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PubMed2006

Direct synthesis of chiral aziridines from N-tert-butyl-sulfinylketimines.

The direct preparation of a range of variously substituted chiral tert-butylsulfinylketimines was achieved in good yield (41-90%), with relatively rapid reaction times (4-15 hours); their synthetic application was examined through the reaction with the ylides derived from trimethylsulfonium iodide and S-allyl tetrahydrothiophenium bromide, affording convenient access to a diverse range of highly substituted chiral aziridines in up to 78% yield and > 90% d.e.

Aziridines↗
PubMed2003

[Occupational aziridine asthma in an engineer at a printing office].

We report on a case of an allergic bronchial asthma of an engineer in a printing office caused by polyfunctional aziridines. The causal relationship between exposure and symptoms could be demonstrated with a specific bronchoprovocation challenge testing. The consequences of the disease are discussed with respect to medical and legal aspects of the system of social security in Germany.

Adult↗
PubMed2002

A new class of acyclic nucleoside phosphonates: synthesis and biological activity of 9-[[(phosphonomethyl)aziridin-1-yl]methyl]guanine (PMAMG) and analogues.

A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and 4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl [[2-(bromomethyl)aziridin-1-yl]]methylphosphonate (9), followed by deesterification reaction in the presence of TMSBr. In similar way, PMAMA, PMAMC, and PMAMT were prepared.

Alkylation↗
PubMed1978

Drug-induced adrenaline release and blood glucose in rats: DL-1-methyl-2-(beta-naphthyl)-aziridine.

Effects of 1-methyl-2-(beta-naphthyl)-aziridine (250059-S), which possesses characteristic tranquilizing actions on levels of blood glucose and liver glygogen, and on adrenaline release from the adrenal gland were studied in rats. While there was no elevation of blood glucose, a decrease of liver glycogen was detected after an s.c. injection of 250059-S (5 or 25 mg/kg). Marked decrease of adrenaline content in adrenal glands was observed 2 hours after subcutaneous administration of 50 mg/kg of this compound. This result is consistent with the marked adrenaline secretion from the adrenal gland into adrenal-venous blood after injection of 25 mg/kg or more of 250059-S. In splanchnicotomized rats, however, 250059-S-induced adrenaline release was not clearly observed. Pretreatment with 250059-S, prevented adrenaline-induced hyperglycemia. 250059-S, at doses of 10 and 25 mg/kg, elevated the plasma insulin level to about twice that of the control. The 250059-S-induced depletion of liver glycogen was not completely blocked by adrenal demedullation, although it completely disappeared with pretreatment with 10 mg/kg of propranolol. In conclusion, 250059-S causes hypersecretion of adrenaline from the adrenal glands through excitation of the splanchnic nerves, though it causes no elevation of blood glucose, mainly because of its direct or indirect blocking action on adrenaline hyperglycemia.

Adrenal Glands↗
PubMed1999

Occupational asthma and contact dermatitis in a spray painter after introduction of an aziridine cross-linker.

A 23-year-old spray painter developed contact dermatitis and respiratory difficulty characterized by small airways obstruction shortly after the polyfunctional aziridine cross-linker CX-100 began to be used in his workplace as a paint activator. The symptoms resolved after he was removed from the workplace and was treated with inhaled and topical steroids. Painters may have an increased risk of asthma due to exposure to a variety of agents, such as isocyanates, alkyd resins, and chromates. This case illustrates the importance of using appropriate work practices and personal protective equipment to minimize exposure. Occupational asthma is diagnosed by a history of work-related symptoms and exposure to known causative agents. The diagnosis is confirmed by serial pulmonary function testing or inhalational challenge testing. The risk of asthma attributable to occupational exposures is probably underappreciated due to underreporting and to inappropriate use of narrow definitions of exposure in epidemiologic studies of attributable risk.

Adult↗
PubMed2004

Synthesis and antiplasmodial activity of a cysteine protease-inhibiting biotinylated aziridine-2,3-dicarboxylate.

Cysteine proteases have been implicated in a variety of processes essential for the survival and progression of the malarial parasite Plasmodium falciparum. Here, we synthesized a cysteine protease inhibitor that contains the electrophilic aziridine-2,3-dicarboxylic acid as the reactive agent and biotin as a targeting label. Diethyl ester and dibenzyl ester derivatives of the inhibitor were active against cathepsin L and the plasmodial protease falcipain 2, but only the latter displayed potent antiplasmodial activity against viable parasites. The morphological changes observed during the intraerythrocytic life stages of Plasmodium suggest that degradation of hemoglobin of the host cell is seriously affected, eventually leading to growth arrest and cell death of the parasites. After incubation of infected erythrocytes with the compound plasmodial proteins were captured, with the biotinyl group of the inhibitor serving as an affinity tag. Among these the cysteine proteases falcipain 2 and falcipain 3 were identified as potential target proteins of the compound as evidenced by tandem mass spectrometry. Apparently, the compound gets access to intracellular compartments and therein targets plasmodial cysteine proteases. Accordingly, the reagent described here appears to be a valuable template to develop cell-permeable, non-radioactive reagents that selectively target enzymes involved in pathogenicity of the parasite.

