Qi Bowen, Wang Xinyi, Zhou Yangyang, Han Qiao, He Ling, Gong Tao, Sun Xun, Fu Yao, Zhang Zhirong
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
Fitoterapia. 2015 Jun;103:242-51. doi: 10.1016/j.fitote.2015.04.008. Epub 2015 Apr 11.
Triptolide (TP), a naturally derived compound, is proven effective in the treatment of nephritis and chronic allograft nephropathy. However, the severe multiorgan toxicity greatly limited it from further clinic use. 2-Glucosamine was demonstrated as a potential targeting ligand that could specifically interact with megalin receptors highly expressed in renal proximal tubules. In this study, 2-glucosamine was employed as a glycosyl donor while triptolide the acceptor to afford a nonhydrolyzable triptolide derivative-triptolide aminoglycoside (TPAG). The kidney-targeting efficiency, pharmacodynamic properties and safety of TPAG were thus evaluated. TPAG displayed 6.94-fold of AUC(0-t, kidney) and 13.96-fold of MRT(0-t, kidney) compared to TP. Additionally, TPAG presented improved protective effect against renal ischemia/reperfusion injury. Compared to TP's multiorgan toxicity, TPAG showed minimum toxicity toward the kidney and genital systems, and greatly lowered toxicity in the liver and immune systems. In sum, our study presented an alternative structure modification of triptolide with improved safety and efficacy profiles.
雷公藤甲素（TP）是一种天然衍生化合物，已被证明在治疗肾炎和慢性移植肾肾病方面有效。然而，其严重的多器官毒性极大地限制了它在临床上的进一步应用。2-氨基葡萄糖被证明是一种潜在的靶向配体，可与肾近端小管中高表达的巨蛋白受体特异性相互作用。在本研究中，2-氨基葡萄糖被用作糖基供体，而雷公藤甲素作为受体，以制备一种不可水解的雷公藤甲素衍生物——雷公藤甲素氨基糖苷（TPAG）。因此评估了TPAG的肾脏靶向效率、药效学性质和安全性。与TP相比，TPAG的AUC(0-t, 肾脏)为其6.94倍，MRT(0-t, 肾脏)为其13.96倍。此外，TPAG对肾缺血/再灌注损伤的保护作用有所改善。与TP的多器官毒性相比，TPAG对肾脏和生殖系统的毒性最小，对肝脏和免疫系统的毒性也大大降低。总之，我们的研究提出了一种雷公藤甲素的结构修饰方法，其安全性和有效性得到了改善。
