Synthesis and investigation of conformationally restricted analogues of lavendustin A as cytotoxic inhibitors of tubulin polymerization

A series of conformationally restricted analogues were synthesized in order to elucidate the possible effects of different amide conformations of lavendustin A derivatives on cytotoxicity in cancer cell cultures and on inhibition of tubulin polymerization. The conformationally restricted analogues were based on the oxazinedione and isoindolone ring systems. In addition, the amide bond was replaced by both cis and trans alkene moieties. Surprisingly, the results indicated very little effect of conformational restriction on biological activity. Because all of the compounds synthesized had similar cytotoxicities and potencies as tubulin polymerization inhibitors, the side chain present on the aniline ring system does not appear to be important in the biological effects of the lavendustins. The hydroquinone ring of lavendustin A may be a more important determinant of the biological activity than the structure surrounding the aniline ring.