Regions of hypoxia often exist in tumours due to inadequate blood supply. Tumour hypoxia is associated with resistance to radio- and chemotherapy as well as a more malignant and aggressive cancer phenotype. Rakicidin A (1  ), a depsipeptide isolated from micromonospora sp., exhibits selective cytotoxicity towards hypoxic cancer cells. Furthermore, Rakicidin A (1  ) induces apoptosis in quiescent hypoxia-adapted chronic myelogenous leukaemia 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. The hypoxia selectivity of Rakicidin A (1  ) is independent of hypoxia-inducible factor 1 (HIF-1) and the cellular target of Rakicidin A (1 ) remains unknown.The macrocyclic ringsystem of Rakicidin A (1  ) constitutes a significant synthetic challenge due to the presence of both a very congested ester bond and a labile exocyclic enamide-pentadienoate functionality. The latter is unique to only a handful of bioactive natural products and may endow the molecule with a unique chemical reactivity. Here, we will present our progress towards the first total synthesis of Rakicidin A (1 ) including efficient fragment synthesis as well as investigations into conditions for macrocyclization that are compatible with the sensitive nature of the ringsystem.

Towards the first total synthesis of Rakicidin A: A hypoxia-selective cytotoxin

247th National Meeting (2014)

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