Zghaib Zahraa, Guichou Jean-François, Vappiani Johanna, Bec Nicole, Hadj-Kaddour Kamel, Vincent Laure-Anaïs, Paniagua-Gayraud Stéphanie, Larroque Christian, Moarbess Georges, Cuq Pierre, Kassab Issam, Deleuze-Masquéfa Carine, Diab-Assaf Mona, Bonnet Pierre-Antoine
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15, avenue Charles Flahault, BP14491, 34093 Montpellier cedex 5, France; Tumorigenèse et Pharmacologie Antitumorale, Lebanese University, BP 90656, Fanar Jdeideh, Lebanon.
CNRS, UMR5048 - Université de Montpellier, Centre de Biochimie Structurale, F-34090 Montpellier, France; INSERM, U1054, F-34090 Montpellier, France.
Bioorg Med Chem. 2016 Jun 1;24(11):2433-2440. doi: 10.1016/j.bmc.2016.04.004. Epub 2016 Apr 1.
Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.
微管被认为是抗癌治疗的重要靶点。EAPB0503及其结构咪唑并[1,2-a]喹喔啉衍生物是具有强大抗癌活性的主要微管干扰剂。在本研究中，描述了几种EAPB0503新衍生物的合成，并报道了13种新型衍生物对A375人黑色素瘤细胞系的抗癌疗效。所有新化合物对人黑色素瘤细胞系（A375）均显示出显著的抗增殖活性，IC50在0.077-122μM范围内。还评估了体外对微管蛋白聚合的直接抑制试验。结果表明，化合物6b、6e、6g和EAPB0503高度抑制微管蛋白聚合，抑制率分别为99%、98%、90%和84%。还结合对微管蛋白秋水仙碱结合位点的分子对接研究讨论了该系列内的构效关系研究。
