Role of the acyl groups in carbohydrate chains in cytotoxic properties of olivomycin A

Abstract

A series of olivomycin A derivatives containing different combinations of the acyl residues in the carbohydrate chains was obtained. The formation of complexes of Mg(2+)-coordinated dimers of these compounds with double-stranded DNA was studied using spectral methods such as absorption, fluorescence and circular dichroism (CD) spectral analyses. There was a good correlation of the values of binding constants of complexes (antibiotic)2Mg(2+)-DNA, the quantum yields of fluorescence and changes of the induced CD spectra with topoisomerase I inhibition and cytotoxicity. We demonstrate that the presence of the acyl groups in the saccharide residues of olivomycin A derivatives is absolutely necessary for a high cytotoxic potency of these antibiotics. On the basis of the experimental results and quantum chemical calculations, we presume that the acyl residue in the 4-O-position in the A-sugar residue is involved, to the most part, in the antibiotic-antibiotic interactions in the (olivomycin)2Mg(2+) dimers, whereas the O-acyl group in E-olivomicose residue largely participates in the formation of the (olivomycin)2Mg(2+)-DNA complexes.

Differential Impact of Random GC Tetrad Binding and Chromatin Events on Transcriptional Inhibition by Olivomycin A

“…The colon carcinoma HCT116 and human embryonic kidney HEK293T (both from American Type Culture Collection, Manassas, VA, USA) cell lines and the genetically modified sublines generated in this study were cultured in Dulbecco modified Eagle’s medium (PanEco, Moscow, Russia) supplemented with 10% fetal bovine serum (HyClone, Logan, UT, USA), 2 mM L-glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin (PanEco, Russia) at 37 °C, 5% CO 2 in a humidified atmosphere. OA was produced at the pilot plant of Gause Institute of New Antibiotics, Moscow [ 43 ] and provided by Professor A.N. Tevyashova.…”

Оливомицин А — Противоопухолевый Антибиотик Группы Ауреоловой Кислоты (Обзор)

“…Óñòàíîâëåíî, ÷òî àöèëüíûå çàìåñòèòåëè â óãëåâîäíûõ öåïÿõ îêàçûâàþò çíà÷èòåëüíîå âëèÿíèå íà îáðàçîâàíèå Mg 2+ -êîîðäèíèðîâàííûõ äèìåðîâ àíòèáèîòèêîâ è îáðàçîâàíèå êîìïëåêñîâ ñ ÄÍÊ è, êàê ñëåäñòâèå, íà áèîëîãè÷åñêóþ àêòèâíîñòü àíòèáèîòèêîâ, âêëþ÷àÿ äåéñòâèå íà òîïîèçîìåðàçó I. Ïîêàçàíî, ÷òî íàëè÷èå àöèëüíûõ ãðóïï â óãëåâîäíûõ öåïÿõ III ÿâëÿåòñÿ àáñîëþòíî íåîáõîäèìûì äëÿ ïðîÿâëåíèÿ àíòèáèîòèêîì ïðîòèâîîïóõîëåâûõ ñâîéñòâ. Âïåðâûå ïîêàçàíà ðàçëè÷íàÿ ðîëü àöèëüíûõ çàìåñòèòåëåé â ïîëîaeåíèÿõ 4-Î îëèîçû è 4-Î îëèâîìèêîçû äëÿ ïðîÿâëåíèÿ àíòèáèîòèêîì III áèîëîãè÷åñêîé àêòèâíîñòè [82].…”