Journal
CHEMICAL SCIENCE
Volume 3, Issue 4, Pages 1070-1074Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c2sc00854h
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Funding
- American Cancer Society
- National Science Foundation
- Searle Scholars program
- Yale University
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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.
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