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PubMed1991

Synthesis and immunopharmacological analysis of selected butanic and butanodionic acid amides containing aziridine unit. II.

In the reaction of butanic and butanodionic acid chlorides with amines, amides 1-10 were produced. Addition of aziridine to a double bonds was performed in alkaline medium which resulted in aziridine derivatives of both acids. Pharmacological study revealed that the preparations examined possess immunotropic, strongly suppressive activity (PFC, E-RFC), partly IgG level; they leave the titer of circulating IgM unchanged. It seems that rather the basic system of acids than the substituents introduced to it are responsible for the effect of the compounds.

Animals↗
PubMed1995

Convulsive properties of N-(3,5-dimethoxy-4-propoxyphenyl-ethyl) aziridine and their influencing by diazepam and triazolam.

Convulsive activity of N-(3,5-dimethoxy-4-propoxy-phenyl-ethyl)-aziridine (FAZ-4), a newly synthetized aziridine compound was studied in rats. There is a lack of tonic component of major paroxysm in comparison with the classical convulsive agent pentylenetetrazol. This effect of FAZ-4 is probably due to the forebrain mechanism without the midbrain involvement. Both anticonvulsants tested suppressed seizures in a different manner, however triazolam exerted stronger anticonvulsive activity than the same dose of diazepam did.

Animals↗
PubMed2005

Palladium pincer complex catalyzed cross-coupling of vinyl epoxides and aziridines with organoboronic acids.

Palladium-catalyzed cross-coupling of vinyl epoxides and aziridines with organoboronic acids was performed by using 0.5-2.5 mol % pincer-complex catalyst. The reactions proceed under mild conditions affording allyl alcohols and amines with high regioselectivity and in good to excellent yields. Under the applied reaction conditions aromatic chloro-, bromo- and iodo substituents are tolerated. Our results indicate that the mechanism of the pincer complex catalyzed and the corresponding palladium(0) catalyzed process is substantially different. It was concluded that the transformations proceed via transmetalation of the organoboronic acids to the pincer-complex catalyst followed by an S(N)2'-type opening of the vinyl epoxide or aziridine substrate. In this process the palladium atom is kept in oxidation state +2 under the entire catalytic process, and therefore oxidative side reactions can be avoided.

Journal Article↗
PubMed2002

Axially dissymmetric (R)-(+)-5,5',6,6',7,7',8,8' octahydro-[1,1']binaphthyldiimine chiral salen type-ligands for copper-catalyzed asymmetric aziridination.

Axially dissymmetric chiral diimine ligand 2 was prepared from the reaction of (R)-(+)-5,5',6,6',7,7',8,8'-octahydro-[1,1']binaphthyl-2,2'-diamine 1 with 2,6-dichlorobenzaldehyde. The catalytic asymmetric aziridination of alkenes was examined using this novel chiral ligand. Excellent enantioselective aziridination of cinnamates was achieved using C(2)-symmetric chiral ligand 2.

Journal Article↗
PubMed1985

Biological activities of tamoxifen aziridine, an antiestrogen-based affinity label for the estrogen receptor, in vivo and in vitro.

Tamoxifen aziridine (TA), an antiestrogen-based affinity label for the estrogen receptor, is highly selective and efficient in its covalent binding to the estrogen receptor (Katzenellenbogen et al., J. biol. Chem. 258 (1983) 3487-3495). Thus, it was of interest to investigate the biological character and potency of this compound and, in particular, to determine if the irreversible attachment of this tamoxifen-derived compound to the estrogen receptor would result in enhanced antiestrogenic properties or in unusual biological activity. The effect of tamoxifen aziridine and tamoxifen (Tam), the parent compound which is an antiestrogen that binds reversibly to the estrogen receptor, were compared with respect to their effects on uterine growth, growth of dimethylbenzanthracene (DMBA)-induced mammary tumors in rats, and proliferation and plasminogen activator activity of MCF-7 human breast cancer cells. In immature (day 20) rats, Tam and TA behaved as weak estrogen agonists and estrogen antagonists in that Tam or TA alone increased uterine weight to levels lower than that evoked by estradiol (E2), and both were able to suppress the stimulation of uterine weight evoked by E2. Administration of Tam and TA via Alzet minipumps (25 or 200 micrograms/rat/day) to mature rats bearing DMBA-induced mammary tumors resulted in marked regression and/or disappearance of most tumors. Uterine weights were also suppressed in these mature rats by Tam and TA. Tam was slightly more potent than TA in evoking tumor regression and in suppressing uterine weights in these in vivo studies. In MCF-7 human breast cancer cells in culture, Tam and TA suppressed cell proliferation and evoked no increase in plasminogen activator activity by themselves, while being very effective in preventing plasminogen activator activity stimulation by E2. Thus, TA displayed a bioactivity profile similar to that of Tam, the reversibly binding ligand, in vitro and in vivo. The covalent attachment of TA to the receptor does not, therefore, markedly alter the biological character or potency of the antiestrogen receptor complex.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

