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ABSTRACT: A novel way of chemical modification of the macrolide antibiotic oligomycin A (1) at the side chain was developed. Mesylation of 1 with methane sulfonyl chloride in the presence of 4-dimethylaminopyridine produced 33-O-mesyl oligomycin in 56% yield. Reactions of this intermediate with sodium azide produced the key derivative 33-azido-33-deoxy-oligomycin A in 60% yield. 1,3-Dipolar cycloaddition reaction with propiolic acid, methyl ester of propiolic acid, and phenyl acetylene resulted in 33-deoxy-33-(1,2,3-triazol-1-yl)oligomycin A derivatives substituted at N4 of the triazole cycle. The mesylated oligomycin A and 33-deoxy-33-azidooligomycin A did not inhibit F0F1 ATFase ATPase; however, 33-azido-33-deoxy-oligomycin A and the derivatives containing 4-phenyltriazole, 4-methoxycarbonyl-triazole and 3-dimethylaminoethyl amide of carboxyltriazole substituents demonstrated a high cytotoxicity against K562 leukemia and HCT116 human colon carcinoma cell lines whereas non-malignant skin fibroblasts were less sensitive to these compounds. Novel series of oligomycin A derivatives allow for the search of intracellular molecules beyond F0F1 ATP synthase relevant to the cytotoxic properties of this perspective chemical class.
Bioorganic & medicinal chemistry 04/2013; · 2.82 Impact Factor
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Lyudmila N Lysenkova,
Konstantin F Turchin,
Alexander M Korolev,
Evgenyi E Bykov, Valery N Danilenko,
Olga B Bekker,
Alexey S Trenin,
Sergei M Elizarov,
Lyubov G Dezhenkova,
Alexander A Shtil,
Maria N Preobrazhenskaya
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ABSTRACT: The antibiotic oligomycin A in the presence of K(2)CO(3) and n-Bu(4)NHSO(4) in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared. The acyclic oligomycin A derivative retained the ability to induce apoptosis in tumor cells at low micromolar concentrations, whereas its antimicrobial potencies decreased substantially. The derivative virtually lost the inhibitory activity against F(0)F(1) ATP synthase-containing proteoliposomes, strongly suggesting the existence of the target(s) beyond F(0)F(1) ATP synthase that is important for the antitumor potency of oligomycin A.
The Journal of Antibiotics 05/2012; 65(8):405-11. · 1.65 Impact Factor
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ABSTRACT: Bifidobacteria are strictly anaerobic bacteria, that are an important component of human microbiote due to their probiotic characteristics. They are frequently exposed to a variety of stresses, therefore, identification of genes implicated in stress responses in bifidobacteria is critical for biomedicine and maintenance of industrial strains. The WhiB-like family proteins unique for Actinobacteria are transcriptional regulators involved in major cellular processes, including stress responses. The aim of this study was the identification of WhiB-like family proteins of the Bifidobacterium genus of the Actinobacteria class and functional characterization of conservative whiB-like genes. The DNA sequence database of 36 strains revealed a family of WhiB-encoding genes. It were identified the wblE orthologs in all Bifidobacteria species and the whiB2 orthologs in all bifidobacterial strains except of all strains of Bifidobacterium animalis subsp. lactis and Bifidobacterium gallicum. Some strains, in particular, those of the Bifidobacterium longum group, contain additional whiB-like genes of different length and a low degree of similarity in sequences. The wblE and whiB2 genes of the Bifidobacterium genus are evolutionary conservative and ancient genes. The real-time PCR analysis showed that transcription of wblE is induced by a variety of stress conditions such as heat shock, osmotic, oxidative stresses, by antibiotic tetracycline and bile salt treatment, the nutrient starvation and entry into late stationary phase. The wblE gene may play a significant role in general stress responses in bifidobacteria.
Anaerobe 05/2012; 18(4):421-9. · 2.41 Impact Factor
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The Journal of Antibiotics 02/2012; 65(4):223-5. · 1.65 Impact Factor
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ABSTRACT: Eukaryotic-like serine/threonine protein kinases (ESTPKs) are widely spread throughout the bacterial genomes. These enzymes can be potential targets of new antibacterial drugs useful for the treatment of socially important diseases such as tuberculosis. In this study, ESTPKs of pathogenic, probiotic, and antibiotic-producing Gram-positive bacteria were classified according to the physicochemical properties of amino acid residues in the ATP-binding site of the enzyme. Nine residues were identified that line the surface of the adenine-binding pocket, and ESTPKs were classified based on these signatures. Twenty groups were discovered, five of them containing >10 representatives. The two most abundant groups contained >150 protein kinases that belong to the various branches of the phylogenetic tree, whereas certain groups are genus- or even species-specific. Homology modeling of the typical representatives of each group revealed that the classification is reliable, and the differences between the protein kinase ATP-binding pockets predicted based on their signatures are apparent in their structure. The classification is expected to be useful for the selection of targets for new anti-infective drugs.
