中山大学学报（自然科学版）（中英文）2025，Vol.64Issue(4)：69-78,10.DOI:10.13471/j.cnki.acta.snus.ZR20250012
新型1,2-二取代肼的FAPα酶靶向前药设计及赋予的抗癌作用特征
FAPα targeting prodrug design of novel 1,2-disubstituted hydrazines and the endowed anti-cancer characteristic
摘要
Abstract
The aim of this study is to investigate the FAPα targeting prodrugs and anti-cancer characteristic of 1,2-disubstituted hydrazines.By bonding carbobenzoxy glycylprolyl(Z-GP-)on the diazinyl of 1,2-disubstituted hydrazines,two FAPα targeting prodrugs of novel 1,2-disubstituted hydrazines,including 2-carbobenzoxy glycylprol-yl-2-(4-methoxy)phenyl-1-(4-(N-isopropyl)aminoformyl)benzyl hydrazine(Z-GP-5a)and 2-carbobenzoxy glycylprolyl-2-(6-methoxy-2-yl)naphth-1-(4-(N-isopropyl)aminoformyl)benzyl hydrazine(Z-GP-5b)have been designed and synthesized.In vitro enzymatic hydrolysis model was set up to verify the cleavage possibility of Z-GP group.Mouse embryonic cells(NIH-3T3)and five common non-primary tumor cell lines including rat glioma cells(C6),mouse melanoma cells(K1735),human liver cancer cells(HepG-2),human breast cancer cells(MDA-MB-231),and murine melanoma cells(B16)were applied to confirm the toxicity-attenuation of both prodrugs.In vitro enzymatic hydrolysis experiments showed that Z-GP-5a and Z-GP-5b can be cleaved by recombinant human resource FAPα enzyme,releasing 2-(4-methoxy)phenyl-1-(4-(N-isopropyl)aminoformyl)benzyl hydrazine(5a)and 2-(6-methoxy-2-yl)naphth-1-(4-(N-isopropyl)aminoformyl)benzyl hydrazine(5b),respectively.This evidence preliminarily indicates the FAP α enzyme targeting characteristic of Z-GP-5a and Z-GP-5b.The cytotoxicity of Z-GP-5a and Z-GP-5b to NIH-3T3 showed less than that of 5a and 5b,respectively,implying the toxicity-attenuation of both prodrugs.By employing MTT assay,under the condition of 48-hour incubation,Z-GP-5a and Z-GP-5b were shown with less anti-cancer activity against five common non-primary tumor cell lines,which are C6,K1735,HepG-2,MDA-MB-231,and B16 than their respective parent compounds 5a and 5b.The anti-growth inhibition activity of Z-GP-5a to C6,K1735,and B16 was 1.23-,2.06-,and 2.38-fold less than that of 5a,respectively;while to HepG-2 and MDA-MB-231,it was 9.95-,and 15.0-fold decrease,respectively.On the other hand,the anti-growth inhibition activity of Z-GP-5b to C6,MDA-MB-231,and B16 was 6.50-,6.14-,and 13.0-fold less than that of 5b,respectively.All data support that Z-GP-5a and Z-GP-5b are the FAPα targeting prodrugs of their respective parent compounds 5a and 5b.It is expected to achieve the effect of reducing toxicity and increasing efficiency clinically.关键词
FAPα酶靶向前药/1,2-二取代肼/抗肿瘤/烷化剂/药物设计合成Key words
FAPα targeting prodrug/1,2-disubstituted hydrazines/anti-cancer/alkylation/drug design-synthesis分类
医药卫生引用本文复制引用
张超,刘璐洁,王婵茜,朱文达,何业谱,刘志军,陈河如..新型1,2-二取代肼的FAPα酶靶向前药设计及赋予的抗癌作用特征[J].中山大学学报（自然科学版）（中英文）,2025,64(4):69-78,10.基金项目
广东省自然科学基金(2021A1515011238 （）
2020A1515010857) （）
