SEARCH · PubMed Health

Results for “Aziridines”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1988

Studies on aziridine derivatives. III. Synthesis and immunopharmacological activity of aziridine derivatives of propionic acid.

Several new aziridine derivatives of propionic acid were synthesized (10-15, 19, 20). o-, m-, p-Chloroanilide of chloroacetic acid 1-3 and chloride of 3-/p-chlorobenzoyl/acrylic acid 16 were the substrates. The compounds 1-3 in reaction with nicotine aldehyde or p-chlorobenzaldehyde were transformed into appropriate anilides of 2,3-epoxypropionic acid 4-9. These, in turn reacted with ethylenimine giving the appropriate 3-aziridine derivatives 10-15. Acid chloride 16 in reaction with amines gave the appropriate amides 17 and 18 which formed 2-aziridine derivatives 19 and 20 when under the influence of ethylenimine. Pharmacological analysis revealed that the aziridine derivatives 12-15, 19 and 20 modulate some immunological reactions with the prevailing effect of the suppressive component (PFC, RFC, IgM level, cellular response to SRBC). The stimulatory effect was observed with some compounds on the level of circulating IgG and GvH reaction. The mechanism of these compounds consists in their interference with the activity of Ts cells and mediators of the immunological reactions.

Animals↗

PubMed1989

Identification of cysteine 530 as the covalent attachment site of an affinity-labeling estrogen (ketononestrol aziridine) and antiestrogen (tamoxifen aziridine) in the human estrogen receptor.

Radiosequence analysis of peptide fragments of the estrogen receptor (ER) from MCF-7 human breast cancer cells has been used to identify cysteine 530 as the site of covalent attachment of an estrogenic affinity label, ketononestrol aziridine (KNA), and an antiestrogenic affinity label, tamoxifen aziridine (TAZ). ER from MCF-7 cells was covalently labeled with [3H]TAZ or [3H]KNA and purified to greater than 95% homogeneity by immunoadsorbent chromatography. Limit digest peptide fragments, generated by prolonged exposure of the labeled receptor to trypsin, cyanogen bromide, or Staphylococcus aureus V8 protease, were purified to homogeneity by high performance liquid chromatography (HPLC), and the position of the labeled residue was determined by sequential Edman degradation. With both aziridines, the labeled residue was at position 1 in the tryptic peptide, position 2 in the cyanogen bromide peptide, and position 7 in the V8 protease peptide. This localizes the site of labeling to a single cysteine at position 530 in the receptor sequence. The identity of cysteine as the site of labeling was confirmed by HPLC comparison of the TAZ-labeled amino acid (as the phenylthiohydantoin and phenylthiocarbamyl derivatives) and the KNA-labeled amino acid (as the phenylthiocarbamyl derivative) with authentic standards prepared by total synthesis. Cysteine 530 is located in the hormone binding domain of the receptor, near its carboxyl terminus. This location is consistent with earlier studies using sodium dodecyl sulfate-polyacrylamide gel electrophoresis to analyze the size of the proteolytic fragments containing the covalent labeling sites for TAZ and KNA and the antigen recognition sites for monoclonal antibodies. The fact that both the estrogenic and antiestrogenic affinity labeling agents react covalently with the same cysteine indicates that differences in receptor-agonist and receptor-antagonist complexes do not result in differential covalent labeling of amino acid residues in the hormone binding domain.

Affinity Labels↗

PubMed1988

A new cytotoxic, DNA interstrand crosslinking agent, 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide, is formed from 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by a nitroreductase enzyme in Walker carcinoma cells.

Walker tumour cells in vivo or in vitro are exceptionally sensitive to the monofunctional alkylating agent 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) (Cobb LM et al., Biochem Pharmacol 18: 1519-1527, 1969). CB 1954 forms DNA interstrand crosslinks in a time-dependent manner in Walker tumour cells but not in non-toxically affected Chinese hamster V79 cells [(Roberts JJ et al., Biochem Biophys Res Commun 140: 1073-1078, 1986)]. However, co-culturing Chinese hamster V79 cells with Walker cells in the presence of CB 1954 renders the hamster cells sensitive to CB 1954 and leads to the formation of interstrand crosslinks in their DNA, findings indicative of the formation by Walker cells of a diffusible toxic metabolite of CB 1954. A flavoprotein, of molecular weight 33.5 kDa as estimated by SDS-polyacrylamide gel electrophoresis, has been isolated from Walker cells and identified as a form of NAD(P)H dehydrogenase (quinone) (DT diaphorase, EC 1.6.99.2). This enzyme, in the presence of NADH or NADPH, catalyses the aerobic reduction of CB 1954 to 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide. This new compound can form interstrand crosslinks in the DNA of Chinese hamster V79 cells to which it is also highly toxic.

