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PubMed2005

Transition metal-catalyzed synthesis and reactivity of N-alkenyl aziridines.

[reaction: see text] Straightforward methods for palladium-catalyzed alkenylation of aziridines with alkenyl halides and copper-catalyzed alkenylation of aziridines with alkenyl boronic acids have been developed. This methodology offers attractive alternatives to the known methods requiring activated alkenyl halides and acetylenes. A wide variety of N-alkenyl aziridines containing substituents other than electron-withdrawing substituents such as cyano groups and sulfones have been synthesized in good yields. Furthermore, these N-alkenyl aziridines exhibit quite a different reactivity from conventional enamines, as demonstrated by their reactivity.

Journal Article↗
PubMed1991

Comparison of tritiated estradiol and tamoxifen aziridine for measurement of estrogen receptors in human breast cancer cytosols.

We examined the estrogen receptor measurement in 265 human breast cancer cytosols by using a specific method based on [3H]tamoxifen aziridine labeling, sequential immunoadsorption with an antiestrogen receptor monoclonal antibody (H-222), sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and autoradiography. These new tools of molecular endocrinology revealed an impressive estrogen receptor molecular polymorphism. Given the recent finding of a similar estrogen receptor polymorphism at the messenger RNA level by several laboratories, it is tempting to speculate about its possible biological significance. To gain insight into the potential clinical relevance of this polymorphism in terms of breast cancer hormone dependence, we compared the 265 cytosols for their [3H]tamoxifen aziridine- and [3H]estradiol-binding capacities using the above-mentioned method and the conventional dextran-coated charcoal assay. We failed to identify a specific [3H]tamoxifen aziridine electrophoretic pattern with respect to the tumor estrogen receptor content as measured by the dextran-coated charcoal assay. However, an excellent correlation overall was found between the intensities of both labeling methods. Some tumors were positive for only one of these two ligands. It will be clinically important to see whether the tumors positive for [3H]tamoxifen aziridine only correspond to the small subset of tumors (10%) which respond to tamoxifen treatment despite very low estrogen receptor levels, as measured by the dextran-coated charcoal technique.

Antibodies, Monoclonal↗
PubMed2005

Development and validation of a separation method for the diastereomers and enantiomers of aziridine-type protease inhibitors.

Aziridine derivatives are attracting pharmacological interest as protease inhibitors. Due to their two centers of chirality, the aziridines studied here are mixtures of two diastereomers and corresponding enantiomers. Applying cyclodextrin-modified capillary electrophoresis resulted in a baseline separation of the four isomers. The most robust separation was obtained by means of 2 mM sulfated beta-cyclodextrin in 50 mM phosphate buffer of pH 2.5. Using this method, 0.25% of the trans-diastereomers aziridine could be precisely and accurately quantified in the presence of 99.75% of the cis-isomers. The corrected peak-area ratios, migration times, and resolutions were found to be robust with respect to small variations of voltage, buffer concentrations, pH, temperature, chiral selector concentration, and different lots.

Aziridines↗
PubMed2005

Comparison of the separation of aziridine isomers applying heptakis(2,3-di-O-methyl-6-sulfato)beta-CD and heptakis(2,3-di-O-acetyl-6-sulfato)beta-CD in aqueous and nonaqueous systems.

Aziridines are attracting interest as protease inhibitors, which might be used, e.g., for treatment of parasitic diseases. Within the framework of greater projects dealing with the search of new selective protease inhibitors, a huge number of aziridines with two stereogenic centers will be synthesized. Thus, a fast and reliable screening method for the evaluation of the isomeric composition is needed. Robust baseline separations were obtained using heptakis(2,3-di-O-acetyl-6-sulfato)beta-CD (HDAS) in acidic methanol and sulfated beta-CD in acidic phosphate buffer. With HDAS the resolutions were higher and migration times shorter. Thus, the method will be used as a screening method for further isomeric mixtures of aziridines.

Aziridines↗
PubMed1987

Aziridine biotransformation by microsomes and lethality to hepatocytes isolated from rat.

