Rakicidin A, a macrocyclic depsipeptide isolated from micromonospora sp., exhibits selective cytotoxicity towards hypoxic cancer cells and induces apoptosis in quiescent stem-like CML cells. Cancer stem cells are suspected to be a major driver of cancer progression and relapse. The hypoxia selectivity of rakicidin A is independent of HIF-1 and the cellular target remains unknown. BE-43547A1 is a related natural product that also displays potent cytotoxicity. The macrocyclic systems of these molecules constitute significant synthetic challenges due to the presence of both congested structural elements and a labile vinylogous dehydroalanine functionality. The latter is unique to this class of natural products. I will present our efforts aimed at the syntheses of both rakicidin A and BE-43547A1 with the further objective to facilitate biological investigations.