Animals↗

PubMed1988

The nitroreductase enzyme in Walker cells that activates 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) to 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide is a form of NAD(P)H dehydrogenase (quinone) (EC 1.6.99.2).

A nitroreductase enzyme has been isolated from Walker 256 rat carcinoma cells which can convert 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) to a cytotoxic DNA interstrand crosslinking agent by reduction of its 4-nitro group to the corresponding hydroxylamino species (Roberts JJ et al., Biochem Biophys Res Commun 140: 1073-1078, 1986; Knox RJ et al., Biochem Pharmacol 37: 4661-4669, 1988). The enzyme has now been identified as a form of NAD(P)H dehydrogenase (quinone) (DT diaphorase, menadione reductase (NMOR), phylloquinone reductase, quinone reductase, EC 1.6.99.2) by comparison of partial protein sequences, coenzymes, substrate and inhibitor specificities, and spectroscopic data. 2-Phenyl-5(4)-aminoimidazole-4(5)-carboxamide and 5(4)-aminoimidazole-4(5)-carboxamide were shown to be inhibitors of the isolated Walker cell enzyme. This observation could explain the reported antagonistic action of the aminoimidazole carboxamides to the antitumour effects of CB 1954.

Amino Acid Sequence↗

PubMed2026

Unveiling Aziridine-Containing Natural Products by Genomic and Spectroscopic Approaches.

Aziridine-containing natural products are prized for their potent bioactivities, yet their scarcity and poorly understood biosynthesis have limited systematic exploration. Here, we address this by integrating genome mining with a 1H-13C coupled HSQC metabolomic approach that exploits the distinctive NMR signatures of aziridines, enabling their direct detection from complex extracts. This strategy unveiled the desertolides, the first macrolides incorporating a rare terminal 2-methyl-aziridine-2-carboxylate moiety. Genetic and isotopic studies identified a dedicated biosynthetic subcluster (desA-desN) that assembles and installs this unit from glutamate, and heterologous expression confirmed the self-sufficiency of this subcluster. Direct MS evidence reveals the aziridine moiety covalently bound to the active-site Cys113 of DesN, establishing this KAS III homolog as the first dedicated aziridine-transferase and a promising tool for polyketide engineering. Bioinformatic analysis uncovered over 50 biosynthetic gene clusters, suggesting that this aziridine-associated biosynthetic logic may be more widespread than currently appreciated. This work establishes a tractable platform for the targeted discovery and engineered biosynthesis of aziridine-containing natural products, opening this underexplored pharmacophore to systematic interrogation.

Aziridines↗

PubMedDate not supplied

Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N''-triethylenethiophosphoramide.

A reaction pathway by which thiotepa (N,N',N''-triethylenethiophosphoramide) and tepa (N,N',N''-triethylenethiophosphoramide), its major metabolite in humans, alkylate and depurinate DNA involves hydrolysis to aziridine (ethylene imine), a highly reactive monofunctional alkylating agent. Hydrolytic cleavage of an N-P bond of thiotepa releases aziridine which reacts with DNA, resulting in depurination and formation of the stable N-7 adduct 7-(2-aminoethyl)guanine and an aminoethyl adduct of adenine. Chromatographically identical alkylated products were observed in the reaction of thiotepa and tepa with individual nucleosides. Adducts with deoxycytidine or thymidine were not detected. Aziridine was measured by HPLC after derivatization with 1,2-naphthoquinone 4-sulfate. On the basis of the identity of the DNA adducts and the rate of formation of aziridine by hydrolysis in vitro, thiotepa is concluded to be a lipophilic, stabilized form of aziridine which serves as a cell-penetrating carrier of aziridine.

Alkylating Agents↗

PubMed1985

Dermatitis from aziridine hardener in printing ink.

13 of 51 workers developed dermatitis of the hands and face after handling a water-based ink containing a polyfunctional aziridine hardening agent. Improper work practices resulted in skin contamination with the ink and its ingredients. The aziridine hardener contained trimethylolpropane triacrylate (TMPTA). The incidence of dermatitis was highest among the ink mixers who handled the undiluted aziridine (6 of 8 workers affected), was lower among printers who handled ink containing 2 to 4% aziridine (7 of 22 workers affected), and was absent in workers who did not handle ink. The mean latency from first contact with the ink to the development of the rash was 3.2 months among the ink mixers, and 6.2 months among the printers. The present findings demonstrate the risk of handling aziridine hardeners when protective clothing is not properly used and when work practices result in direct skin contact. Further research should be performed to discern whether aziridine compounds themselves, free of TMPTA, can cause dermatitis.

