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

doi:10.6023/cjoc201908015

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

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

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 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 Chao^a, Liu Zhijun^a,b, Li Yanbing^a, He Yepu^a, Lin Xiaohong^b, Chen Heru^a,c

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).

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Abstract

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 (P_e) 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

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Zhang Chao, Liu Zhijun, Li Yanbing, He Yepu, Lin Xiaohong, Chen Heru. 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[J]. Chinese Journal of Organic Chemistry, 2020, 40(2): 536-540.

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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

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

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