Evaluation of indenoisoquinoline topoisomerase I inhibitors using a hollow fiber assay

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 16; pp. 4395 - 4399
• Main Authors: Morrell, Andrew, Jayaraman, Muthusamy, Nagarajan, Muthukaman, Fox, Brian M., Meckley, Marintha Rae, Ioanoviciu, Alexandra, Pommier, Yves, Antony, Smitha, Hollingshead, Melinda, Cushman, Mark
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.08.2006; Elsevier
• Subjects: Anticancer; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biological Assay - methods; Camptothecin - chemistry; Camptothecin - pharmacology; Cell Line, Tumor; DNA - chemistry; Drug Screening Assays, Antitumor - methods; Enzyme Inhibitors - pharmacology; General aspects; Hollow fiber assay; Humans; Indenoisoquinoline; Isoquinolines - chemistry; Medical sciences; Models, Chemical; Pharmacology. Drug treatments; Topoisomerase I inhibitor; Topoisomerase I Inhibitors; Hollow fiber assay; Indenoisoquinoline; Anticancer; Topoisomerase I inhibitor; Antineoplastic agent; Intraperitoneal administration; Enzyme; DNA topoisomerase; Lactam; Enzyme inhibitor; Malignant tumor; In vivo; Isomerases; Cell line; Structure activity relation; Hollow fiber; Subcutaneous administration; Covalent complex; Mechanism of action; Chemical synthesis; Tumor cell
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.05.048

The indenoisoquinolines are a novel class of non-camptothecin topoisomerase I (Top1) inhibitors whose mechanism of action involves trapping the covalent complex formed between DNA and Top1 during cellular processes. As an ongoing evaluation of the indenoisoquinolines for Top1 inhibition and anticancer activity, indenoisoquinoline analogs have been screened in the National Cancer Institute’s hollow fiber assay (HFA). Some of the derivatives demonstrated significant activity at intraperitoneal and subcutaneous fiber placement sites, along with net cancer cell kill in one or more cell lines.