palmerolide-a and Melanoma

Palmerolides D-G are new bioactive macrolides isolated from the Antarctic tunicate Synoicum adareanum and are related to the melanoma-selective cytotoxin palmerolide A. Most of these palmerolides are potent V-ATPase inhibitors and have sub-micromolar activity against melanoma. Though palmerolide A remains the most potent of this series of natural products against mammalian V-ATPase, recent data suggests that palmerolide D is the most potent against melanoma. A comparison of the bioactivity data obtained for these natural product palmerolides has provided insight into the substructures necessary to retain V-ATPase inhibition and cytotoxic activity.

Topics: Animals; Antarctic Regions; Antineoplastic Agents; Cattle; Humans; Macrolides; Melanoma; Molecular Conformation; Nuclear Magnetic Resonance, Biomolecular; Stereoisomerism; Urochordata; Vacuolar Proton-Translocating ATPases

A formal total synthesis of palmerolide A has been accomplished by assembling three fragments by means of successive Julia-Kocienski olefination, Yamaguchi esterification, and ring-closing metathesis (RCM). Our initial efforts to combine the first two fragments through a Julia-Kocienski reaction between a secondary sulfone and a ketone were not successful; nevertheless, it was feasible between a primary sulfone and aldehyde. Yamaguchi esterification with the third fragment then set the stage for a RCM reaction. Initial failure of the RCM with a PMB-ether adjacent to the olefins and the difficulty in cleaving the PMB-ether prompted us to change the choice of protecting groups, which then paved the way to the macrocyclic core of palmerolide A.

Topics: Alkenes; Antineoplastic Agents; Cell Line, Tumor; Esterification; Humans; Macrolides; Melanoma; Molecular Conformation