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目的合成18种氨基酸酯基二硫代甲酸酯类化合物(化合物1～18),并进行体外抗肿瘤活性以及抗乙肝病毒(HBV)活性评价。方法以L-苯丙氨酸、L-丙氨酸、L-亮氨酸、L-异亮氨酸、L-谷氨酸及L-甘氨酸的甲酸酯为原料,通过碱催化,与CS2和卤代烷缩合反应,合成18种氨基酸酯基二硫代甲酸酯类化合物。化合物的结构及组成经过质谱、1 H-NMR和熔点仪测试技术进行了表征。利用MTT法测定目标化合物1～18对子宫颈癌HeLa、肝癌HepG2、胃癌BGC-823、乳腺癌MCF-7、结肠癌SW-480细胞株的增殖抑制作用;ELISA法测定对HBsAg和HBeAg的抑制效果;实时荧光定量PCR法检测上清液中HBV DNA的表达量。结果化合物11、12、17和18对上述5种肿瘤细胞株增殖有较好的抑制作用;相对于阳性对照拉米呋啶,化合物14和15能够较好的抑制HBV抗原的分泌和病毒DNA的复制。化合物14抑制HBV DNA、HBsAg和HBeAg的IC50值分别是0.43、0.28和0.1mmol·L-1;化合物15的IC50值分别为0.24、0.02、0.03mmol·L-1。结论这些二硫代甲酸酯类衍生物中,化合物11、12、17和18在体外具有抑制肿瘤细胞增殖的活性;化合物14和15在体外对HBV有较好的抑制作用。该研究为进一步开发二硫酯在抗肿瘤及抗病毒方面奠定了很好的基础。
Objective To synthesize 18 kinds of amino acid ester dithiocarbamates (compounds 1 ~ 18) and evaluate the antitumor activity in vitro and the activity against hepatitis B virus (HBV). Methods L-phenylalanine, L-alanine, L-leucine, L-isoleucine, L-glutamic acid and L-glycine formate, And halogenated alkyl condensation reaction, synthesis of 18 kinds of amino acid ester dithiocarbamate compounds. The structure and composition of the compounds were characterized by mass spectrometry, 1 H-NMR and melting point test. The inhibitory effects of target compounds 1-18 on the proliferation of cervical cancer HeLa, HepG2, gastric cancer BGC-823, breast cancer MCF-7 and colon cancer SW-480 cell lines were determined by MTT assay. The inhibition of HBsAg and HBeAg by ELISA The effect of HBV DNA in supernatant was detected by real-time fluorescence quantitative PCR. Results Compounds 11, 12, 17 and 18 inhibited the proliferation of the above five tumor cell lines. Compared with the positive control lamivudine, compounds 14 and 15 were able to inhibit HBV antigen secretion and viral DNA copy. The IC50 values of compound 14 for inhibiting HBV DNA, HBsAg and HBeAg were 0.43, 0.28 and 0.1 mmol·L-1, respectively. The IC50 values of compound 15 were 0.24, 0.02 and 0.03 mmol·L-1, respectively. Conclusion Among these dithioformate derivatives, compounds 11, 12, 17 and 18 have the activity of inhibiting the proliferation of tumor cells in vitro. Compounds 14 and 15 have good inhibitory effect on HBV in vitro. This study laid a good foundation for the further development of dithioesters in the aspects of anti-tumor and anti-virus.