Proteins Structure Function and Bioinformatics 01/2012; 80(5):1363-76. · 3.39 Impact Factor
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ABSTRACT: SUMMARYObjective. Glycogen synthase kinase 3 (GSK-3) is a promising target for the treatment of various human diseases such as type 2 diabetes, Alzheimer's disease and inflammation. Successful inhibition of the homologues of this kinase in Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani makes the kinase an attractive target for the treatment of malaria, trypanosomiasis and leishmaniasis, respectively. The aim of this work was to compare the binding sites of the GSK-3 kinases of different parasites and to analyse them as possible targets for therapeutic compounds. Methods. Both a sequence alignment and homology models of the structure of 21 different GSK-3 homologues belonging to mammals, insects, pathogenic fungi, nematodes, trematodes and protozoa have been analysed, 17 of them being studied for the first time. Results. The structure of the kinases and, in particular, their binding sites, were found to be rather conserved, possessing small insertions or deletions and conserved amino acid substitutions. Nevertheless, the kinases of most species of parasite did have some amino acid differences from the human kinase, which could be exploited for the design of selective drugs. Conclusion. Comparison of the human and parasite GSK-3 ATP binding site models has shown that the development of selective drugs affecting parasite GSK-3 is possible. Known inhibitors of human GSK-3 can also be used as starting scaffolds for the search for drugs acting against parasitic diseases.
Parasitology 02/2011; · 2.96 Impact Factor
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ABSTRACT: Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecule as weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria.
Current topics in medicinal chemistry 01/2011; 11(11):1352-69. · 4.47 Impact Factor
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ABSTRACT: The first examples of chemical modification of antibiotic oligomycin A are described. The interaction of oligomycin A with hydroxylamine yielded six-membered nitrone annelated with the antibiotic at the positions 3,4,5,6,7. The reaction with 1-aminopyridinium iodide in pyridine led to pyrazolo[1,5-a]pyridine conjugated with the antibiotic at the positions 2 and 3 (product of addition to the C(2)-C(3) double bond followed by spontaneous oxidation). The structures of the compounds obtained were supported by NMR and mass spectrometry methods including the (15)N-labeling of compounds.
The Journal of Antibiotics 11/2009; 63(1):17-22. · 1.65 Impact Factor
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Valery N Danilenko,
Alexander Y Simonov,
Sergey A Lakatosh,
Michael H G Kubbutat,
Frank Totzke,
Christoph Schächtele,
Sergey M Elizarov,
Olga B Bekker,
Svetlana S Printsevskaya,
Yuryi N Luzikov,
Marina I Reznikova,
Alexander A Shtil,
Maria N Preobrazhenskaya
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ABSTRACT: Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.
Journal of Medicinal Chemistry 01/2009; 51(24):7731-6. · 4.80 Impact Factor
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ABSTRACT: The aminoglycoside 3′-phosphotransferase typeVIII (APHVIII) encoding gene (aphVIII) from Streptomyces rimosus was introduced by glass-bead high-efficiency transformation into the nuclear genome of green unicellular alga Chlamydomonas reinhardtii for induction of transformants resistant to aminoglycoside antibiotics. The aphVIII structural sequence was flanked by S. rimosus regulatory sequences which failed to direct expression in C. reinhardtii. The pSU937 plasmid containing these sequences was able to transform C. reinhardtii strain cw15 arg7–8 mt+ for paromomycin resistance (PmR) at a frequency (1.3–1.9) × 10-7, probably as a result of in vivo gene fusion and expression of the aphVIII gene from regulatory elements of nuclear DNA. Evidence for the real C. reinhardtii transformation includes blot-hybridization with a probe specific for aphVIII and demonstration of APHVIII enzyme activity in crude cell extracts of transformants. Integrated Streptomyces DNA sequences, APHVIII enzyme activity and the aminoglycoside-resistance phenotype were stable through mitosis in the presence and absence of selection. The PmR phenotype was inherited by the meiotic progeny of transformants from crosses with wild-type strains.
Gene 12/1996; · 2.34 Impact Factor
