新型Hsp90抑制剂的设计合成及其抗真菌和抗肿瘤活性研究  

Design,synthesis and antifungal and antitumor activity research of novel Hsp90 inhibitors

作　　者：施乔 韩贵焱 张俊腾 刘娜 SHI Qiao;HAN Guiyan;ZHANG Junteng;LIU Na(School of Pharmacy,Naval Medical University,Shanghai 200433,China)

机构地区：[1]海军军医大学药学系,上海200433

出　　处：《药学实践与服务》2025年第3期124-135,共12页Journal of Pharmaceutical Practice and Service

基　　金：国家自然科学基金(82373734)。

摘　　要：目的以Hsp90抑制剂Ganetespib为先导化合物,设计、合成兼具协同氟康唑(FLC)抗耐药真菌和抗肿瘤双重作用的新型Hsp90抑制剂。方法前期研究发现Ganetespib具有良好协同FLC抗耐药真菌活性,协同指数(FICI)=0.023~0.039,本研究对Ganetespib进行结构改造,将其吲哚环替换为含不同取代基的苯环,设计合成一系列新化合物,并测定其体外协同FLC抗耐药真菌C.albicans 0304103和抗肿瘤(HEL、HL60和A549细胞)及Hsp90α抑制等活性,探讨其构效关系和作用机制。结果19个新化合物的化学结构经氢谱(1H NMR)、碳谱(13C NMR)和高分辨质谱(HRMS)确证;绝大多数化合物具有较强的Hsp90α抑制活性、良好的协同FLC抗耐药真菌活性和抗肿瘤活性,苯环上供电子基取代对提升协同FLC抗耐药真菌活性有利;其中,化合物F3和F5具有优秀的协同FLC抗耐药真菌活性(FICI均为0.047)和抗肿瘤活性(IC50分别为0.025~0.15μmol/L,0.021~0.23μmol/L),且能下调真菌耐药基因和外排泵基因表达水平,抑制真菌生物被膜的形成,并能阻滞HEL细胞的细胞周期于G0/G1期。结论新型Hsp90抑制剂如F3和F5均能有效发挥协同FLC抗耐药真菌和抗肿瘤双重活性,这为研发具有协同FLC抗耐药真菌和抗肿瘤双重作用的新药提供新的思路。Objective To design and synthesize novel Hsp90 inhibitors with dual functions of synergistically enhancing the antifungal activity of fluconazole(FLC)against drug-resistant fungi and anti-tumor activity based on the Hsp90 inhibitor Ganetespib.Methods The previous research found that Ganetespib had a good synergistic anti-resistant fungal activity with FLC,with a fractional inhibitory concentration index(FICI)of 0.023 to 0.039.In this study,structural modifications were made to Ganetespib by replacing its indole ring with a phenyl ring containing different substituents to design and synthesize a series of new compounds.The in vitro synergistic anti-resistant fungal activity against C.albicans 0304103 in combination with FLC,anti-tumor activity(against HEL,HL60 and A549 cells),and Hsp90αinhibition activity were determined to explore their structure-activity relationship and mechanism of action.Results The chemical structures of 19 new compounds were confirmed by 1H NMR,13C NMR and HRMS.Most of the compounds exhibited strong Hsp90αinhibitory activity,good synergistic activity against drug-resistant fungi in combination with FLC and anti-tumor activity.The substitution of electron-donating groups on the benzene ring was beneficial to enhancing the synergistic activity against drug-resistant fungi in combination with FLC.Among them,compounds F3 and F5 showed excellent synergistic activity against drug-resistant fungi in combination with FLC(FICI were both 0.047)and anti-tumor activity(IC50 were 0.025 to 0.15μmol/L and 0.021 to 0.23μmol/L respectively),and could down-regulate the expression levels of drug resistance genes and efflux pump genes in fungi,inhibit the formation of fungal biofilms,and arrest the cell cycle of HEL cells at G0/G1 phase.Conclusion The novel Hsp90 inhibitors such as F3 and F5 could both effectively exert the dual activities of synergizing with FLC to combat drug-resistant fungi and fight against tumors,which provided a new idea for the development of new drugs with dual functions of synergi

关 键 词：HSP90抑制剂 Ganetespib 白念珠菌 抗真菌耐药性 抗肿瘤 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]