Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl analogues, the structure鈥揳ctivity relationship of antimitotic ottelione A (
4) against tubulin and various cancer cells was established. The results indicated that compound
4 was a colchicine-competitive inhibitor and that the C-1 vinyl group is unnecessary for its potency, whereas the C-7 exocyclic double bond is essential, possibly because of its irreversible interaction with tubulin. Further optimization of the substituents on the phenylmethyl group at the C-3 position generated compound
10g with a 3鈥?fluoro-4鈥?methoxyphenylmethyl substituent, which was 6鈥?8-fold more active against MCF-7, NCI-H460, and COLO205 cancer cells relative to
4. Results from in vitro tubulin polymerization assay confirmed the potency of compounds
4,
10g, and
11a.
Keywords:
ottelione A; antimitotic; microtubule; tubulin; anticancer