To clarify the relationship of aziridine biotransformation to their cytotoxic activities, the metabolism of optical isomers of typical cytotoxic and non-cytotoxic aziridines was studied in isolated hepatocytes, rat liver microsomes, mitochondria and L-1210 mouse leukemia cells. Cytotoxic 1-methyl-2-beta-naphthylaziridine (NAZ) gave nitrosomethane as one of the bioactivation products in isolated hepatocytes and simultaneously induced a marked decrease in cellular ATP followed by cell lethality. NAZ itself did not directly affect the respiratory function of mitochondria in isolated hepatocytes or in buffer solution, however, it inhibited the mitochondrial activity in the presence of microsomes in the buffer solution. Nitroso-t-butane or nitrosomethane dimer, used as a substitute for extremely labile nitrosomethane, strongly inhibited the respiration of mitochondria. On the other hand, optical isomers of 2-aziridinecarboxylic acid (AZC) which did not give nitrosomethane in isolated hepatocytes or microsomes also did not show cytotoxicity. Thus, the cytotoxicity of NAZ seems to be induced by bioactivation via cellular oxidases with the nitrosomethane generated being a major toxic component. This may occur with most of the cytotoxic aziridine derivatives.

Adenosine Triphosphate↗
PubMed2004

Modification of indium-tin oxide (ITO) glass with aziridine provides a surface of high amine density.

The surface of indium-tin oxide (ITO) substrates was successfully modified with aziridine. Modification of the surface was achieved through facile ring-opening, and hyperbranching polymerization of the ring-strained heterocycle initiated from the reactive group on the surface. Amine density of the aziridine-modified ITO measured with UV-vis spectrophotometry is 10 amines/nm2. Cyclic voltammetric analysis showed that the aziridine-modified electrode was less active for Ru(NH3)6(3+) in comparison with the pristine electrode, while no difference was observed for Fe(CN)6(4-). Electrochemical impedance spectroscopic experiments unveiled that the modified electrode was more efficient for electron transfer to the latter species than to the former.

Amines↗
PubMed1998

Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.

Some epimeric 20-hydroxy, 20-oxime, 16 alpha, 17 alpha-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase (P450(17) alpha) and 5 alpha-reductase (5 alpha-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestigated. NaBH4 in the presence of CeCl3 gave better stereo-selectivity for 20 beta-ol [20 alpha/20 beta-OH (4 alpha/4 beta) = 1/2.7] than LTBAH or the Meerwein-Pondroff method reported; reduction with Zn in HOAc formed exclusively 20 alpha-ol (4 alpha b). The 20 alpha- and 20 beta-hydroxy-4,16-pregnadien-3-one (9 alpha) and (9 beta) were synthesized from the alcohols 4 alpha b and 4 beta b. Several 20-oxime pregnadienes and 16 alpha, 17 alpha-, 17,20- and 20,21-aziridinyl-5-pregnene derivatives were also synthesized. LiAlH4 reduction of the 16-en-20-oxime (12b) yielded 20 (R)-(13a) and 20(S)-17 alpha,20-aziridine (13b) and 20(R)-17 beta,20-aziridine (14a). Several compounds inhibited the human P450(17) alpha with greater potency than ketoconzole. The 5 alpha-R enzyme assay showed that while (9 alpha) did not have any activity, (9 beta) and (3b) were potent 5 alpha-reductase (IC50 = 21 and 31 nM) inhibitors with activities similar to finasteride. The 20-oximes (17a) and (17b) were potent dual inhibitors for both 5 alpha-R (IC50 = 63 and 115 nM, compared to 33 nM for finasteride) and P450(17) alpha (IC50 = 43 and 25 nM, compared to 78 nM for ketoconazole).

5-alpha Reductase Inhibitors↗
PubMed2005

N-tosyloxycarbamates as a source of metal nitrenes: rhodium-catalyzed C-H insertion and aziridination reactions.

The rhodium-catalyzed decomposition of N-tosyloxycarbamates to generate metal nitrenes which undergo intramolecular C-H insertion or aziridination reaction is described. Aliphatic N-tosyloxycarbamates produce oxazolidinones with high yields and stereospecificity through insertion in benzylic, tertiary, and secondary C-H bonds. Intramolecular aziridination occurs with allylic N-tosyloxycarbamates to produce aziridines as single diastereomers. The reaction proceeds at room temperature using a rhodium catalyst and an excess of potassium carbonate and does not require the use of strong oxidant, such as hypervalent iodine reagents. A rhodium nitrene species is presumably involved, as both reactions are stereospecific.

Aziridines↗
PubMed2005

Silylmethyl-substituted aziridine and azetidine as masked 1,3- and 1,4-dipoles for formal [3 + 2] and [4 + 2] cycloaddition reactions.

