Issue 4, 2012

Characterization of a reductively-activated elimination pathway relevant to the biological chemistry of the kinamycins and lomaiviticins

Abstract

The lomaiviticins (1 and 2) and kinamycins (3–5) are bacterial metabolites with potent antimicrobial and antiproliferative activities. Herein we establish that 1–5 are capable of generating electrophilic acylfulvene intermediates (6) under mildly reducing conditions. These acylfulvenes 6 are formed by a multistep process comprising two-electron reduction and loss of dinitrogen to form an ortho-quinone methide, followed by elimination. Based on these studies, the structure of the product formed from 1 in DNA-cleavage assays is proposed (26). We also show that the bis(hydroxynaphthoquinone) substructures of the lomaiviticins activate the metabolites toward reduction. Finally, based on COMPARE and time-dependent cell response profiling analyses, we show that kinamycin C (4) and the monomeric lomaiviticin aglycon (24) operate by a mechanism of action that is distinct from simple diazofluorenes, such as 23.

Graphical abstract: Characterization of a reductively-activated elimination pathway relevant to the biological chemistry of the kinamycins and lomaiviticins

Supplementary files

Article information

Article type
Edge Article
Submitted
27 Oct 2011
Accepted
02 Dec 2011
First published
22 Dec 2011

Chem. Sci., 2012,3, 1070-1074

Characterization of a reductively-activated elimination pathway relevant to the biological chemistry of the kinamycins and lomaiviticins

S. P. Mulcahy, C. M. Woo, W. Ding, G. A. Ellestad and S. B. Herzon, Chem. Sci., 2012, 3, 1070 DOI: 10.1039/C2SC00854H

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