Identification And Synthesis Of Mycalol Analogues With Improved Potency Against Anaplastic Thyroid Carcinonia Cell Lines

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-cytotokic than 1 on cell lines,derivecl from human ATC. Structures inclusive of the 2'R,3R,4S,7R,8S,19R absolute configuration were asigned 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 mycal61-578 (3) as the most potent analogue, with an IC50 of 2.3 mu M on FRO cells: