2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin- 5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity.

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.
Authors	Eric Van Quaquebeke, Tine Mahieu, Patrick Dumont, Janique Dewelle, Fabrice Ribaucour, Gentiane Simon, Sébastien Sauvage, Jean-François Gaussin, Jérôme Tuti, Mohamed El Yazidi, Frank Van Vynckt, Tatjana Mijatovic, Florence Lefranc, Francis Darro, Robert Kiss
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 17 Pg. 4122-34 (Aug 23 2007) ISSN: 0022-2623 [Print] United States
PMID	17658777 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	2,2,2-trichloro-N-((2-(2-(dimethylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-benzo(de)isoquinolin-5-yl)carbamoyl)acetamide Acetamides Antineoplastic Agents Imides Isoquinolines Naphthalimides Organophosphonates Topoisomerase I Inhibitors Deoxycytidine amonafide Irinotecan Urea Adenine Camptothecin Gemcitabine
Topics	Acetamides (chemical synthesis, pharmacology, toxicity) Adenine Animals Antineoplastic Agents (chemical synthesis, pharmacology, toxicity) Apoptosis Autophagy Camptothecin (analogs & derivatives, pharmacology) Cell Line, Tumor Cellular Senescence Deoxycytidine (analogs & derivatives, pharmacology) Drug Screening Assays, Antitumor Erythrocyte Count Female Humans Imides (pharmacology, toxicity) Irinotecan Isoquinolines (chemical synthesis, pharmacology, toxicity) Leukocyte Count Maximum Tolerated Dose Mice Naphthalimides (chemical synthesis, pharmacology, toxicity) Neoplasm Transplantation Organophosphonates Platelet Count Structure-Activity Relationship Topoisomerase I Inhibitors Urea (analogs & derivatives, chemical synthesis, pharmacology, toxicity) Gemcitabine

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