Optimization of the Indenone Ring of Indenoisoquinoline Topoisomerase I Inhibitors

2007/08/04 by Andrew Morrell, Michael S. Placzek, Seth Parmley +4 · 6 citations
Biochemistry, Genetics and Molecular Biology · Pharmacology, Toxicology and Pharmaceutics · #Cancer therapeutics and mechanisms #Synthesis and bioactivity of alkaloids #Bioactive Compounds and Antitumor Agents

paper · doi:10.1021/jm070307+

openalex publication_date 2007/08/04 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

Two series of indenoisoquinoline topoisomerase I inhibitors have been prepared to investigate optimal substituents on the indenone ring at the 9-position. The more exhaustive series was prepared using a nitrated isoquinoline ring that has been previously demonstrated to enhance biological activity. After preliminary biological evaluation, a more focused series of inhibitors was prepared utilizing a 2,3-dimethoxy-substituted isoquinoline ring. The results of the two series indicate the existence of superior functional groups such as methoxy, fluorine, and cyano for the indenoisoquinoline 9-position. Interestingly, these functional groups coincide with established structure-activity relationships for the 11-position of camptothecin.

Citations

• Synthesis and Mechanism of Action Studies of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal an Inhibitor with a Flipped Orientation in the Ternary DNA−Enzyme−Inhibitor Complex As Determined by X-ray Crystallographic Analysis
• New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening
• Synthesis of New Indeno[1,2-c]isoquinolines: Cytotoxic Non-Camptothecin Topoisomerase I Inhibitors

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• Design, Synthesis, and Evaluation of Dibenzo[c,h][1,6]naphthyridines as Topoisomerase I Inhibitors and Potential Anticancer Agents
• Next generation topoisomerase I inhibitors: Rationale and biomarker strategies
• The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives
• Topoisomerase inhibitor [wikipedia]