Podophyllotoxin analogues active versus Trypanosoma brucei.
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.
Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Md Jashim
MJ
Uddin
David C
DC
Smithson
Kristin M
KM
Brown
Brenda C
BC
Crews
Michele
M
Connelly
Fangyi
F
Zhu
Lawrence J
LJ
Marnett
R Kiplin
RK
Guy
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002460:Cell Line; D006801:Humans; D007213:Indomethacin / Q000737:chemistry / Q000633:toxicity; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014344:Trypanocidal Agents; D011034:Podophyllotoxin; D007213:Indomethacin