新型含有金刚烷苯乙烯结构单元化合物的合成和初步抗肿瘤增殖

以金刚烷苯乙烯为结构单元,设计合成了3个含有亲水性基团的新型小分子(8a、8b和8c),利用核磁共振谱、红外光谱和高分辨质谱等技术手段对其进行了结构表征。用1-溴代金刚烷作为原料在Pd/C和K2CO3的作用下发生傅克烷基化反应高产率得到金刚烷甲苯(2),随后在N-溴代琥珀酰亚胺(NBS)和(三苯基膦烯基)乙酸甲酯过氧化苯甲酰(BPO)的作用下发生溴代反应得到了金刚烷苄基溴的化合物3,苄基溴在酸性条件下氧化生成醛(4),该醛与维蒂希试剂发生Wittig反应得到甲酸甲酯(5),随后发生碱性条件水解得到重要的中间体6。最后该中间体与3个结构不同的苯胺类化合物发生偶联反应生成了3个目标化合物。通过MTS法评价了3个化合物对人肝癌细胞(SMMC7721)、乳腺癌细胞(MCF-7)、宫颈癌细胞(Hela)、肺癌细胞(A549)的增殖抑制活性。结果表明,部分化合物表现出较好的抑制活性。其中,目标化合物8c对人肝癌细胞表现出较好的抗肿瘤活性(IC_(50)=1.6μmol/L或0.73 mg/L),与现有药物阿霉素相当(0.44 mg/L),有望成为潜在的抗肿瘤药物分子。该类化合物可能在靶向抗肿瘤药物研发方面具有较好的研究前景,所合成的金刚烷苯乙烯类衍生物的抗肿瘤活性、靶点及作用机制还有待进一步研究。

Synthesis and Primary Antitumor Proliferation of p-Adamantanylcinnamides

Three aniline p-adamantanylcinnamides(8a~8c) were designed and synthesized from cross coupling of 1-bromoadamantane with toluene followed by oxidation, homologation and amidation. The inhibitory assays of these compounds against human hepatocellular carcinoma cell SMMC7721, breast cancer cell MCF-7, cervical cancer cell Hela and lung cancer cell A549 by MTS method showed that compound 8c exhibited good antitumor activity against human hepatoma cells(IC₅₀=1.6 μmol/L or 0.73 mg/L) compared with doxorubicin(0.44 mg/L). This indicates that aniline p-adamantanylcinnamide is a good template for the development of anti-tumor drugs. The antitumor activity, cellular targets and the mode of action of aniline p-adamantanylcinnamide derivatives will be further studied.