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

Rushworth, James L.; Thawani, Aditya R.; Fajardo-Ruiz, Elena; Meiring, Joyce C. M.; Heise, Constanze; White, Andrew J. P.; Akhmanova, Anna; Brandt, Jochen R.; Thorn-Seshold, Oliver und Fuchter, Matthew J. (2022): [5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity. In: JACS Au, Bd. 2, Nr. 11: S. 2561-2570

Abstract

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 pi-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- stilbenesthemselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• Sprache: Englisch