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目的为了克服上市药物伊立替康酶转化率低、个体差异大以及由乙酰胆碱酯酶抑制作用而引发的毒副作用等不足,设计合成高效低毒的新喜树碱前药。方法以线性氨基酸为连接子,氨基酸N端通过氨基甲酸酯键与7-乙基-10-羟基喜树碱(SN38)的10-OH相连,并选择生物相容性好的N-甲基哌嗪通过酰胺键与氨基酸分子C端相连,利用N-甲基哌嗪结构中氮原子的碱性与盐酸成盐以提高水溶性。以苄基保护的一系列氨基酸为起始原料,将其通过与三光气反应生成相应的异氰酸酯,再与SN38 10-OH通过氨基甲酸酯键相连,随后通过催化氢化反应脱去结构中的苄基保护基,游离出羧基,N-甲基哌嗪通过酰胺键与游离羧基相连,最后成盐,得系列目标化合物,并对其进行体外细胞毒性评价、乙酰胆碱酯酶活性评价及稳定性测定。结果与结论共合成11个未见文献报道的新化合物,其结构经1H-NMR及MS谱确证。目标化合物在人结肠癌细胞株SW1116、人肺腺癌细胞株A549及人胃癌细胞株SGC-7901中的细胞毒性均强于阳性对照药物伊立替康。稳定性实验结果表明目标化合物可在生理条件下充分释放出活性药物,且在酸性条件下可稳定存在。乙酰胆碱酯酶活性评价结果表明,所有化合物对乙酰胆碱酯酶的抑制活性较伊立替康明显降低,IC50值均在10μmol·L-1以上,较伊立替康提高了100倍,极大地降低了化合物对乙酰胆碱酯酶的抑制作用,降低了毒副作用。本文还对此系列化合物的构效关系进行了初步讨论。
Objective To overcome the shortcomings of low conversion rate of listed drug irinotecan, individual differences and toxicity and side effects caused by inhibition of acetylcholinesterase, a new camptothecin prodrug with high potency and low toxicity was designed and synthesized. Methods A linear amino acid was used as the linker. The N-terminal amino acid was linked to the 10-OH of 7-ethyl-10-hydroxycamptothecin (SN38) via urethane bond and the biocompatible N-methyl Piperazine is linked to the C-terminal of the amino acid molecule through an amide bond, and utilizes the basicity of the nitrogen atom in the N-methylpiperazine structure to form a salt with hydrochloric acid to improve water solubility. A series of benzyl protected amino acids are used as starting materials, which are reacted with triphosgene to form the corresponding isocyanates, which are then linked to the SN38 10-OH via a carbamate bond, followed by catalytic hydrogenation to remove the benzylic Free carboxyl group, N-methylpiperazine is connected to the free carboxyl group via amide bond, and finally salified to obtain a series of target compounds. The cytotoxicity, acetylcholinesterase activity and stability of the compounds were evaluated in vitro. RESULTS AND CONCLUSIONS A total of 11 new compounds were reported in the literature, whose structures were confirmed by 1H-NMR and MS spectra. The cytotoxicity of the target compound in human colon cancer cell line SW1116, human lung adenocarcinoma cell line A549 and human gastric cancer cell line SGC-7901 was stronger than that of the positive control drug irinotecan. The stability of the experimental results show that the target compound can fully release the active drug under physiological conditions, and under acidic conditions can be stably present. The results of the evaluation of acetylcholinesterase activity showed that the inhibitory activity of all compounds on acetylcholinesterase was significantly lower than that of irinotecan, the IC50 values were above 10 μmol·L-1, which was 100 times higher than that of irinotecan, Acetylcholinesterase inhibition, reduce the toxic side effects. The structure-activity relationship of this series of compounds is also discussed in this paper.