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PubMed2004

Efficient synthesis of azide-bearing cofactor mimics.

8-Azido-5'-aziridino-5'-deoxyadenosine (6), a novel cofactor mimic, was synthesized in nine steps from commercially available 2',3'-isopropylideneadenosine in approximately 4% overall yield. Crucial to this success was a very unorthodox phthalimide cleavage procedure, C8 azidation prior to aziridination and late stage alkylation of the 5' amino group with iodoethanol necessitated by the high degree of lability endowed by the aryl azide moiety. Aziridine 6 is envisioned as a useful biochemical tool by which to probe DNA and protein methylation patterns.

Adenosine↗
PubMed2005

Theoretical studies about the influence of different ring substituents on the nucleophilic ring opening of three-membered heterocycles and possible implications for the mechanisms of cysteine protease inhibitors.

Epoxides, aziridines, and thiiranes are electrophilic building blocks that are widely used in synthetic organic chemistry. As a result of their reactivity against nucleophiles they are also used as electrophilic "warheads" for irreversible peptidic or peptidomimetic cysteine protease inhibitors. A general feature of these inhibitors is the remarkable higher inhibition potency of derivatives containing a free carboxylic acid in comparison to corresponding esters. In contrast, experimental investigations about the reaction of methyl thiolate with substituted epoxides revealed a contrary reactivity pattern. These studies also gave information about the regioselectivity of such reactions; however, mechanistic studies were not performed. By analyzing the computed energy profiles of the corresponding reactions we investigate the substituent effects (H vs ester vs carboxylic acid) on the kinetics and thermodynamics of the ring opening by the nucleophile methyl thiolate. Our model computations nicely explain experimental results concerning variations in the reactivities and the regioselectivities and indicate different reasons for the increased inhibition potency of three-membered heterocycles containing an acidic substituent. For aziridines an intramolecular water-mediated acid catalysis seems to be the main reason for the high activity of these inhibitors in acidic media. For epoxides and thiiranes this catalysis is not found, confirming the hypothesis that an ionic interaction between negatively charged carboxylate and the histidinium ion of the active site of the proteases mainly causes the high inhibitory activity of the acids compared to the esters.

Aziridines↗
PubMed2006

Novel synthesis of cis-3,5-disubstituted morpholine derivatives.

1-tert-Butyl-2-(allyloxymethyl)aziridine has been transformed for the first time diastereoselectively into cis-3,5-di(bromomethyl)-4-tert-butylmorpholine via an electrophile-induced ring closure using bromine in dichloromethane. The latter morpholine has been used as a substrate for the synthesis of the corresponding 3,5-di(methoxymethyl)morpholine and 3,5-di(cyanomethyl)morpholine upon nucleophilic displacement of both bromo atoms. Further evaluation of this protocol toward the synthesis of 4-arylmethyl- and 4-alkylmethyl-3,5-di(bromomethyl)morpholines showed that the premised cyclization of the corresponding 2-(allyloxymethyl)aziridines into 3,5-di(bromomethyl)morpholines only proceeded well for the N-neopentylmorpholine, which was subsequently transformed into a 3-oxa-7-thia-9-azabicyclo[3.3.1]nonane derivative. Also, in some other cases, the desired 3,5-di(bromomethyl)morpholines were isolated in low yields and transformed into the corresponding 3,5-di(cyanomethyl)morpholines.

Aziridines↗
PubMed2006

Practical synthesis of trans-tert-butyl-2-aminocyclopentylcarbamate and resolution of enantiomers.

Optically active trans-tert-butyl-2-aminocyclopentylcarbamate (1) has potential utility as a scaffold for chiral ligands and as a modified backbone unit for peptide nucleic acids (PNAs). We have developed a short and practical synthesis of 1 via aziridine opening of tosyl-activated cyclopentene aziridine 2 and optical resolution of racemic 1 with 10-camphorsulfonic acid (CSA). The route provides ready access to multigram quantities of both enantiomers without the need for chromatography.

Azides↗
PubMed2000

Synthesis of cyclic sulfonamides via intramolecular copper-catalyzed reaction of unsaturated iminoiodinanes.

Olefinic primary sulfonamides were treated with iodobenzene diacetate and potassium hydroxide in methanol to give intermediate iminoiodinanes. Catalytic copper(I) or (II) triflate then provided intramolecular nitrene delivery leading to aziridine formation except in one case where a rare copper-catalyzed C-H insertion was observed. The aziridines could be opened by various nucleophiles (methanol, thiophenol, allylmagnesium bromide, benzylamine) to give the corresponding substituted cyclic sulfonamides.

Aziridines↗
PubMed2001

Stereoselective synthesis of chiral 2,3-cis-2-ethynylaziridines by base-mediated intramolecular amination of bromoallenes.

