title: Synthesis and cytotoxicity of oligomycin A derivatives modified in the side chain.
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.
authors.affiliation: Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russian Federation.
authors.forename: Lyudmila N
authors.initials: LN
authors.lastname: Lysenkova
authors.forename: Konstantin F
authors.initials: KF
authors.lastname: Turchin
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Korolev
authors.forename: Lyubov G
authors.initials: LG
authors.lastname: Dezhenkova
authors.forename: Olga B
authors.initials: OB
authors.lastname: Bekker
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
authors.forename: Valery N
authors.initials: VN
authors.lastname: Danilenko
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
mesh_terms: D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000737:chemistry; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D061565:Cycloaddition Reaction; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008698:Mesylates / Q000737:chemistry; D008969:Molecular Sequence Data; D009840:Oligomycins / Q000737:chemistry* / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D019810:Sodium Azide / Q000737:chemistry; D013302:Streptomyces / Q000187:drug effects / Q000254:growth & development; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D003603:Cytotoxins; D008698:Mesylates; D009840:Oligomycins; D014230:Triazoles; C031004:oligomycin A; D019810:Sodium Azide; C030209:methanesulfonyl chloride; D015761:4-Aminopyridine; D006180:Proton-Translocating ATPases; C003885:4-dimethylaminopyridine