Identification and Synthesis of Mycalol Analogues with Improved Potency against Anaplastic Thyroid Carcinoma Cell Lines

Abstract

The marine metabolite mycalol (1) has a specific inhibitory activity on cells of anaplastic thyroid carcinoma (ATC), a very aggressive and rare cancer that does not have effective conventional therapy. In this study, we describe six new related analogues (2-7) that differ in the length of the terminal alkyl residue and the presence of acetate or 3S-hydroxybutyrate (3S)-3HB as a substituent at C-19. Despite the structural analogies, some of the new members were significantly more cytotoxic than 1 on cell lines derived from human ATC. Structures inclusive of the 2'R,3R,4S,7R,8S,19R absolute configuration were assigned to 2-7 on the basis of detailed spectroscopic analysis, synthesis of different isomers, and application of ECD and Mosher's methods. This work led to the identification of mycalol-578 (3) as the most potent analogue, with an IC₅₀ of 2.3 μM on FRO cells.