2-tert-Butyldiphenylsilylmethyl-substituted aziridine and the corresponding azetidine reacted efficiently with nitriles and carbonyl substrates to generate imidazoline, oxazolidine, and tetrahydropyrimidine products. The azetidine rearranged efficiently to the pyrrolidine skeleton involving migration of silicon under BF3.Et2O conditions. The tert-butyldiphenylsilylmethyl function, latent to CH2OH group, controlled not only the regioselectivity of aziridine and azetidine cleavage but also the relative stereochemistry of the substituents in the products derived from substituted aziridine.

Azetidines↗
PubMed1995

Synthesis and biological evaluation of novel C-4 aziridine-bearing paclitaxel (taxol) analogs.

Three novel C-4 aziridine-bearing paclitaxel analogs, 3-5, have been synthesized during the course of our continuing effort at C-4 modification. The key step in the synthesis is the aziridine ring formation at the C-4 position via an intramolecular Mitsunobu reaction. The syntheses and the biological evaluation of these C-4 aziridine-containing derivatives are herein discussed.

Aziridines↗
PubMed2006

Synthesis of 1-arylmethyl-2-(cyanomethyl)aziridines and their ring transformation into methyl N-(2-cyanocyclopropyl)benzimidates.

1-Arylmethyl-2-(cyanomethyl)aziridines were prepared in high yields from the corresponding 2-(bromomethyl)aziridines upon treatment with potassium cyanide in DMSO. Ring opening of the aziridine moiety with N-chlorosuccinimide in CCl4 and subsequent treatment of the thus formed 4-chloro-3-(N-chloro-N-(alpha,alpha-dichlorobenzyl)amino)butanenitriles with sodium methoxide in methanol resulted in novel methyl N-(2-chloro-1-(cyanomethyl)ethyl)benzimidates, although in low yields. The latter gamma-chloro nitriles were smoothly converted into methyl N-(2-cyanocyclopropyl)benzimidates as precursors of biologically relevant beta-ACC derivatives through a 1,3-cyclization protocol by reaction with potassium tert-butoxide in THF.

Aziridines↗
PubMed2006

Guanidinium ylide mediated aziridination: identification of a spiro imidazolidine-oxazolidine intermediate.

We successfully isolated a spiro imidazolidine-oxazolidine intermediate in the reaction of guanidinium ylide mediated aziridination using alpha-bromocinnamaldehyde. X-ray crystallographic analysis unambiguously revealed that the stereogenic centers of the spiro intermediate were in a trans configuration. The role of the spiro compound as an intermediate in the aziridination reaction was confirmed by observation of its smooth chemical conversion into aziridine products.

Aldehydes↗
PubMed2005

Efficient aziridination of olefins catalyzed by mixed-valent dirhodium(II,III) caprolactamate.

[reaction: see text] A mild, efficient, and selective aziridination of olefins catalyzed by dirhodium(II) caprolactamate [Rh(2)(cap)(4).2CH(3)CN] is described. Use of p-toluenesulfonamide (TsNH(2)), N-bromosuccinimide (NBS), and potassium carbonate readily affords aziridines in isolated yields of up to 95% under extremely mild conditions with as little as 0.01 mol % Rh(2)(cap)(4). Aziridine formation occurs through Rh(2)(5+)-catalyzed aminobromination and subsequent base-induced ring closure. An X-ray crystal structure of a Rh(2)(5+) halide complex, formed from the reaction between Rh(2)(cap)(4) and N-chlorosuccinimide, has been obtained.

Alkenes↗
PubMed2003

Functionalised enones as starting materials for the construction of aziridine scaffolds.

alpha-Substituted beta-keto esters have been transformed by means of a straightforward procedure into aziridine-1,2-dicarboxylates, which have been efficiently converted into alkenyl aziridine-1,2-dicarboxylates through Wittig olefination reaction. The possibility of aziridine ring elaborations and the presence of an olefin function make these new molecules suitable scaffolds for further derivatisation into potential bioactive targets.

Aziridines↗
PubMed2004

Catalytic asymmetric heterogeneous aziridination of styrene derivatives using bis(oxazoline)-modified Cu2+-exchanged zeolite Y.

