Cover image for Vol. 12 Issue 6

Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)

Impact Factor: 2.98

ISI Journal Citation Reports © Ranking: 2015: 18/59 (Chemistry Medicinal); 77/255 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

October 10, 2013

VIP: Tetrahydroisoquinoline-Based Steroidomimetic and Chimeric Microtubule Disruptors

VIP: Tetrahydroisoquinoline-Based Steroidomimetic and Chimeric Microtubule DisruptorsMatthew P. Leese, Fabrice L. Jourdan, Meriel R. Major, Wolfgang Dohle, Ernest Hamel, Eric Ferrandis, Ann Fiore, Philip G. Kasprzyk, Barry V. L. Potter*

Tubulin is a well-validated cancer drug target. The vinca alkaloids, taxanes, and other taxane site binders have found wide therapeutic application and constitute arguably one of the most successful classes of anticancer agent. Nevertheless, significant problems persist with existing drugs, such as limited therapeutic window, acquired resistance, lack of oral bioavailability, and problematic formulation. The alternative colchicine site binding microtubule disruptors seemingly possess great potential, yet attempts to translate their preclinical promise into the clinic are still elusive, although some compounds are in development. Considerable potential for new microtubule disruptors with enhanced profiles and tissue specificity is thus clearly evident, and this work demonstrates the design of new agents that address several crucial problems. Together with colleagues at the NCI (USA) and Ipsen in the USA and France, Potter's group at the University of Bath (UK) has focused on an endogenous steroidal lead, designing a partial surrogate of the steroidal core, combining structural elements from different series addressing the same target and also building in a motif they have previously pioneered in clinical translation that confers attractive oral activity and delivery and imbues resistance to metabolism. Design of these new chimeric molecules was achieved within the parameters associated with an orally bioavailable drug, and both cell and xenograft data confirm their promise. The compounds are easily synthesized, amenable to aqueous formulation using benign excipients, and they also inhibit the proliferation of taxane-resistant cell lines. A novel series of orally active microtubule disruptors with excellent activities, combined with a desirable pharmaceutical profile has thus been designed and is attractive for development.

Received June 10, 2013; published online October 9, 2013, DOI: 10.1002/cmdc.201300261.

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