有机化学 ›› 2020, Vol. 40 ›› Issue (2): 536-540.DOI: 10.6023/cjoc201908015 上一篇    下一篇

研究简报

靶向抗肿瘤药N-(N'-苄氧羰基甘氨酰脯氨酰)丙卡巴肼(Z-GP-Pcb)的环境友好合成及其透过血脑屏障活性评价

张潮a, 刘志军a,b, 李艳冰a, 何业谱a, 林晓洪b, 陈河如a,c   

  1. a 暨南大学药学院 中药及天然药物研究所 广州 510632;
    b 广州药本君安医药科技股份有限公司 广州 510663;
    c 广东省中药药效物质基础及创新药物研究重点实验室 广州 510632
  • 收稿日期:2019-08-10 修回日期:2019-09-21 出版日期:2020-02-25 发布日期:2019-10-09
  • 通讯作者: 陈河如 E-mail:thrchen@jnu.edu.cn
  • 基金资助:
    广东省自然科学基金(No.2018B030311020)资助项目.

Environment-Friendly Synthesis of Targeted Anticancer Drug N-(N'-Carbobenzoxyglycylprolyl)procarbazine (Z-GP-Pcb) and the Evaluation of Its Activity to Penetrate Blood-Brain Barrier

Zhang Chaoa, Liu Zhijuna,b, Li Yanbinga, He Yepua, Lin Xiaohongb, Chen Herua,c   

  1. a Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632;
    b Guangzhou PharmCherub Medical Sci. &Tech. Incorporated Corporation, Guangzhou 510663;
    c Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou 510632
  • Received:2019-08-10 Revised:2019-09-21 Online:2020-02-25 Published:2019-10-09
  • Supported by:
    Project supported by the Natural Science Foundation of Guangdong Province (No. 2018B030311020).

利用靶向策略设计了抗肿瘤药物N-(N'-苄氧羰基甘氨酰脯氨酰)丙卡巴肼(Z-GP-Pcb),发展了3步法合成丙卡巴肼(Pcb).首先以4-甲基苯甲醛为原料,经二溴异氰脲酸(DBI)转化为N-异丙基-4-甲基苯酰胺.该化合物经2-碘酰基苯甲酸(IBX)直接氧化为N-异丙基-4-甲酰基苯酰胺,随后还原胺化得Pcb.最后与N-苄氧羰基甘氨酰脯氨酸缩合得Z-GP-Pcb,总收率49.9%.另外,本研究还建立了体外平行人造膜渗透测血脑屏障(PAMPA-BBB)方法评价Z-GP-Pcb透过血脑屏障(BBB)活性,发现其透膜常数(Pe)为(19.22±4.25)×10-6 cm·s-1,大于母药Pcb[(11.14±1.34))×10-6 cm· s-1],具有较高的透过BBB活性.

关键词: 药物合成, 丙卡巴肼, 药物设计, 靶向抗肿瘤, 成纤维细胞激活蛋白α

Anti-cancer drug N-(N'-carbobenzoxyglycylprolyl)procarbazine (Z-GP-Pcb) has been designed based on targeting strategy and a 3-step method has been developed for the synthesis of procarbazine (Pcb). Firstly, 4-methylbenaldehyde, as starting material, was transformed into N-isopropyl-4-methylbenzamide using dibromoisocyanuric acid (DBI). This compound was then directly oxidized to N-isopropyl-4-formylbenzamide by 2-iodoxybenzoic acid (IBX). A reductive amination reaction was then followed leading to Pcb. At last, Pcb was condensed with N-carbobenzoxyglycylproline resulting in Z-GP-Pcb. The overall yield was 49.9%. Furthermore, an in vitro blood-brain barrier (BBB) permeation assay (PAMPA-BBB) was set up to evaluate the permeation activity of Z-GP-Pcb. It was found that the permeation constant (Pe) was (19.22±4.25)×10-6 cm·s-1, which was more than that of the parent drug Pcb[(11.14±1.34))×10-6 cm·s-1]. This evidence suggests that Z-GP-Pcb possesses high activity to penetrate BBB.

Key words: drug synthesis, procarbazine, drug design, targeted anti-cancer, fibroblast activation protein-α