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 Chemjournal_title
Bioorganic & medicinal chemistryauthors
Keerthi K,Rajapakse A,Sun D,Gates KSdoi
10.1016/j.bmc.2012.10.021subject
Has Abstractpub_date
2013-01-01 00:00:00pages
235-41issue
1eissn
0968-0896issn
1464-3391pii
S0968-0896(12)00836-Xjournal_volume
21pub_type
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