Animals↗
PubMed1989

Molecular orbital calculations on tumour-inhibitory phenyl aziridines: QSARs.

1. Molecular orbital calculations, by the MINDO/3 method, on tumour-inhibitory phenyl aziridines are reported. 2. The generation of quantitative structure-activity relationships (QSARs) shows that biological activity, chemical reactivity and hydrophobicity can be explained in terms of theoretically-derived electronic structural parameters.

Antineoplastic Agents↗
PubMed2000

Bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) by human NAD(P)H quinone oxidoreductase 2: a novel co-substrate-mediated antitumor prodrug therapy.

A novel prodrug activation system, endogenous in human tumor cells, is described. A latent enzyme-prodrug system is switched on by a simple synthetic, small molecule co-substrate. This ternary system is inactive if any one of the components is absent. CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] is an antitumor prodrug that is activated in certain rat tumors via its 4-hydroxylamine derivative to a potent bifunctional alkylating agent. However, human tumor cells are resistant to CB 1954 because they are unable to catalyze this bioactivation efficiently. A human enzyme has been discovered that can activate CB 1954, and it has been shown to be commonly present in human tumor cells. The enzyme is NQO2 [NAD(P)H quinone oxidoreductase 2], but its activity is normally latent, and a nonbiogenic co-substrate such as NRH [nicotinamide riboside (reduced)] is required for enzymatic activity. There is a very large (100-3000-fold) increase in CB 1954 cytotoxicity toward either NQO2-transfected rodent or nontransfected human tumor cell lines in the presence of NRH. Other reduced pyridinium compounds can also act as co-substrates for NQO2. Thus, the simplest quaternary salt of nicotinamide, 1-methyl-3-carboxamidopyridinium iodide, was a co-substrate for NQO2 when reduced to the corresponding 1,4-dihydropyridine derivative. Increased chain length and/or alkyl load at the 1-position of the dihydropyridine ring improved specific activity, and compounds more active than NRH were found. However, little activity was seen with either the 1-benzyl or 1-(2-phenylethyl) derivatives. A negatively charged substituent at the 3-position of the reduced pyridine ring also negated the ability of these compounds to act as cosubstrates for NQO2. In particular, 1-carbamoylmethyl-3-carbamoyl-1,4dihydropyridine was shown to be a co-substrate for NQO2 with greater stability than NRH, with the ability to enter cells and potentiate the cytotoxicity of CB 1954. Furthermore, this agent is synthetically accessible and suitable for further pharmaceutical development. NQO2 activity appears to be related to expression of NQO1 (DT-diaphorase), an enzyme that is known to have a favorable distribution toward certain human cancers. NQO2 is a novel target for prodrug therapy and has a unique activation mechanism that relies on a synthetic co-substrate to activate an apparently latent enzyme. Our findings may reopen the use of CB 1954 for the direct therapy of human malignant disease.

Animals↗
PubMedDate not supplied

[Skin and respiratory allergic disease caused by polyfunctional aziridine].

BACKGROUND: Polyfunctional aziridine (PFA) hardener is increasingly used in water-based paints and inks as a replacement for organic solvents. Allergic contact dermatitis, contact urticaria, respiratory allergy in occupationally exposed patients with hypersensitivity to PFA are reported. OBJECTIVES: The aim was to study a population of adhesive tape printers for occupational respiratory and skin sensitisation to PFA hardener. Also 2 cases of occupational asthma in workers exposed to PFA in tanneries are reported. METHODS: A standard series prick and patch tests was carried out on 15 workers with skin symptoms out of 36 adhesive tape printers exposed to PFA. Prick tests with a 1% PFA water solution and patch tests with a dilution series (0.1-0.32-0.5-1%) of PFA in petrolatum were performed. Lung and nasal provocation tests with PFA hardener were also carried out on 4 subjects with skin and respiratory symptoms. RESULTS: Skin sensitivity to PFA prick tests was demonstrated in 8.3% of the exposed population; 22.2% of the exposed workers suffered from allergic contact dermatitis due to PFA with positive patch tests for this compound. One case of occupational rhinitis due to PFA was diagnosed. CONCLUSIONS: PFA is a strong sensitizer and the use of gloves and protective clothing appears to be insufficient to prevent occupational allergic diseases. Elimination of PFA from production processes is desirable.

