The 3,4,5-trimethoxyphenyl moiety is a common motif employed in anticancer drug discovery, due to its prevalence in a variety of important natural products such as Combretastatin. Work undertaken by our group and others has demonstrated that structural diversification of this template can lead to potent anticancer activity.

The synthesis and biological evaluation of a series of novel indole-trimethoxyphenyl derivatives are described herein. The consolidation of the combretastatin and bisindolyl templates towards the inclusion of a novel heterocyclic headgroup proffered a versatile pharmacophore with which to pursue chemical diversification. Rationalising the enhancement of existing H-bonding interactions or potential exploitation of new contacts, the introduction of substituted maleimides constituted an overarching theme. This allowed for the evaluation of the effects pertaining to oxygen insertion, extended maleimide substitution and N-functionalisation. Photo-mediated dehydrogenation of a key synthetic intermediate offered access to trimethoxyphenylcarbazoles, representing the first time a panel of such congeners has been reported with further derivatisation also possible.

Subsequent evaluation of anticancer activity of the indole-trimethoxyphenyl conjugates utilising the NCI-60 cell screen showed growth inhibitory profiles towards numerous cell lines including: A498 renal, IGROV1 ovarian, DU-145 prostate, SW-620 colon and MCF-7 breast cancer cell lines. The influence of structure on anticancer activity is described.