6-芳基-β-咔啉衍生物的合成及抗肿瘤活性研究

Synthesis and anticancer activity of 6-Aryl-β-Carboline derivatives

以L-色氨酸为原料,设计合成了一系列新型6-取代-β-咔啉衍生物(6a-6u)。目标化合物经^(1)H NMR,^(13)C NMR和HRMS确证结构,并采用四甲基偶氮唑盐(MTT)法测试了其体外抗肿瘤(A549、BGC-823、CT-26、Bel-7402和MCF-7)活性。结果表明,在β-咔啉环的C^(6)位引入具有吸电子取代基的苯基基团(如3,4,5-三氟苯基,6-氰基苯基)所得到的6l-6n和6t是最具潜力的化合物,其在体外抗肿瘤活性测试中分别对2株肿瘤细胞具有良好抑制作用,IC_(50)值均低于10μmol·L^(-1)。之后进行了分子对接,探究了目标化合物对VEGFR-2蛋白,PDGFR-α蛋白和KIT激酶蛋白的亲和力以及结合模式,以了解其与靶点的结合情况。

A series of novelβ-carbolines possessing different substituents at R6 and N9 positions were synthesized from the L-tryptophan.All newly synthesized compounds were characterized by nuclear magnetic resonance(NMR)and High resolution mass spectra(HRMS),and antitumor activities against A549(lung carcinoma),BGC-823(gastric carcinoma),CT-26(murine colon carcinoma),Bel-7402(liver carcinoma)and MCF-7(breast carcinoma)cell lines in vitro were investigated by methyl thiazolyl tetrazolium(MTT)assay.The results demonstrated that compounds 6l-6n and 6t possessing electron-withdrawing substituents(e.g.,3,4,5-trifluorophenyl,6-cyanophenyl)at the R6-position,were found to be the most potent compounds(IC_(50) value lower than 10μmol·L^(-1) against the investigated 2 cancer cell lines).Furthermore,In order to understand the combination,molecular docking was performed to investigate their binding mode and affinities towards VEGFR-2,PDGFR-α,and KIT kinase.