Synthesis and cytotoxicity of oligomycin A derivatives modified in the side chain |
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Authors: | Lyudmila N Lysenkova Konstantin F Turchin Alexander M Korolev Lyubov G Dezhenkova Olga B Bekker Alexander A Shtil Valery N Danilenko Maria N Preobrazhenskaya |
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Institution: | 1. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russian Federation;2. Vavilov Institute of General Genetics, Russian Academy of Sciences, 3 Gubkin Street, Moscow 119991, Russian Federation;3. Autonomous Non-Commercial Research Center of Biotechnology of Antibiotics BIOAN, 3 Gubkin Street, Moscow 119991, Russian Federation;4. Blokhin Cancer Center, Russian Academy of Medical Sciences, 24 Kashirskoye Shosse, Moscow 115478, Russian Federation |
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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. |
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Keywords: | Oligomycin A 33-Azido-33-deoxy-oligomycin A Huisgen 1 3-dipolar cycloaddition reaction 33-Deoxy-33-(1 2 3-triazol-1-yl)oligomycins Cytotoxicity |
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