Adult↗
PubMed1989

Effects of mescaline and its derivative N-[3,4,5-trimethoxyphenylethyl]-aziridine on the spatial orientation of rats in a T-maze.

The central effect of mescaline and of its derivative N-[3,4,5- trimethoxyphenylethyl]-aziridine (FAZ) after their stereotaxic administration into the lateral ventricle of the brain was studied in behavioural experiments on rats. The effect of the two substances was tested by a method studying memory elicitation in response to appetitive motivation in a multiple T-maze. The results show that both substances worsened the behaviour in question. The negative effect of mescaline (lengthening of the time of passage through the maze) was manifested both immediately and several weeks after a single dose. FAZ likewise worsened the test reaction, but its effect was less pronounced than that of mescaline.

Animals↗
PubMed1990

[Chemistry of alpha-aminonitriles. Aziridine-2-carbonitrile: photochemical formation from 2-aminopropenenitrile].

2-Aminopropenenitrile in solvents such as MeCN, MeOH, or H2O is photoisomerized by UV light to racemic aziridine-2-carbonitrile (rac-2); the larger part of the starting material, however, fragments to HCN and MeCN. The observed photocyclization constitutes a structural connection within an ensemble of C3H4N2 compounds considered to be potentially relevant to prebiotic chemistry.

Acetonitriles↗
PubMed1996

Tamoxifen aziridine labeling of the estrogen receptor-potential utility in detecting biologically aggressive breast tumors.

Expression of estrogen receptor (ER) is a helpful predictor of response to endocrine therapy and disease free survival in breast cancer patients. The presence of variant estrogen receptors has been demonstrated at the RNA/DNA level and might represent an escape of tumors from hormonal control mechanisms. However, the demonstration that the corresponding peptides do exist is a real challenge. Denaturing polyacrylamide gel electrophoresis (SDS-PAGE) of covalently bound [3H]tamoxifen aziridine ([3H]TAZ) to ER demonstrates a specific, multiband peptide pattern recognized by anti-ER monoclonal antibodies (anti-ER Mo Abs). The native 66 kDa ER form identified through its hormone binding domain by the H-222 Mo Ab was the most prominent one followed by 50, 35, and 28 kDa forms on fluorography. Such patterns from early human breast tumors were compared to the ones of more advanced disease, namely large primary breast cancers, metastatic lymph nodes, and soft tissue relapses: in these cases, molecular forms of 43 and 35 kDa were identified with a remarkable consistency. The 43 kDa peptide was more frequently identified by the H-226 Mo Ab (which maps a region near the DNA binding domain)-albeit with low labeling intensity as compared to H-222 Mo Ab. In addition, the 43 kDa peptide was inversely correlated to ER levels. This altered ER or related peptide could potentially be a marker of biologically aggressive breast tumors.

Antibodies, Monoclonal↗
PubMed1987

Induction of DNA crosslinks in vitro upon reduction of the nitroimidazole-aziridines RSU-1069 and RSU-1131.

The interaction of the nitroimidazole-aziridines RSU-1069 and RSU-1131, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH 7 results in strand breakage. The yields of DNA single strand breaks (ssb), "alkali-labile" damage and DNA crosslinks induced by these alkylating agents have been assessed. It is shown that DNA crosslinks are induced only by the reduced nitro-compounds. RSU-1069, as parent or reduced compound, is more efficient at producing these effects than the equivalent form of RSU-1131. Further, RSU-1069 is about 2 X more susceptible to nucleophilic attack by inorganic phosphate and deoxynucleotides than RSU-1131. RSU-1069 also shows greater selectivity for reaction with the nucleotide base moiety than does the less-reactive monomethyl analogue, RSU-1131. The yields of ssb and "alkali-labile" damaged sites induced by the two agents reflect their respective chemical reactivities and appear largely to determine their aerobic cytotoxicities. In contrast, the yield of DNA crosslinks induced by the reduced compounds appears to correspond rather better with the observed hypoxic cytotoxicities. From these findings it is suggested that the induction of DNA crosslinks by these agents may play a major role in their effectiveness as hypoxia-selective cytotoxins.

DNA↗
PubMed1988

Enhancement of DNA damage in mammalian cells upon bioreduction of the nitroimidazole-aziridines RSU-1069 and RSU-1131.

