A series of aroylquinoline derivatives ([6,6]-fused heterocycle) were synthesized and evaluated for anticancer activity. 5-Amino-6-methoxy-2-aroylquinoline 15 showed more potent antiproliferative activity (IC50 values ranging from 0.2 to 0.4 nM) as compared to combretastatin A-4 (CA4, IC50 = 1.9-835 nM) against various human cancer cell lines and a MDR-resistant cancer cell line. Compound 15 (IC50 = 1.6 μM) exhibited more potent inhibition of tubulin polymerization than CA4 (IC50 - 2.1 μM) and showed strong binding property to the colchicine binding site of microtubules. In an attempt to mimic the 3,4,5-trimethoxyphenyl-Z-stilbene moiety of combretastatin A-4, a series of N-aryl-5,6,7-trimethoxyindoldes ([6,5]-fused tieterocycle) were synthesized via copper-catalyzed Ullmann-tyfype N-aryarylation through corresponding 5,6,7-trimethoxyindole and aryl halides. These synthesized compounds demonstrated potent antiproliferative activity providing a novel skeleton for potent tubulin polymerization inhibitors. Compound 6 demonstrated substantial vascular disrupting activity (VDA), which was capable to disrupt formed capillaries in concacentration-dependent manner without affecting cell viability.
