Synthesis and biological evaluation of 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4

A series of novel 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge to retain the cis-orientations of A-ring and B-ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines. Compounds 6a–d exhibited superior potency, with IC50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors. A series of novel crolibulin and combretastatin A-4 (CA-4) analogues using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge were discovered. Compounds (6a–d) exhibited cytotoxicity with IC50 values ranging from 0.030 to 0.31 μM. [Display omitted] •A series of novel 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and CA-4 using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge were discovered.•Compound 6a (IC50 = 0.030 μM) exhibited antiproliferative activity higher than crolibulin and CA-4.•Compound 6a possessed comparable microtubule depolymerization activity to CA-4.