Skip to main content
Article
Characterization of a Reductively-Activated Elimination Pathway Relevant to the Biological Chemistry of the Kinamycins and Lomaiviticins
Chemistry Department Faculty Publications
  • Seann P. Mulcahy, Providence College
  • Christina M. Woo
  • Weidong Ding
  • George A. Ellestad
  • Seth B. Herzon
Description

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.

Disciplines
Publisher
Chemical Science
Date
1-1-2012
Type
Article
Format
Text
None
.pdf (text under image)
Language
English
Citation Information
Seann P. Mulcahy, Christina M. Woo, Weidong Ding, George A. Ellestad, et al.. "Characterization of a Reductively-Activated Elimination Pathway Relevant to the Biological Chemistry of the Kinamycins and Lomaiviticins" (2012)
Available at: http://works.bepress.com/seann_mulcahy/9/