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.

Abstract

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 (7a), Cys (11a), and Met (12a) and the 3R,3'S isomer derived from D-Pro (7c), 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-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 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 7 and 11 was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity and DNA-binding properties were investigated.

• Authors: 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, Ettore Novellino
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 8 Pg. 1787-98 (Apr 19 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17375902 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Ligands
• Naphthalenes
• Pyrazines
• Topoisomerase II Inhibitors
• DNA
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• DNA (chemistry)
• DNA Topoisomerases, Type II (chemistry)
• Drug Design
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Ligands
• Magnetic Resonance Spectroscopy
• Models, Molecular
• Naphthalenes (chemical synthesis, chemistry, pharmacology)
• Pyrazines (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Topoisomerase II Inhibitors