Structure validation of Aplidinone A, a cytotoxic tunicate metabolite, and synthesis of its structural derivatives for SAR studies

Aplidinone A is a natural product isolated from the Mediterranean ascidian Aplidium conicum with interesting antiapoptotic properties; it is an example of terpene quinones containing the unusual 1,1-dioxo-1,4-thiazine ring. The structure of this compound had been determined by spectroscopic analysis while the regiochemistry of the thiazine ring was defined by a comparison of the experimental 13C chemical shifts with those predicted by GIAO shielding calculations for the model compounds A-1 and A-2. Successively, the synthesis of compounds A1 and A2 allowed us to confirm the proposed regiochemistry and provided useful quantities of these compounds to initiate SAR studies. The designed synthetic procedure was also adopted to prepare other quinones analogues, compounds B1 and B2, which revealed a very interesting pharmacological activity.