ABSTRACT
Amonafide (1), a naphthalimide which binds to DNA by intercalation and poisons topoisomerase IIalpha, has demonstrated activity in phase II breast cancer trials, but has failed thus far to enter clinical phase III because of dose-limiting bone marrow toxicity. Compound 17 (one of 41 new compounds synthesized) is a novel anticancer naphthalimide with a distinct mechanism of action, notably inducing autophagy and senescence in cancer cells. Compound 17 (2,2,2-trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157)) was found to have a 3-4-fold higher maximum tolerated dose compared to amonafide and not to provoke hematotoxicity in mice at doses that display significant antitumor effects. Furthermore, 17 has shown itself to be superior to amonafide in vivo in models of (i) L1210 murine leukemia, (ii) MXT-HI murine mammary adenocarcinoma, and (iii) orthotopic models of human A549 NSCLC and BxPC3 pancreatic cancer. Compound 17, therefore, merits further investigation as a potential anticancer agent.
Subject(s)
Acetamides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Isoquinolines/chemical synthesis , Naphthalimides/chemical synthesis , Urea/analogs & derivatives , Acetamides/pharmacology , Acetamides/toxicity , Adenine , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Apoptosis , Autophagy , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Cell Line, Tumor , Cellular Senescence , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Drug Screening Assays, Antitumor , Erythrocyte Count , Female , Humans , Imides/pharmacology , Imides/toxicity , Irinotecan , Isoquinolines/pharmacology , Isoquinolines/toxicity , Leukocyte Count , Maximum Tolerated Dose , Mice , Naphthalimides/pharmacology , Naphthalimides/toxicity , Neoplasm Transplantation , Organophosphonates , Platelet Count , Structure-Activity Relationship , Topoisomerase I Inhibitors , Urea/chemical synthesis , Urea/pharmacology , Urea/toxicity , GemcitabineABSTRACT
Analysis of the methanolic extract of Calotropis procera root barks enabled the identification of a novel cardenolide (2''-oxovoruscharin) to be made. Of the 27 compounds that we hemisynthesized, one (23) exhibited a very interesting profile with respect to its hemisynthetic chemical yield, its in vitro antitumor activity, its in vitro inhibitory influence on the Na+/K+-ATPase activity, and its in vivo tolerance. Compound 23 displayed in vitro antitumor activity on a panel of 57 human cancer cell lines similar to taxol, and higher than SN-38 (the active metabolite of irinotecan), two of the most potent drugs used in hospitals to combat cancer.
