靶向iNOS的雷公藤甲素氨基酸前药的合成

Synthesis of triptolide amino acid prodrugs targeting iNOS

雷公藤甲素(TL)是从卫矛科雷公藤中提取的环氧二萜内酯,具有显著的抗炎和免疫抑制活性,但TL本身毒性较大、水溶性差、治疗窗窄,极大地限制其在临床上的应用。以炎症部位过度表达的诱导型一氧化氮合酶(iNOS)为靶点,在TL结构中引入iNOS底物及其类似物设计合成系列雷公藤甲素氨基酸前药,提高其水溶性和靶向性。雷公藤甲素氨基酸前药的化学合成以TL为原料,首先与琥珀酸酐缩合得到雷公藤甲素琥珀酸酯(TR),然后在HATU/DIPEA缩合体系下与未保护ω-NH 2的氨基酸一锅法合成9个目标化合物(TR-1~TR-9),其结构经^1H-NMR,^13C-NMR和HRMS(ESI)确证。雷公藤甲素氨基酸前药的HPLC归一化含量和稳定性均满足后续的生物活性实验要求,有利于该类新药筛选的顺利实施。

Triptolide(TL)is an epoxide diterpenoid lactone extracted from Radix et Rhizoma Tripterygii Wilfordii,which has significant anti-inflammatory and immunosuppressive activities.However,toxicity,poor water-solubility and narrow therapeutic window of TL itself greatly limits its clinical application.iNOS,the inducible nitric oxide synthase(iNOS)overexpressed in inflammatory sites,were used as the target,and iNOS substrates and their analogues were introduced into TL structures to design and synthesize triptolide prodrugs,so as to improve their water-solubility and targeting properties.TL was used as raw material for the chemical synthesis of triptolide amino acid prodrugs.Triptolide succinate(TR)was produced by condensation with succinic anhydride,and 9 target compounds were synthesized by HATU/DIPEA condensation system with amino acids without amino protection group.Their structures were supported by^1H-NMR,^13C-NMR and HRMS(ESI).The normalized content and stability of triptolide amino acid prodrugs by HPLC met the requirements of subsequent bioactivity experiments,which was conducive to the smooth implementation of the screening of this new drug.