Wang Yujie, Xu Keshi, Liu Hongchun, Zhang Wei, Hu Chun, Li Yingxia
School of Pharmacy, Fudan University, Shanghai 201203, China.
Key Laboratory of Structure-based Drug Design & Discovery, Ministry of Education of China, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
Bioorg Med Chem Lett. 2023 Oct 15;95:129493. doi: 10.1016/j.bmcl.2023.129493. Epub 2023 Oct 2.
Auristatins-glucuronide conjugates designed targeting the β-Glucuronidase in tumor microenvironment were synthesized and evaluated on stabilities, the release of auristatins and the antitumor activities in this study. Conjugates 20 and 21 showed remarkable stabilities in phosphate buffer and bovine serum solution, and excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase pretreated and untreated cancer cells (IC = 5.7 nM ∼ 9.7 nM, IC (-Enz) > 1 μM). Furthermore, conjugate 20 showed potent antitumor efficacy in HCT-116 xenograft mouse model without inducing side effects.
本研究合成了靶向肿瘤微环境中β-葡萄糖醛酸酶的奥瑞他汀-葡萄糖醛酸缀合物，并对其稳定性、奥瑞他汀释放情况及抗肿瘤活性进行了评估。缀合物20和21在磷酸盐缓冲液和牛血清溶液中表现出显著的稳定性，并且在针对经β-葡萄糖醛酸酶预处理和未处理的癌细胞的体外抗增殖活性之间具有出色的选择性（IC = 5.7 nM至9.7 nM，IC(-Enz)>1 μM）。此外，缀合物20在HCT-116异种移植小鼠模型中显示出强大的抗肿瘤功效，且未引发副作用。
