Structure-activity studies of novobiocin analogs as modulators of the cytotoxicity of etoposide (VP-16).

Abstract

We have previously reported that the antibiotic novobiocin enhanced the toxicity of the anticancer agent etoposide (VP-16) to several drug-sensitive and -resistant tumor cell lines. The increase in VP-16 cytotoxicity produced by novobiocin was not due to the combined effects of these agents on topoisomerase II, but to inhibition by novobiocin of VP-16 efflux, which in turn led to increased accumulation of VP-16 and increased formation of potentially lethal VP-16-stabilized topoisomerase II-DNA covalent complexes. We have now identified novobiocin analogs that are essentially equivalent to novobiocin as inhibitors of the activity of topoisomerase II, but that are more potent than novobiocin (a) as modulators of the cytotoxicity of VP-16 to WEHI-3B leukemia and A549 lung carcinoma cells and (b) in increasing VP-16 accumulation in these cell lines. Thus, removal of the sugar moiety of novobiocin to form novobiocic acid enhanced the potency of the antibiotic as a modulator of VP-16, whereas the substituted coumarin ring alone (U-7587) was devoid of VP-16 modulatory activity. Modifications of the side chain of novobiocin significantly influenced modulatory activity, with cyclonovobiocic acid, which was formed from novobiocic acid by acid-catalyzed cycloaddition, being the most active in enhancing the cytotoxicity of VP-16. The increased potency of novobiocic acid and cyclonovobiocic acid as modulators of VP-16 activity was achieved with no change from novobiocin in the capacity of these analogs to inhibit the catalytic activity of mammalian topoisomerase II, indicating a change in the specificity of these analogs.

• Authors: G Rappa, K Shyam, A Lorico, O Fodstad, A C Sartorelli
• Journal: Oncology research (Oncol Res) Vol. 12 Issue 3 Pg. 113-9 ( 2000) ISSN: 0965-0407 [Print] United States
• PMID: 11216669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP-Binding Cassette Transporters
• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Multidrug Resistance-Associated Proteins
• Topoisomerase II Inhibitors
• Novobiocin
• Etoposide
• Adenosine Triphosphate

Topics

• ATP-Binding Cassette Transporters (physiology)
• Adenosine Triphosphate (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Etoposide (pharmacology)
• Humans
• Multidrug Resistance-Associated Proteins
• Novobiocin (pharmacology)
• Structure-Activity Relationship
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured