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.

journal_name

Bioorg Med Chem

authors

Keerthi K,Rajapakse A,Sun D,Gates KS

doi

10.1016/j.bmc.2012.10.021

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

235-41

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(12)00836-X

journal_volume

21

pub_type

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