title: Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents.
abstract: A new series of indole analogues based on our earlier lead compound, 2-(1H-indol-5-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine (42), was prepared as tubulin inhibitors in an effort to find a molecule with improved cytotoxic potency and metabolic stability. A series of indolyl-imidazopyridines (IIP) were synthesized and exhibited potent tubulin polymerization inhibitory activity with potent IC50 values ranging from 3 to 175 nM against a panel of human melanoma and prostate cancer cell lines. Among these compounds, the 6-indolyl compound 43 showed improved cytotoxic potency (average IC50 of 9.75 nM vs 55.75 nM) and metabolic stability in human liver microsomes (half-life time was 56.3 min vs. 45.4 min) as compared to previously reported 42. It was also shown to be effective against P-glycoprotein (P-gp) mediated multiple drug resistance (MDR) and taxol resistance.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center , Memphis, Tennessee 38163, United States.
authors.forename: Dong-Jin
authors.initials: DJ
authors.lastname: Hwang
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center , Memphis, Tennessee 38163, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center , Memphis, Tennessee 38163, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, Health Science Center , Memphis, Tennessee 38163, United States.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
keywords: Colchicine-binding site; antiproliferative activity; liver microsomal stability; melanoma; multiple drug resistance; prostate cancer; structure−activity relationship (SAR); tubulin polymerization inhibitor