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

被引:108
作者
Moarbess, Georges [1 ]
Deleuze-Masquefa, Carine [1 ]
Bonnard, Vanessa [1 ]
Gayraud-Paniagua, Stephanie [1 ]
Vidal, Jean-Remi [3 ]
Bressolle, Francoise [2 ,3 ]
Pinguet, Frederic [3 ]
Bonnet, Pierre-Antoine [1 ]
机构
[1] Univ Montpellier 1, Fac Pharm, Lab Pharmacochim & Biomol, EA 4215, F-34093 Montpellier 5, France
[2] Univ Montpellier 1, Fac Pharm, Lab Pharmacocinet Clin, EA 4215, F-34093 Montpellier 5, France
[3] Ctr Reg Lutte Contre Canc, F-34000 Montpellier, France
关键词
imidazoquinoxalines; pyrazoloquinoxaline; imiquimod; melanoma; in vitro activity; pharmacodynamic evaluation;
D O I
10.1016/j.bmc.2008.05.022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (c) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:6601 / 6610
页数:10
相关论文
共 21 条
  • [1] Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma:: A phase III study
    Avril, MF
    Aamdal, S
    Grob, JJ
    Hauschild, A
    Mohr, P
    Bonerandi, JJ
    Weichenthal, M
    Neuber, K
    Bieber, T
    Gilde, K
    Porta, VG
    Fra, J
    Bonneterre, J
    Saïag, P
    Kamanabrou, D
    Pehamberger, H
    Sufliarsky, J
    Larriba, JLG
    Scherrer, A
    Menu, Y
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (06) : 1118 - 1125
  • [2] Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma
    Bong, AB
    Bonnekoh, B
    Franke, I
    Schön, MP
    Ulrich, J
    Gollnick, H
    [J]. DERMATOLOGY, 2002, 205 (02) : 135 - 138
  • [3] Imidazoquinoxaline Src-family kinase p56Lck inhibitors:: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity
    Chen, P
    Doweyko, AM
    Norris, D
    Gu, HH
    Spergel, SH
    Das, J
    Moquin, RV
    Lin, J
    Wityak, J
    Iwanowicz, EJ
    McIntyre, KW
    Shuster, DJ
    Behnia, K
    Chong, S
    de Fex, H
    Pang, SH
    Pitt, S
    Shen, DR
    Thrall, S
    Stanley, P
    Kocy, OR
    Witmer, MR
    Kanner, SB
    Schieven, GL
    Barrish, JC
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (18) : 4517 - 4529
  • [4] Design and synthesis of novel imidazo[1,2-a]quinoxalines as PDE4 inhibitors
    Deleuze-Masquéfa, C
    Gerebtzoff, G
    Subra, G
    Fabreguettes, JR
    Ovens, A
    Carraz, M
    Strub, MP
    Bompart, J
    George, P
    Bonnet, PA
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (05) : 1129 - 1139
  • [5] GIBSON SJ, 1995, J INTERFERON CYTOKIN, V15, P2207
  • [6] Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway
    Hemmi, H
    Kaisho, T
    Takeuchi, O
    Sato, S
    Sanjo, H
    Hoshino, K
    Horiuchi, T
    Tomizawa, H
    Takeda, K
    Akira, S
    [J]. NATURE IMMUNOLOGY, 2002, 3 (02) : 196 - 200
  • [7] Topical immunomodulators for the treatment of external genital warts, cutaneous warts and molluscum contagiosum
    Hengge, UR
    Cusini, M
    [J]. BRITISH JOURNAL OF DERMATOLOGY, 2003, 149 : 15 - 19
  • [8] MEGYERI K, 1995, MOL CELL BIOL, V15, P2207
  • [9] EAPB0203, a member of the imidazoquinoxaline family, inhibits growth and induces caspase-dependent apoptosis in T-cell lymphomas and HTLV-I-associated adult T-cell leukemia/lymphoma
    Moarbess, Georges
    El-Hajj, Hiba
    Kfoury, Youmna
    El-Sabban, Marwan E.
    Lepelletier, Yves
    Hermine, Olivier
    Deleuze-Masquefa, Carine
    Bonnet, Pierre-Antoine
    Bazarbachi, Ali
    [J]. BLOOD, 2008, 111 (07) : 3770 - 3777
  • [10] Impairment of TNF-α production and action by imidazo[1,2-α] quinoxalines, a derivative family which displays potential anti-inflammatory properties
    Morjaria, S.
    Deleuze-Masquefa, C.
    Lafont, V.
    Gayraud, S.
    Bompart, J.
    Bonnet, P. A.
    Dornand, J.
    [J]. INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY, 2006, 19 (03) : 525 - 538