[125I]iododesethyl tamoxifen aziridine: synthesis and covalent labeling of the estrogen receptor with an iodine-labeled affinity label.

Iododesethyl tamoxifen aziridine (I-Tam-Az), an analog of the estrogen receptor-affinity label tamoxifen aziridine (Tam-Az) in which the ethyl group has been replaced by an iodine, has been prepared by two routes: (a) metallation of a bromotriarylethylene system, followed by reaction with iodine, and aziridinylation, and (b) direct iodination of a trimethylstannyl triarylethylene system that is the immediate precursor of I-Tam-Az. The latter method can be used to prepare [125I]I-Tam-Az rapidly and in good yield, both at carrier-added and no-carrier-added levels; specific activities greater than 200 Ci/mmol have been obtained. In competitive radiometric binding assays with the estrogen receptor, I-Tam-Az has an apparent affinity of ca. 20%, equivalent to that of Tam-Az. It also undergoes rapid and selective time-dependent, irreversible binding to the estrogen receptor. [125I]I-Tam-Az reacts covalently with estrogen receptor in uterine cytosol preparations; its attachment is rapid and efficient, but somewhat less selective than that of Tam-Az. Estrogen receptor in intact MCF-7 human breast cancer cells can also be labeled with [125I]I-Tam-Az, and autoradiographic analysis of salt extracts of labeled nuclear estrogen receptor on SDS-polyacrylamide slab gels shows highly selective labeling of a 65K protein. [125I]I-Tam-Az is an efficient, selective affinity label for the estrogen receptor, available at high specific activity, and should be useful in studies on estrogen receptor structure, dynamics, and chromatin interactions.

Affinity Labels↗
PubMedDate not supplied

A comparison of 11 beta-chloromethylestradiol and tamoxifen aziridine as affinity labeling reagents for estrogen receptors.

The tritium-labeled from of 11 beta-chloromethylestradiol was prepared by metal hydride reduction of the 17-keto derivative. Affinity labeling experiments were carried out using [3H] 11 beta-chloromethylestradiol and [3H]tamoxifen aziridine with estrogen receptor from crude, calf uterine cytosol and partially purified (heparin-sepharose chromatography) preparations. Both compounds formed highly stable receptor complexes. Estrogen specific, covalent binding, however, was indicated only for [3H]tamoxifen aziridine. An equilibrium dissociation constant of 2.8 x 10(-10) M was determined for the receptor-[3H] 11 beta-chloromethylestradiol interaction. Measurement of hormone dissociation kinetics at 30 degrees C revealed a slow, single phase dissociation of 11 beta-chloromethylestradiol from the receptor (dissociation rate constant, 1.3 x 10(-3) min-1). This contrasted with the normal biphasic dissociation pattern of estradiol in which the dissociation rate constant for the slower component was 16.7 x 10(-3) min-1. The results indicate that 11 beta-chloromethylestradiol readily converts the estrogen receptor to a high affinity binding form and suggest that the radiolabeled hormone may prove useful for studies of estrogen action.

Affinity Labels↗
PubMed2006

Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents.

The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new trypanocidal drugs. Series of aziridine-2,3-dicarboxylate-based cysteine protease inhibitors have been tested, most of them inhibiting rhodesain in the low micromolar range. Among these, only dibenzyl aziridine-2,3-dicarboxylates display trypanocidal activity being equipotent to the drug eflornithine. The Leu-Pro-containing aziridinyl tripeptides 13a-f are the most promising as they are not cytotoxic to macrophages up to concentrations of 125microM.

