Design, synthesis and biological evaluation of a novel series of anthrapyrazoles linked with netropsin-like oligopyrrole carboxamides as anticancer agents

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 11; pp. 3974 - 3984
• Main Authors: Zhang, Rui, Wu, Xing, Guziec, Lynn J., Guziec, Frank S., Chee, Gaik-Lean, Yalowich, Jack C., Hasinoff, Brian B.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.06.2010; Elsevier
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Anthracyclines - chemical synthesis; Anthracyclines - pharmacology; Anthrapyrazole; Anticancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cytotoxic; DNA; DNA - chemistry; DNA - metabolism; Drug Design; General aspects; Humans; Intercalating Agents; Intercalator; K562 Cells; Medical sciences; Minor groove; Netropsin; Pharmacology. Drug treatments; Pyrroles; Topoisomerase I; Topoisomerase II; Intercalator; Anthrapyrazole; Minor groove; DNA; Topoisomerase I; Anticancer; Cytotoxic; Netropsin; Topoisomerase II; Antineoplastic agent; Intercalating agent; Nylon; Oligopeptides; Peptides; Pyrrole derivative polymer; Cytotoxicity; Oligomer; Modeling; Isomerases; Molecular model; Chemical synthesis; DNA topoisomerase (ATP-hydrolysing); Enzyme; DNA topoisomerase; Guanidines; In vitro; Biological activity; Topoisomerase 11; Anthrapyrazole derivatives; Carboxamide
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.028

Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. Combilexin molecules, which combine DNA minor groove binding and intercalating functionalities, have the potential for increased DNA binding affinity and increased selectivity due to their dual mode of DNA binding. This study describes the synthesis of DNA minor groove binder netropsin analogs containing either one or two N-methylpyrrole carboxamide groups linked to DNA-intercalating anthrapyrazoles. Those hybrid molecules which had both two N-methylpyrrole groups and terminal (dimethylamino)alkyl side chains displayed submicromolar cytotoxicity towards K562 human leukemia cells. The combilexins were also evaluated for DNA binding by measuring the increase in DNA melting temperature, for DNA topoisomerase IIα-mediated double strand cleavage of DNA, for inhibition of DNA topoisomerase IIα decatenation activity, and for inhibition of DNA topoisomerase I relaxation of DNA. Several of the compounds stabilized the DNA–topoisomerase IIα covalent complex indicating that they acted as topoisomerase IIα poisons. Some of the combilexins had higher affinity for DNA than their parent anthrapyrazoles. In conclusion, a novel group of compounds combining DNA intercalating anthrapyrazole groups and minor groove binding netropsin analogs have been designed, synthesized and biologically evaluated as possible novel anticancer agents.