Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (2): 536-540.DOI: 10.6023/cjoc201908015 Previous Articles     Next Articles


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 发布日期:2019-10-09
  • 通讯作者: 陈河如
  • 基金资助:

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 Published:2019-10-09
  • Supported by:
    Project supported by the Natural Science Foundation of Guangdong Province (No. 2018B030311020).

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