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Synthesis and characterization of a small analogue of the anticancer natural product leinamycin.

Abstract
Leinamycin (1) is a Streptomyces-derived natural product that displays nanomolar IC(50) values against human cancer cell lines. In the work described here, we report the synthesis and characterization of a small leinamycin analogue 19 that closely resembles the 'upper-right quadrant' of the natural product, consisting of an alicyclic 1,2-dithiolan-3-one 1-oxide heterocycle connected to an alkene by a two-carbon linker. The results indicate that this small analogue contains the core set of functional groups required to enable thiol-triggered generation of both redox active polysulfides and an episulfonium ion intermediate via the complex reaction cascade first seen in the natural product leinamycin. The small leinamycin analogue 19 caused thiol-triggered oxidative DNA strand cleavage in a manner similar to the natural product, but did not alkyate duplex DNA effectively. This highlights the central role of the 18-membered macrocycle of leinamycin in driving efficient DNA alkylation by the natural product.
AuthorsKripa Keerthi, Anuruddha Rajapakse, Daekyu Sun, Kent S Gates
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 1 Pg. 235-41 (Jan 01 2013) ISSN: 1464-3391 [Electronic] England
PMID23168080 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Biological Products
  • Lactams
  • Macrolides
  • Sulfhydryl Compounds
  • Thiazoles
  • Thiones
  • leinamycin
  • DNA
Topics
  • Alkylation (drug effects)
  • Antineoplastic Agents (chemistry, metabolism, pharmacology)
  • Biological Products (chemistry, metabolism, pharmacology)
  • DNA (metabolism)
  • DNA Cleavage (drug effects)
  • Humans
  • Lactams (chemistry, metabolism, pharmacology)
  • Macrolides (chemistry, metabolism, pharmacology)
  • Neoplasms (drug therapy, metabolism)
  • Oxidation-Reduction
  • Streptomyces (chemistry)
  • Sulfhydryl Compounds (metabolism)
  • Thiazoles (chemistry, metabolism, pharmacology)
  • Thiones (chemistry, metabolism, pharmacology)

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