2,2,2-Trichloro- N -({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1 H -benzo[de]isoquinolin- 5-yl}carbamoyl)acetamide (UNBS3157), a Novel Nonhematotoxic Naphthalimide Derivative with Potent Antitumor Activity
2007; American Chemical Society; Volume: 50; Issue: 17 Linguagem: Inglês
10.1021/jm070315q
ISSN1520-4804
AutoresEric 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, Róbert Kiss,
Tópico(s)Synthesis and biological activity
ResumoAmonafide (1), a naphthalimide which binds to DNA by intercalation and poisons topoisomerase IIα, 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.
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