Topoisomerase II inhibitors and therapeutic uses therefor

US5622960A · kind A · utility

Assignee

• The United States of America, as represented by the Department of Health and Human Services · US

Inventors

• Yves Pommier · Bethesda, US
• Timothy L. Macdonald · Charlottesville, US
• Jose S. Madalengoitia · Charlottesville, US

Key dates

• Filing date: Oct 23, 1992
• Grant date: Apr 22, 1997
• Expiry date: Oct 23, 2012

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D499/14
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

Azatoxin and derivatives thereof are illustrative of a new class of antitumor drugs that are topoisomerase II (top 2) inhibitors. The pharmacophore inhibits the catalytic activity of the purified enzyme but does not unwind relaxed or supercoiled DNA. It is nonintercalative and has at least two domains: a quasi-planar polycyclic ring system, which may bind between DNA base pairs, and a pendant substituent thought to interact with the enzyme, with the DNA grooves or with both. In SV40 and c-myc DNA, azatoxin induces numerous double-strand breaks according to a cleavage pattern which differs from those of known top 2 inhibitors. Azatoxin also is a potent inhibitor of tubulin polymerization.