Indenoisoquinolines as antineoplastic agents

US6509344B1 · kind B1 · utility

Assignees

• The United States of America, as represented by the Department of Health and Human Services · US
• National Institutes of Health, Office of Technology Transfer · US

Inventors

• Mark S. Cushman · West Lafayette, US
• Pamela Nagafuji · Arlington, US
• Muthusamy Jayaraman · Cambridge, US
• Yves G. Pommier · Bethesda, US

Key dates

• Filing date: Jul 20, 2001
• Grant date: Jan 21, 2003
• Expiry date: Jul 20, 2021

Classification

• Technology area (CPC A): Human Necessities
• CPC primary: A61P35/00
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity versus topoisomerase I. The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline and cis-6-allyl-5,6,12,13-tetrahydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-(11H)indeno[1,2-c]isoquinoline. Two of the most potent topoisomerase I inhibitors were 6-(3-carboxy-1-propyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (26) and 6-ethyl-2,3-dimethoxy-8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinolinium chloride (27). Two additional potent topoisomerase I inhibitors, 6-allyl-5,6-dihydro-2,3-dimethoxy-8,9-(methylenedioxy)-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (13c) and 5,6-dihydro-6-(4-hydoxybut-1-yl)-2,3-dimethoxy-8,9-methylenedioxy-5,11 dioxo-(11H)-indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect topoisomerase II.