Design, synthesis and Cytotoxic Evaluation of a New Series of 3-Substituted-spiro[(dihydropirazin-2,5-dione)-6,3’-(2’,3’-dihydrothieno[2,3-b]naphtho-4’,9’-dione)] Derivatives

A series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3¢-(2¢,3¢-dihydrothieno[2,3-b]naphtho-4¢,9¢- dione)] derivatives were prepared using an easy synthetic route via condensation of the 3-amino-3- (ethoxycarbonyl)-2,3-dihydrothieno[2,3-b]naphtho-4,9-dione system and amino acids followed by intramolecular lactamization. Amino acids containing alkyl and aryl, linear and cyclic, polar and apolar, and basic and acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines revealed, for the 3S,3¢R isomers derived from Pro , Cys , and Met and the 3R,3¢S isomer derived from D-Pro , a cytotoxic potency comparable to or greater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in several other sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drugresistance mechanism. In particular, only a partial cross-resistance to these compounds was observed in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx), whereas a very low level of cross-resistance to compounds containing the Pro and Met residues was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP).