Synthesis and evaluation of a series of benzothiophene
acrylonitrile analogs as anticancer agents
Synthesis and evaluation of a series of benzothiophene acrylonitrile analogs as anticancer agents
Narsimha Reddy Penthalaa, Vijayakumar, N. Sonara, Jamie Hornb, Markos Leggasb,*, Jai Shankar K. B. Yadlapallia, and Peter A. Crooksa,* aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
Abstract
A new library of small molecules with structural features resembling combretastatin analogs was synthesized and evaluated for anticancer activity against a panel of 60 human cancer cell lines. Three novel acrylonitrile analogs (5, 6 and 13) caused a significant reduction in cell growth in almost all the cell lines examined, with GI50 values generally in the range 10–100 nM. Based on the structural characteristics of similar drugs, we hypothesized that the cytotoxic activity was likely due to interaction with tubulin. Furthermore, these compounds appeared to overcome cellassociated P-glycoprotein (P-gp)-mediated resistance, since they were equipotent in inhibitingOVCAR8 and NCI/ADR-Res cell growth. Given that antitubulin drugs are among the most effective agents for the treatment of advanced prostate cancer we sought to validate the results from the 60 cell panel by studying the representative analog 6 utilizing prostate cancer cell lines, as well as exploring the molecular mechanism of the cytotoxic action of this analog.