The Cytotoxicity of (-)-lomaiviticin A Arises from Induction of Double-strand Breaks in DNA

Overview

Journal Nat Chem

Specialty Chemistry

Date 2014 May 23

PMID 24848236

Citations 43

Authors

Laureen C Colis

Christina M Woo

Denise C Hegan

Zhenwu Li

Peter M Glazer

Seth B Herzon

Affiliations

Soon will be listed here.

Abstract

The metabolite (-)-lomaiviticin A, which contains two diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups, inhibits the growth of cultured human cancer cells at nanomolar-picomolar concentrations; however, the mechanism responsible for the potent cytotoxicity of this natural product is not known. Here we report that (-)-lomaiviticin A nicks and cleaves plasmid DNA by a pathway that is independent of reactive oxygen species and iron, and that the potent cytotoxicity of (-)-lomaiviticin A arises from the induction of DNA double-strand breaks (dsbs). In a plasmid cleavage assay, the ratio of single-strand breaks (ssbs) to dsbs is 5.3 ± 0.6:1. Labelling studies suggest that this cleavage occurs via a radical pathway. The structurally related isolates (-)-lomaiviticin C and (-)-kinamycin C, which contain one diazofluorene, are demonstrated to be much less effective DNA cleavage agents, thereby providing an explanation for the enhanced cytotoxicity of (-)-lomaiviticin A compared to that of other members of this family.

Citing Articles

Isolation, Structure Elucidation and Biological Evaluation of Lomaiviticins F-H, Dimeric Benzofluorene Glycosides from Marine-Derived sp. Bacterium.

Zhang F, Wang W, Braun D, Ananiev G, Liao W, Harper M Mar Drugs. 2025; 23(2).

PMID: 39997189 PMC: 11857394. DOI: 10.3390/md23020065.

A Stereoselective Oxidative Dimerization En Route to (-)-Lomaiviticin A.

DiBello M, Xu Z, Palazzo A, Herzon S Org Lett. 2025; 27(4):937-941.

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