The
biological importance of microtubules in mitosis, as well as in interphase, makes them an interesting target for the development of
anticancer agents. Small molecules such as benzo[b]
thiophenes are attractive as inhibitors of
tubulin polymerization. Thus, a new class of compounds that incorporated the structural motif of the 2-(3',4',5'-trimethoxybenzoyl)-3-aryl/arylamino
benzo[b]thiophene molecular skeleton, with electron-donating (Me, OMe, SMe or OEt) or electron-withdrawing (F and Cl) substituents on the B-ring, was synthesized and evaluated for antiproliferative activity, inhibition of
tubulin polymerization and cell cycle effects. The most promising compound in this series was 2-(3',4',5'-trimethoxybenzoyl)-3-(4'-ethoxyphenyl)-
benzo[b]thiophene (4e), which significantly inhibited
cancer cell growth at submicromolar concentrations, especially against HeLa and Jurkat cells, and interacted with
tubulin. As determined by flow cytometric analysis, 4e caused G2/M phase arrest and apoptosis in a time- and concentration-dependent manner. The block in G2/M was correlated with increased expression of
cyclin B1 and phosphorylation of cdc25c. Moreover, 4e perturbed mitochondrial membrane potential and caused activation of
caspase-3 and cleavage of poly(
ADP-rybose)
polymerase (PARP), events that are involved in 4e-induced apoptosis.