Acrylates↗

PubMed1988

Comparative DNA damage induced by nitroimidazole-aziridine drugs: 1. Effects of methyl substitution on drug action.

RSU-1069 (1-(-3-aziridinyl-2-hydroxypropyl)-2-nitroimidazole) is a bifunctional chemo- and radiosensitizing agent. The properties of these functional groups may be examined by comparison of drug-induced DNA damage oxically, a measure of aziridine-induced damage and, during anoxic electrochemical reduction of the nitro-group, a measure of DNA damage resulting from the combined activity of reduced nitro group intermediates and alkylation by the aziridine moiety. In this study, a series of nitroimidazole aziridines have been studied and compared. The compounds used were RSU-1069, five methyl substituted derivatives: RSU-1131, RSU-1150, RSU-1164, RSU-1172, RB-7040; a 4-nitroimidazole derivative, RSU-1170, and RSU-1137, the non-alkylating hydrolysis product of RSU-1069. DNA damage, occurring oxically or as a consequence of nitro reduction, decreases with increasing substitution of the aziridine ring. Most DNA damage occurring oxically is produced by RSU-1069 and RSU-1170, both compounds having unsubstituted aziridine rings; least DNA damage is produced by RSU-1137. In general, the extent of DNA damage during electrochemical reduction is greater than that occurring oxically, this being due to an assumed combination of alkylation and reduced nitro-group intermediates. There is a direct correlation between the half-lives of the compounds and the extent of DNA damage occurring under oxic conditions. A direct correlation of the aerobic toxicities of the compounds tested, relative to RSU-1069, and the number of unsubstituted sites available for nucleophilic attack on the aziridine moiety has also been shown.

Coliphages↗

PubMed1977

The interaction of 1-(2(diarylmethoxy)ethyl)aziridines with histamine receptors in the longitudinal muscle strip of the guinea pig ileum.

The time course of the onset and decline of histamine antagonism by 1-(2-(diarylmethoxy)ethyl)aziridines, compounds which could be expected to have H1-receptor alkylating properties, was investigated on the longitudinal muscle strip of the guinea pig ileum. Experiments were performed with normal preparations and with muscle strips pretreated with a prostaglandin synthesis inhibitor in order to prevent spontaneous rise of muscle tone. In contrast to the previously reported observation that antihistaminic potency decreased with prolongation of the preincubation time, histamine antagonism by the aziridine compounds remained at a constant level for more than 60 min in the presence of indomethacin. This indicated that the aziridines are not hydrolyzed either directly in solution or after interaction with the tissue since the supposed hydrolysis product had a significantly lower antihistaminic activity. A comparison between 1-(2-diphenylmethoxy)ethyl)aziridine and diphenhydramine showed the former compound to have a slightly more rapid onset and a considerably more rapid decline of histamine receptor blockade. It was concluded that 1-(2-(diarylmethoxy)ethyl)aziridines did not alkylate the histamine H1-receptor in the longitudinal muscle layer of the guinea pig ileum.

Animals↗

PubMed1987

Estrogenic affinity labels: synthesis, irreversible receptor binding, and bioactivity of aziridine-substituted hexestrol derivatives.

To develop an affinity label for the estrogen receptor that would be an estrogen agonist, rather than antagonist, we prepared several aziridine derivatives of the potent nonsteroidal estrogen hexestrol [3R,4S)-3,4-bis(4-hydroxyphenyl)hexane) bearing an aziridine function on the side chain. Three functional groups link the hexestrol ligand and the aziridine: a carbonyl group (ketone or ester), a thioether, or a methylene chain. The apparent competitive binding affinity of these derivatives for the estrogen receptor ranges from 1.8% to 25% that of estradiol, and most of them bind in a time-dependent, irreversible manner with the receptor, although the rate and efficiency of this binding vary widely, often with relatively small changes in structure. This is consistent with the irreversible attachment requiring a precise alignment of activating and reacting residues in the binding site of the receptor. The estrogenic and antiestrogenic activity of these aziridine derivatives was investigated in MCF-7 human breast cancer cells. Most of the compounds are agonists, with one being an antagonist. The derivative (6R,7S)-1-N-aziridinyl-6,7-bis(4-hydroxyphenyl)-5-nonanone (keto-nonestrol aziridine 3) appears to have the most ideal behavior of the estrogenic affinity labeling agents prepared: It is an agonist, and it binds to receptor irreversibly, efficiently, and quite rapidly.

