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

• Published in: Bioorganic & medicinal chemistry 2008-07, Vol.16 (13), p.6601-6610
• Main Authors: Moarbess, Georges, Deleuze-Masquefa, Carine, Bonnard, Vanessa, Gayraud-Paniagua, Stéphanie, Vidal, Jean-Rémi, Bressolle, Françoise, Pinguet, Frédéric, Bonnet, Pierre-Antoine
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Survival; Cell Survival - drug effects; Chemical Sciences; Databases, Factual; Female; General aspects; Humans; Imidazoles; Imidazoles - chemistry; Imidazoquinoxalines; Imiquimod; In vitro activity; Medical sciences; Medicinal Chemistry; Melanoma; Mice; Mice, Nude; Molecular Structure; Pharmacodynamic evaluation; Pharmacology. Drug treatments; Pyrazoles; Pyrazoles - chemistry; Pyrazoloquinoxaline; Quinoxalines; Quinoxalines - chemical synthesis; Quinoxalines - chemistry; Quinoxalines - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.05.022

EAPB0203 bearing phenethyl as substituent at position 1 and methylamine at position 4 showed the highest activity on human melanoma cell lines compared to fotemustine and imiquimod used as references. In vivo, EAPB0203 treatment schedules caused a significant decrease in tumor size compared to vehicle control and fotemustine treatments. 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.