F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action

• Published in: Biochemical pharmacology 2000-04, Vol.59 (7), p.807-819
• Main Authors: Perrin, Dominique, van Hille, Benoı̂t, Barret, Jean-Marc, Kruczynski, Anna, Etiévant, Chantal, Imbert, Thierry, Hill, Bridget T
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - drug effects; Adenosine Triphosphatases - metabolism; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; antitumour agent; Biological and medical sciences; Camptothecin - pharmacology; Catalysis; Cattle; Cell Nucleus - enzymology; DNA - metabolism; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; dual catalytic inhibitor; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors - pharmacology; Enzyme Stability; Etoposide - pharmacology; Evaluation Studies as Topic; F 11782; General aspects; Humans; Medical sciences; Naphthalenes - pharmacology; non-intercalating agent; Pharmacology. Drug treatments; Pyrans - pharmacology; Saccharomyces cerevisiae; topoisomerase I; Topoisomerase I Inhibitors; topoisomerase II; Topoisomerase II Inhibitors
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(99)00382-2

F 11782, a novel epipodophylloid, proved a potent inhibitor of the catalytic activities of both topoisomerases I and II. Unlike classical inhibitors such as camptothecin or etoposide, F 11782 did not stabilise cleavable complexes induced by either topoisomerases I or II nor did it preferentially inhibit the religation step of the catalytic cycle of either enzyme. F 11782 neither intercalated DNA nor bound in its minor groove, and showed only weak inhibition of the ATPase activity associated with topoisomerase II. F 11782 appeared to act by inhibiting the binding of topoisomerases I and II to DNA in a manner dependent both on drug and enzyme concentrations, via a mechanism not previously described or shared by other known topoisomerase ‘poisons’ or inhibitors. In contrast, F 11782 had only a weak effect or none at all on various other DNA-interacting enzymes. In conclusion, F 11782, as a non-intercalating, specific catalytic inhibitor of both topoisomerases I and II with an original mechanism of action, may be considered to represent the first of a new class of topoisomerase-interacting agents.