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.
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.
Unibioscreen SA, 40 Avenue Joseph Wybran, 1070 Brussels, Belgium.
Eric
E
Van Quaquebeke
Tine
T
Mahieu
Patrick
P
Dumont
Janique
J
Dewelle
Fabrice
F
Ribaucour
Gentiane
G
Simon
Sébastien
S
Sauvage
Jean-François
JF
Gaussin
Jérôme
J
Tuti
Mohamed
M
El Yazidi
Frank
F
Van Vynckt
Tatjana
T
Mijatovic
Florence
F
Lefranc
Francis
F
Darro
Robert
R
Kiss
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000225:Adenine; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis; D001343:Autophagy; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004906:Erythrocyte Count; D005260:Female; D006801:Humans; D007094:Imides / Q000494:pharmacology / Q000633:toxicity; D000077146:Irinotecan; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D007958:Leukocyte Count; D020714:Maximum Tolerated Dose; D051379:Mice; D053644:Naphthalimides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D009368:Neoplasm Transplantation; D063065:Organophosphonates; D010976:Platelet Count; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D000093542:Gemcitabine
C523820:2,2,2-trichloro-N-((2-(2-(dimethylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-benzo(de)isoquinolin-5-yl)carbamoyl)acetamide; D000081:Acetamides; D000970:Antineoplastic Agents; D007094:Imides; D007546:Isoquinolines; D053644:Naphthalimides; D063065:Organophosphonates; D059004:Topoisomerase I Inhibitors; D003841:Deoxycytidine; C037020:amonafide; D000077146:Irinotecan; D014508:Urea; D000225:Adenine; D002166:Camptothecin; D000093542:Gemcitabine