Evaluation of indenoisoquinoline topoisomerase I inhibitors using a hollow fiber assay.

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.

Synthesis and anticancer activity of simplified indenoisoquinoline topoisomerase I inhibitors lacking substituents on the aromatic rings.

The indenoisoquinolines are a class of cytotoxic topoisomerase I inhibitors that offer certain advantages over the camptothecins, including the greater stabilities of the compounds themselves, as well as the greater stabilities of their drug-enzyme-DNA cleavage complexes. To investigate the possible biological roles of the di(methoxy) and methylenedioxy substituents present on the aromatic rings of the previously synthesized indenoisoquinoline topoisomerase I inhibitors, a series of compounds lacking these substituents was synthesized and tested for both cytotoxicity in cancer cell cultures and for enzyme inhibitory activity. The results indicate that the aromatic substituents make a small, but consistently observable contribution to the biological activity.