炔基化聚天冬酰胺开环衍生物的合成及生物相容性研究

Synthesis and biocompatibility of ethynylated open ring derivatives of polyasparamide

目的合成一种新的炔基化聚天冬酰胺-g-苯丙氨酸衍生物用作功能化药物载体。方法以L-苯丙氨酸为原料制备苯丙氨酸甲酯盐酸盐,对聚琥珀酰亚胺(polyasparamide,PSI)进行开环反应得到聚天冬酰胺-g-苯丙氨酸衍生物PSI-Phe-OMe,使用炔丙胺进一步开环得到炔基化的聚天冬酰胺-g-苯丙氨酸衍生物PSI-Phe-OMe-PA;通过1HNMR进行聚合物结构确证;通过MTT法、显微观察法和碘化丙啶(PI)染色法等确定PSI-Phe-OMe-PA对细胞增殖、形态以及细胞周期的影响。结果1HNMR确证了PSI-Phe-OMe-PA的分子结构,苯丙氨酸甲酯盐酸盐对PSI的开环率为40%,炔丙胺进一步开环后可使开环率接近100%;MTT实验表明PSI-Phe-OMePA对NIH 3T3和Hep G2 2种细胞的毒性较小,在浓度为100μg/m L时细胞存活率仍在80%左右,且对细胞形貌和细胞周期无显著影响。结论苯丙氨酸甲酯和炔丙胺可依次对聚琥珀酰亚胺进行开环合成炔基化的聚天冬酰胺开环衍生物PSI-Phe-OMe-PA,且PSIPhe-OMe-PA是一类安全的功能化药物载体。

Objective To synthesize a new ethynylated open ring derivatives of polyasparamide as functional drug carrier. Methods L-phenylalanine methyl ester hydrochloride was prepared using L-phenylalanine and then was used for ring opening reaction of polysuccinimide. To synthesize the target product of PSI-Phe-OMe-PA,the obtained polyasparamide-g-phenylalanine derivatives（ PSI-Phe-OMe） was further ring opened by propargylamine. The structure of PSI-Phe-OMe-PA was confirmed by1 H NMR. The biocompatibility of PSI-Phe-OMe-PA was evaluated by MTT method,inverted microscope observation and cell cycles analysis（ propidium iodide staining）. Results The ring-opening rate of polyasparamide by L-phenylalanine methyl ester and propargylamine was 40% and 100%,respectively. All results of biocompatibility studies indicated that PSI-Phe-OMe-PA may be a good candidate for functional drug carrier. Conclusion Based on the ring-opening capability of amino-group and the specificity of click reaction,L-phenylalanine methyl ester hydrochloride and propargylamine were used successively to react with polyasparamide. PSI-Phe-OMe-PA is a biocompatible functional drug carrier.