The Rakicidin Family of Anticancer Natural Products – Synthetic Strategies towards a New Class of Hypoxia-Selective Cytotoxins

Rakicidin A is a prominent member of a small class of macrocyclic lipodepsipeptide natural products that contain an electrophilic 4-amido-2,4-pentadienoate (APD) functionality. Rakicidin A displays selective growth inhibitory activity against hypoxic cancer cells as well as imatinib-resistant chronic myelogenous leukemia (CML) cells. In this paper we present and discuss the two known synthetic routes to rakicidin A, which provide an instructive comparison of strategies used to address the synthetic challenges inherent to rakicidin A. In addition to the synthetic discussion we provide a status on the ongoing biological investigations and emerging structure–activity relationships of the rakicidin scaffold. 1 Introduction 2 The APD-CLD Class of Natural Products 3 Total Syntheses of Rakicidin A 4 Biological Investigations of Rakicidin A and Analogues 5 Conclusion and Perspectives