[reaction: see text] Novel stereoselective synthesis of 2,3-cis-2-ethynylaziridines from amino allenes is presented. While sodium hydride mediated intramolecular amination of (4S,aS)-4-alkyl-4-[N-(arylsulfonyl)amino]-1-bromobuta-1,2-dienes yields a mixture of 2,3-cis- and 2,3-trans-2-ethynylaziridines in which the cis-isomer predominates (79:21-89:11), the amination of (4S,aR)-isomers affords 2,3-cis-aziridines in excellent selectivities (91:9-100:0). Conversion of 2,3-trans-2-ethynylaziridines into the corresponding cis-isomers via a sequence of reactions (methanesulfonic acid mediated ring-opening reaction, bromination, and aziridination) is also described.

Alkadienes↗
PubMed2002

Diastereocontrol by a hydroxyl auxiliary in the synthesis of pyrrolidines via radical cyclization.

[reaction: see text] Organoselenium precursors of 3-aza-5-hexenyl radicals carrying a 1-hydroxyalkyl group in the 2-position were prepared by addition of organometallic reagents to N-allyl-2-aziridinecarbonitrile, reduction of the resulting aziridine ketone, and regioselective benzeneselenol ring opening of the aziridine. Reductive radical cyclization was highly selective, affording the corresponding trans-2,4-disubstituted pyrrolidine (cis/trans ca. 1/10) as the major diastereomer. Recrystallization afforded material that was substantially more enriched in the trans isomer (cis/trans < 1/25).

Aziridines↗
PubMed2006

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

[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, spring-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.

Amino Alcohols↗
PubMed2003

Bifurcated, modular syntheses of chiral annulet triazacyclononanes.

Three chiral 2,6-disubstituted tri-N-methyl azamacrocycles have been prepared by modular methods. These macrocycles were accessed from three chiral 1,4,7-triazaheptanes intermediates that were prepared by two independent routes. The first of these routes involved the benzylamine opening of chiral tosyl aziridines followed by debenzylation but was problematic on solubility grounds. A second, more effective, route was developed which avoided debenzylation by using ammonia in the nucleophilic opening of chiral tosyl aziridines.

Aza Compounds↗
PubMed2001

Viral capsid mobility: a dynamic conduit for inactivation.

Mass spectrometry and fluorescent probes have provided direct evidence that alkylating agents permeate the protein capsid of naked viruses and chemically inactivate the nucleic acid. N-acetyl-aziridine and a fluorescent alkylating agent, dansyl sulfonate aziridine, inactivated three different viruses, flock house virus, human rhinovirus-14, and foot and mouth disease virus. Mass spectral studies as well as fluorescent probes showed that alkylation of the genome was the mechanism of inactivation. Because particle integrity was not affected by selective alkylation (as shown by electron microscopy and sucrose gradient experiments), it was reasoned that the dynamic nature of the viral capsid acts as a conduit to the interior of the particle. Potential applications include fluorescent labeling for imaging viral genomes in living cells, the sterilization of blood products, vaccine development, and viral inactivation in vivo.

Animals↗
PubMed2004

The p53-dependent apoptotic pathway of breast cancer cells (BC-M1) induced by the bis-type bioreductive compound aziridinylnaphthoquinone.

INTRODUCTION: Several aziridinylbenzoquinone drugs have undergone clinical trials as potential antitumor drugs. These bioreductive compounds are designed to kill cells preferentially within the hypoxia tumor microenvironment. The bioreductive compound of bis-type naphthoquinone synthesized in our laboratory, 2-aziridin-1-yl-3-[(2-{2-[(3-aziridin-1-yl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)thio]ethoxy}ethyl)thio]naphthoquinone (AZ-1), had the most potent death effect on the breast cancer cells BC-M1 in our previous screening. In the present study, we determined that the mechanism of the death effect of BC-M1 cells induced by AZ-1 was mediated by the apoptosis pathway. METHODS: We evaluated the cytotoxicity of AZ-1 and the anti-breast cancer drugs tamoxifen and paclitaxel to BC-M1 cells and MCF-7 cells by the MTT assay and measured the apoptosis phenomena by Hoechst 33258 staining for apoptotic bodies. We also quantified the sub-G1 peak area and the ratio of the CH2/CH3 peak area of the cell membrane in BC-M1 cells by flow cytometry and 1H-NMR spectra, respectively. The apoptosis-related protein expressions, including p53, p21, the RNA-relating protein T-cell restricted intracellular antigen-related protein, cyclin-dependent kinase 2 (cell cycle regulating kinase) and pro-caspase 3, were detected by western blot, and the caspase-3 enzyme activity was also quantified by an assay kit. RESULTS: AZ-1 induced two of the breast cancer cell lines, with IC50 = 0.51 microM in BC-M1 cells and with IC50= 0.57 microM in MCF-7 cells, and showed less cytotoxicity to normal fibroblast cells (skin fibroblasts) with IC50= 5.6 microM. There was a 10-fold difference between two breast cancer cell lines and normal fibroblasts. Of the two anti-breast cancer drugs, tamoxifen showed IC50= 0.12 microM to BC-M1 cells and paclitaxel had much less sensitivity than AZ-1. The expression of p53 protein increased from 0.5 to 1.0 microM AZ-1 and decreased at 2.0 microM AZ-1. The p21 protein increased from 0.5 microM AZ-1, with the highest at 2 microM AZ-1. Regarding the AZ-1 compound-induced BC-M1 cells mediating the apoptosis pathway, the apoptotic body formation, the sub-G1 peak area, the ratio of CH2/CH3 of phospholipids in the cell membrane and the enzyme activity of caspase-3 were all in direct proportion with the dose-dependent increase of the concentration of AZ-1. The death effect-related proteins, including T-cell restricted intracellular antigen-related protein, cyclin-dependent kinase 2, and pro-caspase-3, all dose-dependently decreased with AZ-1 concentration. CONCLUSIONS: The AZ-1-induced cell death of BC-M1 cells mediating the apoptosis pathway might be associated with p53 protein expression, and AZ-1 could have the chance to be a candidate drug for anti-breast cancer following more experimental evidence, such as animal models.