Affinity Labels↗

PubMed1977

Alkylating esters. X. The reaction of some aziridine alkylating agents with methionine and S-methyl cysteine.

Two biologically active aziridine ring-containing compounds, N,N-ethylene urethane (I) and N,N-ethylene urea (II), have been shown to react with methionine in dilute phosphate buffer (pH 7.4) at 37 degree C. Degradative procedures indicate that the aziridine ring effectively alylates the thio ether group of methionine and other thio ether-containing amino acids to produce sulphonium salts (V). By using [35S]methionine, the sulphonium salts have been shown to be quite stable under physiological conditions (t1/2 7--9 days) hydrolysing to convert the methionine residue to homoserine. It is proposed that similar alkylations of methionyl residues in vivo by aziridine-alkylating agents may explain the complex, and al yet unknwn, metabolic fate of the aziridine ring and could also be a factor contributing to the diverse effects that these agents have on living cells.

Alkylating Agents↗

PubMed1985

Induction of DNA strand breaks by RSU-1069, a nitroimidazole-aziridine radiosensitizer. Role of binding of both unreduced and radiation-reduced forms to DNA, in vitro.

[2-14C]-RSU-1069 [1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol], either as a parent (unreduced) or following radiation reduction, binds to calf thymus DNA in vitro. Radiation-reduced RSU-1069 binds to a greater extent and more rapidly than the parent compound. RSU-1137, a nonaziridino analogue of RSU-1069, binds following radiation reduction. Radiation-reduced misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol) exhibits binding ratios a thousand-fold less than those of reduced RSU-1069. There is no evidence for binding of parent misonidazole. Both parent and reduced RSU-1069 cause single strand breaks (ssbs) in pSV2 gpt plasmid DNA with the reduced compound causing a greater number of breaks. Parent and reduced RSU-1137 and misonidazole do not cause ssbs. It is inferred that the aziridine moiety present in both parent and reduced RSU-1069 is required for ssb production. RSU-1069 reacts with inorganic phosphate probably via nucleophilic ring-opening of the aziridine fragment. Incubation of plasmid DNA with reduced RSU-1069 in the presence of either phosphate or deoxyribose-5-phosphate at concentrations greater than 0.35 mol dm-3 prevents strand breakage, whereas 1.2 mol dm-3 deoxyribose does not protect against strand breakage formation. From these findings it is proposed that the observed binding to DNA occurs via the aziridine and the reduced nitro group of RSU-1069 and that these two have different target sites. Binding to DNA via the reduced nitro group may serve to increase aziridine attack due to localization at or near its target.

Acetates↗

PubMed1987

Synthesis and biological properties of actinomycin D chromophoric analogues substituted at the 7-carbon with aziridine and aminopropoxy functions.

The growing importance of functionalized aziridines in numerous organic biomolecules led us to develop syntheses of novel actinomycin D (AMD) analogues substituted with an aziridine. Reaction of 7-hydroxyactinomycin D with 2-(iodomethyl)aziridine produced the desired 7-(2-aziridinylmethoxy)actinomycin analogue. In an attempt to develop an alternate route to this analogue, 7-(2-azido-3-iodopropoxy)actinomycin was subjected to reduction with dimethylamine-borane complex; the reaction did not produce the three-membered aziridine; instead the reaction product was found to be linear 7-(2-aminopropoxy)actinomycin D. Calf-thymus-DNA binding of these analogues was comparable to that of AMD as examined by UV-visible difference spectral measurements, thermal denaturation of DNA, and CD techniques. The analogues were found to be about 1/4 to 1/30 as cytotoxic to human lymphoblastic CCRF-CEM leukemia and B16 melanoma cells in vitro as AMD.

Cell Line↗

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↗

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↗

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↗

PubMed1986

Interaction of the aziridine moiety of RSU-1069 with nucleotides and inorganic phosphate. Implications for alkylation of DNA.

The aziridine moiety of RSU-1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridino-2-propanol] alkylates inorganic phosphate and a range of nucleotides in aqueous solutions of pH 7.0. From the rate constants obtained and a study of the adducts formed it is demonstrated that phosphate is a major target on nucleotides at neutral pH, although additional sites may exist particularly on dGMP and dAMP. From the dependence of reactivity on pH and the influence of ionic strength, it is established that the protonated aziridine is the reactive species and that hydrolysis is insignificant when compared to the rate of phosphorylation. The reaction kinetics detailed in this study are discussed in terms of DNA alkylation and strand breakage effected by the aziridine moiety of RSU-1069.

Adamantane↗