Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400)

• Published in: Journal of medicinal chemistry Vol. 59; no. 10; pp. 4890 - 4899
• Main Authors: Lv, Peng-Cheng, Elsayed, Mohamed S. A, Agama, Keli, Marchand, Christophe, Pommier, Yves, Cushman, Mark
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.05.2016; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Benzodioxoles - chemical synthesis; Benzodioxoles - chemistry; Benzodioxoles - metabolism; Benzodioxoles - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - metabolism; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; CANCER-CELLS; NITRATED INDENOISOQUINOLINES; STEREOSELECTIVE HYDROLYSIS; CLEAVAGE COMPLEXES; NORMAL TISSUE; LACTAM SIDE-CHAIN; CAMPTOTHECIN DERIVATIVES; DNA TOPOISOMERASES; ANTITUMOR-ACTIVITY; TOPOISOMERASE-I INHIBITORS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00220

Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents with two compounds in clinical trials. Recent metabolism studies of indotecan (LMP400) led to the discovery of the biologically active 2-hydroxylated analogue and 3-hydroxylated metabolite, thus providing strategically placed functional groups for the preparation of a variety of potential ester prodrugs of these two compounds. The current study details the design and synthesis of two series of indenoisoquinoline prodrugs, and it also reveals how substituents on the O-2 and O-3 positions of the A ring, which are next to the cleaved DNA strand in the drug-DNA-Top1 ternary cleavage complex, affect Top1 inhibitory activity and cytotoxicity. Many of the indenoisoquinoline prodrugs were very potent antiproliferative agents with GI50 values below 10 nM in a variety of human cancer cell lines.