The broad objective of our research program is to investigate the chemistry and biology of structurally unique natural products that show promising differential cytotoxicity against solid human tumor cell lines, ultimately providing new insights related to cancer biology and potential lead compounds for preclinical evaluation against solid human tumors. This renewal application specifically focuses on the synthesis of the novel natural products Psymberin / Irciniastatin and Palmerolide. Psymberin / Irciniastatin are related metabolites isolated from marine sponges. They were reported to potently inhibit the growth of solid human tumor cell lines. Structurally, they relate to the pederin / mycalamide family of protein synthesis inhibitors, but unlike the latter, psymberin displayed an unprecedented differential cytotoxicity among cancer cell lines. We propose a total synthesis of Psymberin / Irciniastatin, analogs thereof, and probe-reagents for mode-of-action studies. We also will develop novel chemistry to prepare Mycalamide-like compounds for direct comparison with Psymberin in order to fully dissect the structural determinants for protein synthesis inhibition and differential cytotoxicity. These studies will provide a solid foundation for lead identification and preclinical studies in the area of human cancer treatment, and provide chemical methodology applicable to other biologically relevant anticancer natural products. In addition, we also propose a novel highly convergent and adaptable total synthesis of Palmerolide, a compound isolated from an Antarctic tunicate. Palmerolide displayed a unique differential cytotoxicity profile in the NCI's 60 cell line panel of human tumors, inhibiting selected melanoma cell lines with three orders of magnitude greater sensitivity relative to other cell lines. This indicates a potential novel mode-of-action and starting point for the development of Palmerolide as a lead for the treatment of melanoma cancer. Our synthetic studies will provide the first entry into an integrated chemical biological evaluation of this unique anticancer natural product. Relevance to public health: A majority of anticancer drugs that are FDA approved or in advanced clinical studies are based on natural product leads. Our research will thoroughly investigate novel natural products with anticancer activity. We will develop efficient syntheses of these natural products and synthetic analogs to identify anticancer leads for the treatment of human tumor cancers.