Synthesis and Biological Evaluation of the First Dual Tyrosyl-DNA Phosphodiesterase I (Tdp1)–Topoisomerase I (Top1) Inhibitors

• Published in: Journal of medicinal chemistry Vol. 55; no. 9; pp. 4457 - 4478
• Main Authors: Nguyen, Trung Xuan, Morrell, Andrew, Conda-Sheridan, Martin, Marchand, Christophe, Agama, Keli, Bermingam, Alun, Stephen, Andrew G, Chergui, Adel, Naumova, Alena, Fisher, Robert, O’Keefe, Barry R, Pommier, Yves, Cushman, Mark
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.05.2012; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; DNA Topoisomerases, Type I - metabolism; Electrophoresis, Polyacrylamide Gel; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Inhibitory Concentration 50; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Molecular Structure; Pharmacology & Pharmacy; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Surface Plasmon Resonance; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; REPAIR; SPINOCEREBELLAR ATAXIA; CLEAVAGE COMPLEXES; CAMPTOTHECIN; CRYSTAL-STRUCTURE; HUMAN-CELLS; TDP1; MAMMALIAN TOPOISOMERASE-I; DAMAGE; COVALENT COMPLEXES
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm300335n

Substances with dual tyrosyl-DNA phosphodiesterase I–topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1–Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC50 = 1.52 ± 0.05 μM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme–drug interactions were gained via structure–activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1–Tdp1 inhibitors.