Alcohol-, Diol-, and Carbohydrate-Substituted Indenoisoquinolines as Topoisomerase I Inhibitors: Investigating the Relationships Involving Stereochemistry, Hydrogen Bonding, and Biological Activity

• Published in: Journal of medicinal chemistry Vol. 54; no. 14; pp. 4937 - 4953
• Main Authors: Peterson, Katherine E, Cinelli, Maris A, Morrell, Andrew E, Mehta, Akhil, Dexheimer, Thomas S, Agama, Keli, Antony, Smitha, Pommier, Yves, Cushman, Mark
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.07.2011; Amer Chemical Soc
• Subjects: Alcohols - chemical synthesis; Alcohols - chemistry; Alcohols - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Screening Assays, Antitumor; Hexoses - chemical synthesis; Hexoses - chemistry; Hexoses - pharmacology; Humans; Hydrogen Bonding; Indenes - chemical synthesis; Indenes - chemistry; Indenes - pharmacology; Life Sciences & Biomedicine; Models, Molecular; Pentoses - chemical synthesis; Pentoses - chemistry; Pentoses - pharmacology; Pharmacology & Pharmacy; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; DNA CLEAVAGE; ANTICANCER; NITRATED INDENOISOQUINOLINES; CAMPTOTHECIN; PLANT ANTITUMOR AGENTS; REBECCAMYCIN ANALOGS; INDOLOCARBAZOLE; BINDING; DERIVATIVES; MJ-III-65 NSC-706744
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101338z

The DNA-relaxing enzyme topoisomerase I (Top1) can be inhibited by heterocyclic compounds such as indolocarbazoles and indenoisoquinolines. Carbohydrate and hydroxyl-containing side chains are essential for the biological activity of indolocarbazoles. The current study investigated how similar functionalities could be “translated” to the indenoisoquinoline system and how stereochemistry and hydrogen bonding affect biological activity. Herein is described the preparation and assay of indenoisoquinolines substituted with short-chain alcohols, diols, and carbohydrates. Several compounds (including those derived from sugars) display potent Top1 poisoning and antiproliferative activities. The Top1 poisoning activity of diol-substituted indenoisoquinolines is dependent upon stereochemistry. Although the effect is striking, molecular modeling and docking studies do not indicate any reason for the difference in activity due to similar calculated interactions between the ligand and Top1–DNA complex and ambiguity about the binding mode. A stereochemical dependence was also observed for carbohydrate-derived indenoisoquinolines. Although similar trends were observed in other classes of Top1 inhibitors, the exact nature of this effect has yet to be elucidated.