Li Na, Wang Junjie, Zhang Lulu, Zhang Xueling, Ju Wei, Zhang Yongqing, Sun Jianbo, Chen Li
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
Sate Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, 15 Yucai Road, Guilin 541004, China.
J Med Chem. 2024 Aug 22;67(16):14329-14344. doi: 10.1021/acs.jmedchem.4c01160. Epub 2024 Aug 2.
As an oleanolic acid derivative, CDDO-Me lacks selectivity for tumors. Based on the high reactive oxygen species (ROS) level in cancer cells, compound was selected from 17 new CDDO arylboronate ester derivatives. A preliminary study revealed that displayed the highest selectivity for cancer cells. Furthermore, could be transformed to by ROS to increase its covalent binding ability and antiproliferation effect (IC of 2.11 vs 0.37 μM) in BGC-823 cells. Interestingly, increased ROS levels to induce apoptosis in BGC-823 cells. Moreover, the LD of (91.2 mg/kg) was much greater than that of CDDO-Me (61.7 mg/kg) in ICR mice. A pharmacokinetic study indicated that could be transformed to in vivo. In addition, exhibited a greater tumor inhibition rate (86.2%) than CDDO-Me (51.7%). Overall, the design of provided an effective modification strategy for CDDO to increase the selectivity for cancer cells.
作为一种齐墩果酸衍生物，CDDO-Me对肿瘤缺乏选择性。基于癌细胞中高活性氧（ROS）水平，从17种新型CDDO芳基硼酸酯衍生物中筛选出化合物。初步研究表明，该化合物对癌细胞具有最高的选择性。此外，该化合物可被ROS转化为另一种化合物，以增强其共价结合能力和在BGC-823细胞中的抗增殖作用（IC分别为2.11 μM和0.37 μM）。有趣的是，该化合物可提高ROS水平以诱导BGC-823细胞凋亡。此外，在ICR小鼠中，该化合物的半数致死量（LD，91.2 mg/kg）远高于CDDO-Me（61.7 mg/kg）。药代动力学研究表明，该化合物在体内可转化为另一种化合物。此外，该化合物的肿瘤抑制率（86.2%）高于CDDO-Me（51.7%）。总体而言，该化合物的设计为CDDO提供了一种有效的修饰策略，以提高对癌细胞的选择性。
