Compounds in the
lavendustin A series have been shown to inhibit both
protein-tyrosine kinases (PTKs) and
tubulin polymerization. Since certain
lavendustin A derivatives can exist in conformations that resemble both the trans-
stilbene structure of the PTK inhibitor
piceatannol and the cis-
stilbene structure of the
tubulin polymerization inhibitor combretastatin A-4, the possibility exists that the ratio of the two types of activities of the lavendustins could be influenced through the synthesis of conformationally restricted analogues. Accordingly, the
benzylaniline structure of a series of pharmacologically active
lavendustin A fragments was replaced by either their cis- or their trans-
stilbene relatives, and effects on both inhibition of
tubulin polymerization and cytotoxicity in
cancer cell cultures were monitored. Both dihydrostilbene and 1,2-diphenylalkyne congeners were also prepared and evaluated biologically. Surprisingly, conformational restriction of the bridge between the two aromatic rings of the lavendustins had no significant effect on
biological activity. On the other hand, conversion of the three phenolic
hydroxyl groups of the
lavendustin A derivatives to their corresponding
methyl ethers consistently abolished their ability to inhibit
tubulin polymerization and usually decreased cytotoxicity in
cancer cell cultures as well, indicating the importance of at least one of the phenolic
hydroxyl groups. Further investigation suggested that the phenolic
hydroxyl group in the
salicylamide ring was required for activity, while the two
phenol moieties in the
hydroquinone ring could be methylated with retention of activity. Two of the
lavendustin A derivatives displayed IC(50) values of 1.4 microM for inhibition of
tubulin polymerization, which ranks them among the most potent of the known
tubulin polymerization inhibitors.