The induction of DNA double-(dsb) and single-(ssb) strand breaks by RSU-1069, RSU-1131 and misonidazole in V79 mammalian cells has been investigated using sedimentation in isokinetic sucrose gradients after incubation for various times (1-3 hr) at 310 K under both hypoxic and aerobic conditions. Double strand breaks are produced by RSU-1069 and RSU-1131 predominantly under hypoxic conditions. Comparison of the cellular DNA damage induced by these agents leads to the following facts: (1) the yield of ssb induced by these agents is substantially increased under hypoxia, (2) RSU-1069 and RSU-1131 are much more effective than misonidazole, on a concentration basis, at causing strand breakage both under hypoxic and aerobic conditions; and (3) RSU-1069 is more efficient on a concentration basis than RSU-1131 at inducing both ssb and dsb under both conditions. From these findings and molecular studies it is suggested that these 2-nitroimidazole aziridines act as monofunctional alkylating agents under aerobic conditions, a factor that governs their aerobic cytotoxicity. Under hypoxic conditions, it is suggested that the induction of dsb and crosslinks by these agents (bifunctional character) may play a major role in determining the ability of such agents to act as hypoxia-selective cytotoxins.

Antineoplastic Agents↗
PubMed1986

The phosphate-group of DNA as a potential target for RSU-1069, a nitroimidazole-aziridine radiosensitizer.

Strand breakage of plasmid DNA by parent and radiation-reduced RSU-1069 (2.0-8.0 mmol dm-3) has been measured in air over 4 hr at 310K. Reduced RSU-1069 was shown to be approximately 4 times as efficient as the parent compound at causing strand breakage. The aziridine moiety of both parent and reduced RSU-1069 is required for strand break production and, furthermore, is capable of alkylating inorganic phosphate (k = 1.0 X 10(-3) dm3 mol-1 s-1) and a series of nucleotides (k = 0.8 - 2.1 X 10(-3) dm3 mol-1 s-1) at pH 7.0. From the determined rate constants and the nature of the adducts observed, it was shown that phosphate is a target on nucleotides, although additional sites probably exist particularly, on dGMP and dAMP. The mechanism of action of RSU-1069 is discussed in terms of its ability to act as a cytotoxic agent, radiosensitizer and bioreductive drug.

DNA, Bacterial↗
PubMed1989

Assessment of the repair and damage of DNA induced by parent and reduced RSU-1069, a 2-nitroimidazole-aziridine.

The cellular repair and damage of DNA induced by parent and reduced RSU-1069, a 2-nitroimidazole-aziridine, was assessed at both the molecular and cellular level. At the molecular level, after in vitro incubation with parent or reduced RSU-1069, plasmid DNA was transfected into Escherichia coli (AB1157) with subsequent selection for gene expression. For equivalent levels of DNA strand breakage following such treatment it is evident from the relative transformation frequencies that interactions with reduced RSU-1069 lead to DNA damage consistent with bifunctional action of a metabolite(s). At the cellular level, the cytoxicity of RSU-1069 was determined for a series of repair deficient mutants of E. coli under both aerobic and hypoxic conditions. The differential aerobic:hypoxic cytotoxicity ratio is approximately 3. We conclude that the repair of cellular DNA damage induced by RSU-1069 involves activation of the gene products under the control of the recA gene and not those under the control of the ada gene. The ability of cellular systems to repair damage induced by RSU-1069 may play a significant role in determining its efficiency to act as a hypoxic cell radiosensitizer and a hypoxia selective cytotoxin.

Aerobiosis↗
PubMed1991

Localization of the estrogen receptor in uterine cells by affinity labeling with [3H]tamoxifen aziridine.

The possibility that estrogen receptors may exist in uterine plasma membranes was investigated by covalent labeling of estrogen receptors in mouse uterine cells with [3H]tamoxifen aziridine (TA). Isolated epithelial and stromal cells of immature mice were incubated with [3H]TA in the presence or absence of unlabeled tamoxifen, homogenized and separated into nuclear, cytosolic and microsomal fractions by differential centrifugation. These fractions were subjected to SDS-polyacrylamide gel electrophoresis and the proteins labeled covalently with TA were visualized by autoradiography. Proteins labeled specifically with [3H]TA were observed almost exclusively in the nuclear fraction of both epithelial and stromal cells. In contrast, very little labeled protein was detected in the cytosolic or microsomal fraction. Although these data do not preclude the possibility that estrogen binding sites are present in plasma membranes of uterine cells, this cellular fraction is definitely not labeled to a significant extent by [3H]TA. Thus, if membrane estrogen binding sites exist, their structural conformations may be different from that of nuclear estrogen receptors.

Affinity Labels↗