β-咔啉杂合咪唑类化合物的合成及抗肿瘤活性

Synthesis and in vitro antitumor activity of novel β-carboline N2-fused imidazole derivatives

摘要:

β-咔啉类生物碱具有广泛的生物活性，包括抗疟活性、抗菌活性以及抗肿瘤活性等。以L-色氨酸为原料，经Pictet-Spengler环化反应、氧化脱羧、N9-烷基化等反应步骤合成一系列β-咔啉杂合咪唑类化合物。目标化合物经1HNMR、13C NMR和HRMS确证结构。采用MTT(噻唑蓝)法检测了目标化合物对肺癌细胞(A549)，胃癌细胞(BGC-823)，结肠癌细胞(CT-26)，肝癌细胞(Bel-7402)和乳腺癌细胞(MCF-7)的体外抗肿瘤活性，结果表明大部分化合物对这五种肿瘤细胞株表现出了中等及优良的抑制活性。特别是化合物3-苄基-11-(3-苯基丙基)-11H-咪唑并[1",5":1,2]吡啶并[3,4-b]吲哚(Ⅴr)，对CT-26，Bel-7402和MCF-7 细胞株的抑制活性均小于10 μmol/L。此外，分子对接结果表明化合物3-苄基-11-甲基-11H-咪唑并[1",5":1,2]吡啶并[3,4-b]吲哚(Ⅴa)，3-苄基-11-丁基-11H-咪唑并[1",5":1,2]吡啶并[3,4-b]吲哚(Ⅴf)和3-苄基-11-(3-苯基丙基)-11H-咪唑并[1",5":1,2]吡啶并[3,4-b]吲哚(Ⅴr)与VEGFR2的多个氨基酸残基具有良好的结合作用。

Abstract:

β-carboline derivatives have been reported to possess multi-therapeutic potential owing to the manifestations of different pharmacological effects. In the current study, L-tryptophan was utilized as a starting material for the efficiently synthesis of several hybrid compounds of the type β-carboline N2-fused imidazole using aromatization, oxidation and decarboxylation reaction. The target products were obtained in good yields and were characterized by NMR (1H and 13C) and HRMS analysis. The newly synthesized β-carboline N2-fused imidazole derivatives were evaluated for their cytotoxic activity against five cancer cells, namely, MCF-7, A-549, BGC-823, CT-26, and Bel-7402 using viability testing tetrazolium dye (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT). The results showed that most of the compounds exhibited moderate to excellent activity against the tested cancer cell lines. Especially compound 3-benzyl-11-(3-phenylpropyl)-11H-imidazo[1",5":1,2]pyrido[3,4-b]indole (Ⅴr), bearing a benzyl group in imidazole ring and a 3-phenylpropyl in β-carboline core, was found to be the most potent anti-proliferative agent against CT-26, Bel-7402, and MCF-7 cell lines with the IC50 values lower than 10 μmol/L. In molecular docking studies, blind docking of compounds 3-benzyl-11-methyl-11H-imidazo [1",5":1,2]pyrido[3,4-b]indole (Ⅴa), 3-benzyl-11-butyl-11H-imidazo[1",5":1,2]pyrido[3,4-b]indole (Ⅴf), and 3-benzyl-11-(3-phenylpropyl)-11H-imidazo[1",5":1,2]pyrido[3,4-b]indole (Ⅴr) were accomplished to find the interactions between the compounds and VEGFR2 enzyme.