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.
Van Quaquebeke
Eric
E
Unibioscreen SA, 40 Avenue Joseph Wybran, 1070 Brussels, Belgium.
Mahieu
Tine
T
Dumont
Patrick
P
Dewelle
Janique
J
Ribaucour
Fabrice
F
Simon
Gentiane
G
Sauvage
Sébastien
S
Gaussin
Jean-François
JF
Tuti
Jérôme
J
El Yazidi
Mohamed
M
Van Vynckt
Frank
F
Mijatovic
Tatjana
T
Lefranc
Florence
F
Darro
Francis
F
Kiss
Robert
R
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