Tumour hypoxia is associated with resistance to radio- and chemotherapy as well as a more malignant and aggressive cancer phenotype. Rakicidin A, a macrocyclic depsipeptide isolated from micromonospora sp., exhibits selective cytotoxicity towards hypoxic cancer cells. Furthermore, rakicidin A induces apoptosis in quiescent hypoxia-adapted chronic myelogenous leukaemia (CML) cells which display stem cell like characteristics. Cancer stem cells are suspected to be the major cause of malignant progression of cancer and recurrence after initial treatment and thus novel compounds that selectively target this sub-population of cancer cells are of very high interest. The hypoxia selectivity of rakicidin A is independent of hypoxia-inducible factor 1 (HIF-1) and the cellular target of rakicidin A remains unknown. BE-43547A1 is a related natural product that also displays cytotoxicity to cancer cells in the nanomolar regime. We will present our efforts aimed at a total chemical syntheses of both these compounds to facilitate biological investigations including target identification. The macrocyclic ring systems of both rakicidin A and BE-43547A1 constitute significant synthetic challenges due to the presence of both congested structural elements and a labile exocyclic enamide-pentadienoate functionality. The latter is unique to this class of bioactive natural products and may in fact endow the molecule with a unique chemical reactivity that may be key to its cellular mechainsm of action.

Investigations into the total synthesis and mechanism of action of a new class of anticancer depsipeptides

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.