The copper-catalysed aziridination of styrene derivatives using either Cu(OTf)2 as a homogeneous catalyst or copper-exchanged zeolite Y modified as a heterogeneous catalyst with bis(oxazoline) using [N-(p-nitrophenylsulfonyl)imino]phenyliodinane (PhI=NNs) as nitrene donor is described and discussed. For the homogeneously catalysed reaction virtually all the substituted derivatives gave lower yields of the aziridine with lower ee when compared with styrene, although 4-chlorostyrene did give enhanced ee. For the heterogeneous catalysed reaction the styrene derivatives often gave enhanced yield, particularly when the substituent was in the 4-position. Particularly high ee was observed for 2-chlorostyrene (95%) and 4-chlorostyrene (94%) and in general the ee observed for the heterogeneously catalysed reaction with the 2- and 4-substituted derivates was significantly higher than that for the equivalent homogeneously catalysed reaction. With copper-exchanged zeolite Y the leaching of Cu2+ into solution during reaction was much lower for the substituted styrene derivatives (0.4-7% of total Cu) than with styrene itself (10.3% of the total Cu). The effect of reaction time on aziridine yield reveals an S-shaped profile that is accentuated by the position of the substituent and this effect is observed for both the homogeneously catalysed pathway and the heterogeneously catalysed reaction. A series of competitive experiments in which styrene was co-reacted with equivalent quantities of 2-, 3- and 4-chlorostyrene revealed that the reaction of styrene enhanced by the other substrate, but the rate of reaction of the substituted styrene was decreased. Co-reaction of 2- and 4-chlorostyrene reveals interesting competitive effects, which are discussed in terms of the nature of the active site.

Aziridines↗
PubMed2006

Novel aziridination of olefins: direct synthesis from sulfonamides using t-BuOI.

tert-Butyl hypoiodite (t-BuOI) was found to be a powerful reagent for synthesis of aziridines from olefins and sulfonamides. The aziridination of olefins was achieved by using sulfonamides with t-BuOI. Our preliminary findings represent the example of metal-free aziridination of olefins with readily accessible sulfonamides as a nitrogen source.

Alkenes↗
PubMed1990

Unique molecular properties of a urea- and salt-stable DNA-binding estrogen receptor dimer covalently labeled with the antiestrogen [3H]desmethylnafoxidine aziridine. A comparison with the estrogen-receptor complex.

A new antiestrogen affinity ligand for the covalent labeling of estrogen receptors, [3H]desmethylnafoxidine aziridine, has been used to investigate the salt- and temperature-independent formation of DNA-binding estrogen receptor forms from untransformed (300 kilodaltons) receptor. Calf uterine estrogen receptor proteins labeled with [3H]estradiol or [3H]desmethylnafoxidine aziridine were quantitatively transformed (greater than 90%) to their DNA-binding configuration in low ionic strength buffers by brief exposure to 3 M urea at 0 C. The urea effect was hormone-dependent and partially reversible. The transformed receptors were purified (ca 250-fold) by affinity chromatography on single-stranded DNA-agarose in the continued presence of 3 M urea to prevent transformation reversal. Scatchard analyses revealed a single class of high affinity radioligand binding sites (Kd = 0.34 nM) unchanged by urea-induced transformation and purification. The DNA-binding receptor form labeled with [3H]desmethylnafoxidine aziridine was stable as a probable dimer in 3 M urea with 0.4 M KCl and displayed no evidence of size (Stokes radius 7.3 to 7.5 nm; 4.2 to 4.3 S; Mr = 136,800) heterogeneity. Sodium dodecyl sulfate-polyacrylamide gradient gel electrophoresis indicated the presence of an intact 67 kDa steroid-binding receptor subunit. Reverse-phase chromatography of the covalently labeled receptor on C4 and phenyl stationary phases revealed no evidence of structural heterogeneity. The surface charge of the estrogen- and antiestrogen-receptor complexes, however, was distinctly different in both the presence and absence of 3 M urea. Thus, exposure to urea was an effective salt- and temperature-independent means for achieving the complete transformation of receptor to its stable DNA-binding dimer configuration. The ligand-induced differences in receptor surface charge and the urea effects on DNA-binding (but not hormone-binding) suggest that both electrostatic and hydrophobic or hydrogen bonding receptor domains are influenced by ligand binding.

Animals↗
PubMed1985

Contact allergy to aziridine paint hardener.

A painter experienced an extensive dermatitis when exposed to a paint primer (undercoating) used to protect wood siding. The primer was an acrylic emulsion with a polyfunctional aziridine added as a self-curing cross-linker or hardener. The polyfunctional aziridine cross-linker was made by reacting propyleneimine with a polyfunctional acrylate, trimethylolpropane triacrylate (TMPTA). Our patient reacted to the cross-linker and also reacted to TMPTA, which is present in excess in the cross-linker. He also cross-reacted to pentaerythritol triacrylate (PETA). Both TMPTA and PETA can be used in the production of aziridine hardeners and both are well known as sensitizers in radiation-dried acrylic printing inks and coatings.

Acrylates↗