In vitro and in vivo anti-tumoral activities of imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline derivatives.
Imidazoquinoxaline and pyrazoloquinoxaline derivatives, analogues of imiquimod, were synthesized, and their in vitro cytotoxic and pharmacodynamic activities were evaluated. In vitro cytotoxicity studies were assessed against melanoma (A375, M4Be, RPMI-7591), colon (LS174T), breast (MCF7), and lymphoma (Raji) human cancer cell lines. In vivo studies were carried out in M4Be xenografted athymic mice. EAPB0103, EAPB0201, EAPB0202, and EAPB0203 showed significant in vitro activities against A375 compared to fotemustine and imiquimod used as references. These compounds were 6-110 and 2-45 times more active than fotemustine and imiquimod, respectively. EAPB0203 bearing phenethyl as substituent at position 1 and methylamine at position 4 showed the highest activity. EAPB0203 has also a more potent cytotoxic activity than imiquimod and fotemustine in M4Be and RPMI-7591 and interesting cytotoxic activity in other tumor cell lines tested. In vivo, EAPB0203 treatment schedules caused a significant decrease in tumor size compared to vehicle control and fotemustine treatments.
Laboratoire de Pharmacochimie et Biomolécules, EA 4215, Faculté de Pharmacie, Université Montpellier I, 15 av. Charles Flahault, BP 14491, 34 093 Montpellier Cedex 5, France.
Georges
G
Moarbess
Carine
C
Deleuze-Masquefa
Vanessa
V
Bonnard
Stéphanie
S
Gayraud-Paniagua
Jean-Rémi
JR
Vidal
Françoise
F
Bressolle
Frédéric
F
Pinguet
Pierre-Antoine
PA
Bonnet
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007093:Imidazoles; D011720:Pyrazoles; D011810:Quinoxalines; C031280:pyrazole