Antineoplastic Agents, Hormonal↗
PubMed2005

Development of useful reactions involving tandem cyclizations based on the novel reactivities of allenic compounds.

This review highlights author's recent study on allenic compounds. In the first section, organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes including those which are not accessible by other means, are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes and tandem reaction leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes are presented. The final section presents aziridination and medium-ring formation by intramolecular reaction of bromoallenes, which are scarcely investigated until quite recently. The latter reaction is based on our recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.

Alkadienes↗
PubMed2005

Development of useful reactions based on the novel reactivities of allenic compounds and their application to tandem cyclizations.

This review highlights a recent study on allenic compounds by the author's group. In the first section, the organocopper-mediated ring-opening reaction of ethynylaziridines and palladium-catalyzed reductive synthesis of allenes are described. In the second section, palladium-catalyzed stereoselective cyclization of allenes, including the tandem reaction, leading to aziridines, pyrrolidines, benzoisoindoles, and cyclopropanes is presented. The final section reviews aziridination and medium-ring formation due to the intramolecular reaction of bromoallenes. The latter reaction is based on the author's recent discovery that bromoallenes can act as allylic dication equivalents in the presence of a palladium catalyst and alcohol.

Alkadienes↗
PubMed1994

Oligonucleotides as probes for studying polymerization reactions in dilute aqueous solution.

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.

Autoradiography↗
PubMed1990

Synthesis and possible applications of biotin-linked copper clusters.

The trifunctional aziridine XAMA-7 (CAS 57116-45-7) has been used to form crosslinks between a deep red-violet copper cluster of the type Cu(I)8Cu(II)6pen12Cl5- (pen=penicillamine) and molecules with biological activity such as d-biotin and proteins. A complex containing biotin, bovine serum albumin and the copper cluster displayed activity toward affinity columns of avidin on Agarose, and the red-violet pigment was immobilized on the gel. This interaction was completely blocked in gels which had been pretreated with d-biotin carboxylic acid. The free and biologically active versions of the cluster have some potential for biomedical applications. For example, the short-lived positron emitter 64Cu (suitable for positron tomography) may be carried in the cluster's structure. The cluster is paramagnetic, but it is a relatively weak effector of water proton spin-lattice relaxation. Other members of this structural group of inorganic compounds may have better magnetic properties, and the crosslinking reaction with aziridines appears to be generally applicable to the group.

Aziridines↗
PubMed1990

Studies with bifunctional bioreductive drugs. I. In vitro oncogenic transforming potential.

The oncogenic transforming potential of a series of bioreductive drugs including RSU-1069 and its various alkyl-substituted derivatives, RB-7040, RB-88716, RSU-1164, and RB-88712, has been compared using the C3H 10T1/2 cell system. While the aziridine moiety at the terminal end of the side chain confers greater cytotoxicity to both the 2-nitroimidazole (RSU-1069) and the 5-nitrofuran (RB-88716), it also increases the oncogenic transforming potential of the drugs correspondingly. By substituting the aziridine ring with methyl groups, the cytotoxicity and oncogenicity of these bioreductive drugs decrease in a way that is proportional to the degree of methylation. A clear structure-activity relationship can be demonstrated from these methyl-substituted derivatives such that a tetramethyl-substituent (RB-7040) is much less cytotoxic and oncogenic than a dimethyl-substituent (RSU-1164). RB-7040, which has in vitro and in vivo sensitizing efficiency comparable to the parental compound RSU-1069, is roughly tenfold less cytotoxic and, at concentrations that achieve an in vitro enhancement ratio of 2.9, induces a transforming frequency that is indistinguishable from the spontaneous rate.

Animals↗
PubMed1978

Platinum complexes as radiosensitizers of hypoxic mammalian cells.

Cis-dichlorodiammineplatinum (II), or cis-PDD, has recently been shown to be a potent radiosensitizer of bacteria, particularly under conditions of acute hypoxia. This study extends this observation to include the radiosensitization of mammalian cell (V-79) by low concentrations of cis-PDD, cis-dichlorobis(aziridine) platinum (II), and the trans-isomer of PDD as measured from survival curve analysis. This radiosensitization was obtained at concentrations of 10 micrometer, 60 micrometer, and 100 micrometer for the cis-PDD, aziridine-platinum, and trans-isomer respectively. The corresponding drug toxicity survival levels were 8, 40 and 50%. Dose modification factors of around 1.3 to 1.4 were observed.

Aziridines↗