Podophyllotoxin analogues active versus Trypanosoma brucei.

Uddin MJ, Smithson DC, Brown KM, Crews BC, Connelly M, Zhu F, Marnett LJ, Guy RK
Bioorg Med Chem Lett. 2010 20 (5): 1787-91

PMID: 20129783 · PMCID: PMC2826502 · DOI:10.1016/j.bmcl.2010.01.009

In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with LogP values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.

Copyright 2010 Elsevier Ltd. All rights reserved.

MeSH Terms (7)

Anti-Inflammatory Agents, Non-Steroidal Cell Line Humans Indomethacin Podophyllotoxin Trypanocidal Agents Trypanosoma brucei brucei

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