Novel noncamptothecin topoisomerase I-targeting anticancer agents.

摘要

DNA topoisomerases are nuclear enzymes involved in maintenance of the supramolecular topology of DNA. Proper topoisomerase function is necessary for replication and transcription. There are two major subtypes, topoisomerase I (TOP1) and topoisomerase II (TOP2), based upon differences in the amino acid sequence as well as mechanistic divergence. Topoisomerase-targeting agents that stabilize the enzyme-DNA complex can exert a cytotoxic effect that is selective for cancer cells. Although TOP2 is targeted by many classes of antitumor agents, there are only two clinically available drugs that target TOP1. Both of the currently available TOP1-targeting agents (HycamptinRTM and CPT-11/CamptosarRTM) are derivatives of camptothecin. These drugs possess a metabolically unstable gamma-lactone structure. In humans, 90% of an administered dose is hydrolyzed to an inactive form which possesses high affinity for human serum albumin. Additionally, the camptothecins are substrates for efflux transporters that are associated with drug resistance. This study pursues the development of noncamptothecin-based TOP1-targeting agents as antineoplastic clinical candidates. Previous research has determined the structural requirements for TOP1-targeting activity in noncharged isosteres of nitidine. Two classes of compounds resulting from this work, benzo[ i]phenanthridines and dibenzo[c,h]cinnolines, have TOP1-targeting activity comparable to that of camptothecin. However, their poor solubility precludes assay of antitumor efficacy in vivo. This study investigates new derivatives that incorporate water-solubilizing groups. It is shown that 11H-5,6,11-triazachrysen-12-ones and 5H-dibenzo[c,h]1,6-naphthyridin-6-ones are very potent TOP1-targeting agents. Moreover, these compounds possess good solubility. When assayed in vivo against the tumor xenograft MDA-MB-435, 8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5 H-dibenzo[c,h]1,6-naphthyridin-6-one produces tumor regression comparable to that of CPT-11 at 1/20th the dose. Additional studies indicate that this 5-substituted 5H-dibenzo[ c,h]1,6-naphthyridin-6-one is not a substrate for efflux pumps, and does not bind to human serum albumin. Preclinical studies are currently in progress to assess the future clinical utility of this new class of antineoplastic agents.