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: Lyudmila N Lysenkova, Konstantin F Turchin, Alexander M Korolev, Lyubov G Dezhenkova, Olga B Bekker, Alexander A Shtil, Valery N Danilenko, Maria N Preobrazhenskaya
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 11 Pg. 2918-24 (Jun 01 2013) ISSN: 1464-3391 [Electronic] England
• PMID: 23623676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Cytotoxins
• Mesylates
• Oligomycins
• Triazoles
• oligomycin A
• Sodium Azide
• methanesulfonyl chloride
• 4-Aminopyridine
• Proton-Translocating ATPases
• 4-dimethylaminopyridine

Topics

• 4-Aminopyridine (analogs & derivatives, chemistry)
• Amino Acid Sequence
• Anti-Bacterial Agents (chemical synthesis, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Cycloaddition Reaction
• Cytotoxins (chemical synthesis, pharmacology)
• Fibroblasts (cytology, drug effects, enzymology)
• Humans
• Mesylates (chemistry)
• Molecular Sequence Data
• Oligomycins (chemistry, pharmacology)
• Proton-Translocating ATPases (chemistry, metabolism)
• Skin (cytology, drug effects, enzymology)
• Sodium Azide (chemistry)
• Streptomyces (drug effects, growth & development)
• Triazoles (chemical synthesis, pharmacology)