported by simple N-donor ligands accommodates a diverse range of coordination geometries, from linear to tetrahedral to seesaw, enabling the electronic and steric parameters of the catalyst to be tuned independently. In addition, the ligand, Ag salt counteranion, Ag/ligand ratio and the solvent all influence the fluxional and dynamic behavior of Ag(I) complexes in solution. Understanding the interplay of these parameters to manipulate the behavior of Ag-nitrenes in a predictable manner is a key design feature of our work. In this Account, we describe successful applications of a variety of design principles to tunable, Ag-catalyzed aminations, including (1) changing Ag/ligand ratios to influence

Reactivity of nitrido complexes of ruthenium(VI), osmium(VI), and manganese(V) bearing Schiff base and simple anionic ligands.

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Man, Wai-Lun; Lam, William W Y; Lau, Tai-Chu

2014-02-18

Nitrido complexes (M≡N) may be key intermediates in chemical and biological nitrogen fixation and serve as useful reagents for nitrogenation of organic compounds. Osmium(VI) nitrido complexes bearing 2,2':6',2″-terpyridine (terpy), 2,2'-bipyridine (bpy), or hydrotris(1-pyrazolyl)borate anion (Tp) ligands are highly electrophilic: they can react with a variety of nucleophiles to generate novel osmium(IV)/(V) complexes. This Account describes our recent results studying the reactivity of nitridocomplexes of ruthenium(VI), osmium(VI), and manganese(V) that bear Schiff bases and other simple anionic ligands. We demonstrate that these nitrido complexes exhibit rich chemical reactivity. They react with various nucleophiles, activate C-H bonds, undergo N···N coupling, catalyze the oxidation of organic compounds, and show anticancer activities. Ruthenium(VI) nitrido complexes bearing Schiff base ligands, such as [Ru(VI)(N)(salchda)(CH3OH)](+) (salchda = N,N'-bis(salicylidene)o-cyclohexyldiamine dianion), are highly electrophilic. This complex reacts readily at ambient conditions with a variety of nucleophiles at rates that are much faster than similar reactions using Os(VI)≡N. This complex also carries out unique reactions, including the direct aziridination of alkenes, C-H bond activation of alkanes and C-N bond cleavage of anilines. The addition of ligands such as pyridine can enhance the reactivity of [Ru(VI)(N)(salchda)(CH3OH)](+). Therefore researchers can tune the reactivity of Ru≡N by adding a ligand L trans to nitride: L-Ru≡N. Moreover, the addition of various nucleophiles (Nu) to Ru(VI)≡N initially generate the ruthenium(IV) imido species Ru(IV)-N(Nu), a new class of hydrogen-atom transfer (HAT) reagents. Nucleophiles also readily add to coordinated Schiff base ligands in Os(VI)≡N and Ru(VI)≡N complexes. These additions are often stereospecific, suggesting that the nitrido ligand has a directing effect on the incoming nucleophile. M≡N is also

Estrogen receptor of primary breast cancers: evidence for intracellular proteolysis

International Nuclear Information System (INIS)

Maaroufi, Younes; Lacroix, Marc; Lespagnard, Laurence; Journé, Fabrice; Larsimont, Denis; Leclercq, Guy

2000-01-01

ER-positive according to [ 3 H]oestradiol-binding assay (dextran-coated charcoal [DCC]) were subjected to hydroxylapatite adsorption. ER isoforms covalently labeled with [ 125 I]tamoxifen aziridine (TAZ) released from this matrix with 0.5 mol/l KCl were subsequently immunoprecipitated with a panel of monoclonal antibodies raised against various domains of ER (H222 [E], H226 [C] or ER1D5 [AB]) before being subjected to SDS-gel electrophoresis. Three approaches were used to identify the origins of the cleaved ER forms: potential truncated ER-α messenger RNAs that may encode ER isoforms of low molecular weights (Northern blot assay) were sought by using ER-α full-length probe; heat treatment of tumour cytosols in the absence or presence of a cocktail of protease inhibitors was performed; and the molecular weight of intracellular ER molecules was determined by in situ [ 125 I]TAZ-labelling, which minimizes ER proteolysis. Breast cancer samples classified as ER-positive according to both biochemical (cytosolic DCC assay) and histochemical (ER1D5 monoclonal antibody) criteria were labelled with [ 3 H]oestradiol and were subsequently subjected to hydroxylapatite adsorption. Hydroxylapatite extraction index (EI) is defined as a ratio of the specifically bound [ 3 H]oestradiol released from the hydroxylapatite matrix with KCl to the total amount of the specifically bound [ 3 H]oestradiol extracted successively with KCl and ethanol: EI= ([ 3 H]oestradiol) [KCl] × 100/([ 3 H]oestradiol) [KCl] + ([ 3 H]oestradiol) [EtOH]. The EI was calculated for each cytosol in order to evaluate the amount of cleaved ER forms present. Persistence of adsorption ER to hydroxylapatite in the presence of KCl (low EI) and ER1D5 positivity established by immunohistochemistry are two independent criteria for the presence of amino-terminal ABC domains. We therefore assessed whether hydroxylapatite determinations performed on cytosols are related to immuno-histochemistry data. Cytosol pools labelled