A series of cis- and trans-
stilbenes related to
combretastatin A-4 (1a), with a variety of substituents at the 3'-position of the aryl B-ring, were synthesized and evaluated for inhibitory activity employing six human
cancer cell lines (NCI-H460 lung
carcinoma, BXPC-3 pancreas, SK-N-SH
neuroblastoma, SW1736 thyroid, DU-145 prostate, and FADU pharynx-squamous
sarcoma) as well as the P-388 murine lymphocyte
leukemia cell line. Several of the cis-
stilbene derivatives were significantly inhibitory against all cell lines used, with potencies comparable to that of the parent 1a. All were potent inhibitors of
tubulin polymerization. The corresponding trans-
stilbenes had little or no activity as
tubulin polymerization inhibitors and were relatively inactive against the seven
cancer cell lines. In terms of inhibition of both
cancer cell growth and
tubulin polymerization, the dimethylamino and bromo cis-
stilbenes were the most potent of the new derivatives, the latter having biological activity approaching that of 1a. As part of the present study, the X-ray crystal structure of the 3'-O-phosphate of
combretastatin A-4 (1b) was successfully elucidated. Compound 1b has been termed the "
combretastatin A-4 prodrug", and it is currently undergoing clinical trials for the treatment of human
cancer patients.