Design, Synthesis, and Cytotoxic Evaluation of a New Series of 3-Substituted Spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] Derivatives

详细信息    查看全文

• 作者：Isabel Gomez-Monterrey ; Pietro Campiglia ; Alfonso Carotenuto ; Daniela Califano ; Claudio Pisano ; Loredana Vesci ; Teresa Lama ; Alessia Bertamino ; Marina Sala ; Antonio Mazzella di Bosco ; Paolo Grieco ; Ett
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 19, 2007
• 年：2007
• 卷：50
• 期：8
• 页码：1787 - 1798
• 全文大小：298K
• 年卷期：v.50,no.8(April 19, 2007)
• ISSN：1520-4804

文摘

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 basicand acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinomaand SW 620 human colon carcinoma cell lines revealed, for the 3S,3'R isomers derived from Pro (7a), Cys(11a), and Met (12a) and the 3R,3'S isomer derived from D-Pro (7c), a cytotoxic potency comparable to orgreater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in severalother sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 wasobserved 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 7 and 11 was found in a tumor cell sublineselected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity andDNA-binding properties were investigated.