Animals↗
PubMed2003

Hyperbranching polymerization of aziridine on silica solid substrates leading to a surface of highly dense reactive amine groups.

Silica solid substrates such as fused silica, silicon wafers with a natural oxide layer, and glass were treated with aziridine to produce reactive primary amine groups on the top surface. We found that the hydroxyl group on the substrate was able to initiate the ring-opening polymerization of aziridine, resulting in highly branched poly(ethyleneimine) on the surface. In dichloromethane, the thickness of the organic film reached 25 A in 20 h and the absolute density of the primary amine group on the surface was 23 amines/nm(2). Atomic force microscopy shows an embossed morphology after the polymerization in dichloromethane, while use of toluene gives a rather smooth surface. The resulting organic layer shows high thermal and pH stability.

Journal Article↗
PubMed2000

Copper(II) complexes of pyridyl-appended diazacycloalkanes: synthesis, characterization, and application to catalytic olefin aziridination.

As part of an ongoing effort to rationally design new copper catalysts for olefin aziridination, a family of copper(II) complexes derived from new tetradentate macrocyclic ligands are synthesized, characterized both in the solid state and in solution, and screened for catalytic nitrene transfer reactivity with a representative set of olefins. The pyridylmethyl-appended diazacycloalkane ligands L6(py)2, L7(py)2, and L8(py)2 are prepared by alkylation of the appropriate diazacycloalkane (piperazine, homopiperazine, or diazacyclooctane) with picolyl chloride in the presence of triethylamine. The ligands are metalated with Cu(ClO4)(2).6H2O to provide the complexes [(L6(py)2)Cu(OClO3)]ClO4 (1), [(L7(py)2)Cu(OClO3)]ClO4 (2), and [(L8(py)2)Cu](ClO4)2 (3), which, after metathesis with NH4PF6 in CH3CN, afford [(L6(py)2)Cu(CH3CN)](PF6)2 (4), [(L7(py)2)Cu(CH3CN)](PF6)2 (5), and [(L8(py)2)Cu](PF6)2 (6). All six complexes are characterized by X-ray crystallography, which reveals that complexes supported by L6(py)2 and L7(py)2 (1, 2, 4, 5) adopt square-pyramidal geometries, while complexes 3 and 6, ligated by L8(py)2 feature tetracoordinate, distorted-square-planar copper ions. Tetragonal geometries in solution and d(x2 - y2), ground states are confirmed for the complexes by a combination of UV-visible and EPR spectroscopies. The divergent flexibility of the three supporting ligands influences the Cu(II)/Cu(I) redox potentials within the family, such that the complexes supported by the larger ligands L7(py)2 and L8(py)2 (5 and 6) exhibit quasi-reversible electron transfer processes (E1/2 approximately -0.2 V vs Ag/AgCl), while the complex supported by L6(py)2 (4), which imposes a rigid tetragonal geometry upon the central copper(II) ion, is irreversibly reduced in CH3CN solution. Complexes 4-6 are efficient catalysts (in 5 mol % amounts) for the aziridination of styrene with the iodinane PhINTs (in 80-90% yields vs PhINTs), while only 4 exhibits significant catalytic nitrene transfer reactivity with 1-hexene and cyclooctene.

Alkenes↗
PubMed2002

Practical olefin aziridination with a broad substrate scope.

The present study illustrates the possibility of a rational approach that bypasses the requirement for stoichiometric amounts of toxic oxidants and metal additives (including reagents and catalysts) in organic redox reactions. We describe an aziridination process that delivers a nitrene functionality to olefins from a readily available N-aminophthalimide. Remarkably, both electron-rich and electron-poor olefins are converted to aziridines with high efficiency. The continuum of applied potentials and the heterogeneous nature of reactions at electrode surfaces allow for the electrochemical discrimination of substrates which have similar redox potentials and therefore cannot be selectively reduced or oxidized using soluble reagents. This selectivity is due to the phenomenon of overpotential, the kinetic inhibition of electron transfer on a particular electrode surface.

Journal Article↗
PubMed2003

Group transfer from nickel imido, phosphinidene, and carbene complexes to ethylene with formation of aziridine, phosphirane, and cyclopropane products.

