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Modification of olivomycin A at the side chain of the aglycon yields the derivative with perspective antitumor characteristics

Research output: Contribution to journalReview ArticleScientificpeer-review

Details

Original languageEnglish
Pages (from-to)7387-7393
Number of pages7
JournalBIOORGANIC AND MEDICINAL CHEMISTRY
Volume19
Issue number24
DOIs
Publication statusPublished - 15 Dec 2011
Publication typeA2 Review article in a scientific journal

Abstract

A novel way of chemical modification of the antibiotic olivomycin A (1) at the side chain of the aglycon moiety was developed. Interaction of olivomycin A with the sodium periodate produced the key acid derivative olivomycin SA (2) in 86% yield. This acid was used in the reactions with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate (PyBOP) or diphenylphosphoryl azide (DPPA) to give corresponding amides. Whereas olivomycin SA was two orders of magnitude less cytotoxic than the parent antibiotic, the amides of 2 demonstrated a higher cytotoxicity. In particular, N,N-dimethylaminoethylamide of olivomycin SA showed a pronounced antitumor effect against transplanted experimental lymphoma and melanoma and a remarkably high binding constant to double stranded DNA. The therapeutic effects of this derivative were achievable at tolerable concentrations, suggesting that modifications of the aglycon's side chain, namely, its shortening to methoxyacetic residue and blocking of free carboxyl group, are straightforward for the design of therapeutically applicable derivatives of olivomycin A.

Keywords

  • Antibiotics, Antitumor activity, Aureolic acid, Chemical modifications, Drug-DNA complexes, Olivomycin A, Olivomycin SA