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

Kripa Keerthi, Anuruddha Rajapakse, Daekyu Sun, Kent S. Gates

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Leinamycin (1) is a Streptomyces-derived natural product that displays nanomolar IC50 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.

Original languageEnglish (US)
Pages (from-to)235-241
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Biological Products
Sulfhydryl Compounds
DNA
DNA Cleavage
Alkylation
Streptomyces
Alkenes
Oxides
Functional groups
Inhibitory Concentration 50
Oxidation-Reduction
Carbon
Cells
leinamycin
Ions
Cell Line
Neoplasms

Keywords

  • Antitumor agent
  • DNA alkylation
  • Natural product

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Synthesis and characterization of a small analogue of the anticancer natural product leinamycin. / Keerthi, Kripa; Rajapakse, Anuruddha; Sun, Daekyu; Gates, Kent S.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 1, 01.01.2013, p. 235-241.

Research output: Contribution to journalArticle

Keerthi, Kripa ; Rajapakse, Anuruddha ; Sun, Daekyu ; Gates, Kent S. / Synthesis and characterization of a small analogue of the anticancer natural product leinamycin. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 1. pp. 235-241.
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