The reactions of nickel complexes bearing terminal imido, phosphinidene, and carbene ligands with ethylene are reported. In all three cases, corresponding three-membered rings, aziridine, phosphirane, and cyclopropane, were produced in moderate to excellent yields. NMR spectra of the phosphinidene (dtbpe)Ni=P(dmp) reaction with ethylene show a [2+2] cycloaddition adduct before phosphirane formation. A labeling study with trans-ethylene-d2 shows formation of aziridine and phosphirane proceeds with net retention of relative stereochemistry.

Journal Article↗
PubMed2004

The Brønsted acid-catalyzed direct aza-Darzens synthesis of N-alkyl cis-aziridines.

A mild protocol for the synthesis of cis-aziridines is described that employs a catalytic amount of Brønsted acid. Despite the potential for diazo compound decomposition via alkylation or homocoupling upon exposure to a proton source, these pathways are slow relative to [2 + 1] annulation in the presence of a Schiff base, leading to aziridine product. The process uses no metals or reagents that must be removed chromatographically, exhibits rapid turnover rates, and produces only atomic nitrogen as a coproduct. High levels of relative stereocontrol are also possible when forming the Schiff base from a chiral nonracemic aldehyde.

Journal Article↗
PubMed1985

Lack of influence of the carbamoyl group on the stereochemistry of the acid-catalyzed opening of the aziridine ring of the mitomycins and of congeners.

The acid-catalyzed opening of the aziridine ring of mitomycins A and C is known to occur predominantly with cis stereochemistry. We have observed that the presence or absence of a carbamoyl group at C-10 of mitomycin C and in certain of its analogues does not have a significant influence on the stereochemistry of the opening of this ring. The trans product obtained from mitomycin C was shown to be stable when treated with acid under the conditions of its formation. Mitomycin B was also shown to yield predominantly the cis product when it was subjected to acid-catalyzed opening of its aziridine ring. The 1H NMR spectra of acetate derivatives prepared from mitomycin B show two sets of signals that are due to two populations of rotamers. The analysis of these spectra has substantiated several previous spectral assignments. This paper also presents some thoughts on acid-catalyzed bifunctional DNA alkylation by mitomycins and 10-decarbamoyloxy-9-dehydromitomycins.

Chemical Phenomena↗
PubMed2001

Ynolate chemistry. Reaction of a silylynolate with aziridines leading to gamma-lactams.

A silylynolate, generated via the carbonylation of lithium silyldiazomethane, was reacted with N-tosyl aziridines to produce various five-membered lactams in good yields. The key step of this reaction involves the ring-opening ketenylation of aziridines by the silylynolate. The reaction proceeded in a highly stereoselective manner, and ketenylation took place at the less hindered carbon. When treated with aldehydes prior to protonation, the alpha-silylated lactam enolates gave alpha-vinylidene gamma-lactams. These reactions represent a unique path to the generation of and for controlling the reactivity of a rare class of reactive intermediates, namely, acyllithium derivatives and ynolates.

Journal Article↗
PubMed2001

Aziridine ring-opening reactions with chiral enolates. Stereocontrolled synthesis of 5-substituted-3-methyl-pyrrolidin-2-ones.

A procedure for performing stereocontrolled aziridine ring-opening reactions with chiral enolates derived from (S,S)-(+)-pseudoephedrine amides has been developed leading to gamma-aminoamides in good yields. The diastereoselectivity of the reaction becomes controlled by the presence of the chiral auxiliary on the enolate, although the stereogenic center contained in the structure of the aziridine has a striking influence on the stereochemical course of the reaction which results in the presence of the corresponding matched and mismatched combinations. Besides, the sense of the asymmetric induction of the chiral auxiliary has resulted to be the opposite to the one found with other type of electrophiles, although it is in good agreement with the trend observed in the reaction of the same kind of enolates with epoxides. Finally, the obtained gamma-aminoamide adducts were converted into enantiopure gamma-amino acids, gamma-aminoesters, and pyrrolidin-2-ones using easy to perform and high yielding reactions.

Journal Article↗
PubMed2003

N-arylation of aziridines.

A range of N-arylaziridines were prepared by the palladium or copper catalyzed amination reaction between N-H aziridines and aryl bromides or arylboronic acids. These results showcase the synthetic utility of metal-bound aziridine species in nitrogen transfer processes.

Journal Article↗