[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

Helicenes are high interest synthetic targets with unique
conjugated
helical structures that have found important technological applications.
Despite this interest, helicenes have had limited impact in chemical
biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a
structural mimic of colchicine, a known antimitotic drug. The synthesis
proceeds via sequential Pd-catalyzed coupling reactions
and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization
in both cell-free and live cell assays. Not only does this demonstrate
the feasibility of using helicenes as bioactive scaffolds against
protein targets, but also suggests wider potential for the use of
helicenes as isosteres of biaryls or cis-stilbenesthemselves
common drug and natural product scaffolds. Overall, this study further
supports future opportunities for helicenes for a range of chemical
biological applications.