摘要/Abstract
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
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