Abbas Hebat-Allah S, Al-Marhabi Aisha R, Eissa Sally I, Ammar Yousry A
Photochemistry Department, National Research Centre, 12622 Doki, Cairo, Egypt; Department of Chemistry, Faculty of Science, King Khaled University, Abha, Saudi Arabia.
Department of Chemistry, Faculty of Science, King Khaled University, Abha, Saudi Arabia; Department of Chemistry, University College in Qunfudah, Umm Al Qura University, Qunfudah, Saudi Arabia.
Bioorg Med Chem. 2015 Oct 15;23(20):6560-72. doi: 10.1016/j.bmc.2015.09.023. Epub 2015 Sep 15.
In an effort to develop potent anti-cancer agents, we have synthesized some substituted quinoxaline derivatives. Reaction of 6-bromo-3-methylquinoxalin-2(1H)-one 1 with aromatic aldehydes furnished the styryl derivatives 2a-e. Alkylation of 1 with ethyl chloroacetate produced the N-alkyl derivatives 3. Hydrazinolysis of the ester derivative 3 with hydrazine hydrate afforded the hydrazide derivative 4. In addition, chlorination of 1 with phosphorus oxychloride afforded the 2-chloro derivative 5 which was used as a key intermediate for the synthesis of substituted quinoxaline derivatives 6-8, N-pyrazole derivative 9, tetrazolo[1,5-a]quinoxaline derivative 10 and Schiff base derivatives 13, 15 via reaction with several nucleophiles reagents. Docking methodologies were used to predict their binding conformation to explain the differences of their tested biological activities. All the tested compounds were screened in vitro for their cytotoxic effect on three tumor cell lines. Some new quinoxaline derivatives were studied as inhibitors of c-Met kinase, a receptor associated with high tumor grade and poor prognosis in a number of human cancers. Compounds 2e, 4, 7a, 12a, 12b and 13 showed the highest binding affinity with CDOCKER energy score, while showed the lowest IC50 values against three types of cancer cell lines. It is worth to mention that, compounds 2e, 7a, 12b and 13 showed comparable inhibition activity to the reference drug, while compounds 4 and 12a showed a more potent inhibition activity than Doxorubicin.
为了开发高效的抗癌药物，我们合成了一些取代喹喔啉衍生物。6-溴-3-甲基喹喔啉-2(1H)-酮1与芳香醛反应得到苯乙烯基衍生物2a-e。1与氯乙酸乙酯进行烷基化反应生成N-烷基衍生物3。酯衍生物3与水合肼进行肼解反应得到酰肼衍生物4。此外，1与三氯氧磷进行氯化反应得到2-氯衍生物5，其用作合成取代喹喔啉衍生物6-8、N-吡唑衍生物9、四唑并[1,5-a]喹喔啉衍生物10和席夫碱衍生物13、15的关键中间体，通过与几种亲核试剂反应得到。采用对接方法预测它们的结合构象，以解释其测试生物活性的差异。所有测试化合物均在体外筛选其对三种肿瘤细胞系的细胞毒性作用。一些新的喹喔啉衍生物被研究作为c-Met激酶的抑制剂，c-Met激酶是一种与多种人类癌症的高肿瘤分级和不良预后相关的受体。化合物2e、4、7a、12a、12b和13与CDOCKER能量得分显示出最高的结合亲和力，同时对三种癌细胞系显示出最低的IC50值。值得一提的是，化合物2e、7a、12b和13显示出与参考药物相当的抑制活性，而化合物4和12a显示出比阿霉素更强的抑制活性。
