Peng Yan, Peng Ying, Zhang Wei, Zhang Siyi, Peng Huiqian, Li Zhen, Li Bo, Liu Linyi, Zhuo Linsheng, Wang Zhen, Wu Junbo, Jiang Weifan
School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Department of Anus and Intestine Surgery, Affiliated Hengyang Hospital of Hunan Normal University and Hengyang Central Hospital, Hengyang, Hunan, China.
Front Pharmacol. 2024 Oct 30;15:1452904. doi: 10.3389/fphar.2024.1452904. eCollection 2024.
-phenyl-2-(aniline) analog is a previously discovered dual inhibitor of Topo I and COX-2, which exhibited significant anti-colon cancer activity , but the poor solubility and moderate anti-cancer activity hindered its further development.
To rectify the suboptimal drug properties of , a series of salt forms were developed and further evaluated through and experiments.
The hydrochloride () has a well-characterized crystal structure and its solubility reached 540.1 μg/mL, which is nearly 1,700 times higher than that of (0.32 μg/mL). Increasing the solubility consistently promotes its effective concentration, further enhancing the COX-2/Topo I inhibitory activity and the anti-tumor activity (IC values of 2.95 ± 0.08 μM for HT29 cells, 7.99 ± 0.85 μM for RKO cells, 10.94 ± 1.30 μM for HCT116 cells), as well as the anti-proliferative and pro-apoptotic activity. Meanwhile, its oral pharmacokinetic property is also improved. The elimination half-life (T1/2) is prolonged from 10.78 to 22.29 h, the maximum plasma concentration (C) is increased 2-fold, and the area under the plasma drug concentration-time curve (AUC) is increased 3-fold. In colon cancer xenograft mouse models, the tumor inhibition rate of was 53.7%, superior to that of (34.7%). Moreover, the results of HE staining showed that had no obvious toxic effects and side effects on other organs, indicating that it was safe .
This study demonstrated that exhibits superior pharmacokinetic properties, anti-colon cancer efficacy, and safety, providing a promising drug candidate for colon cancer therapy.
-苯基-2-(苯胺)类似物是一种先前发现的拓扑异构酶I和COX-2双重抑制剂，具有显著的抗结肠癌活性，但溶解度差和抗癌活性中等阻碍了其进一步开发。
为改善的药物性能欠佳问题，开发了一系列盐形式，并通过实验和实验进行进一步评估。
盐酸盐()具有特征明确的晶体结构，其溶解度达到540.1μg/mL，比(0.32μg/mL)高出近1700倍。增加的溶解度持续提高其有效浓度，进一步增强COX-2/拓扑异构酶I抑制活性和抗肿瘤活性(HT29细胞的IC值为2.95±0.08μM，RKO细胞为7.99±0.85μM，HCT116细胞为10.94±1.30μM)，以及抗增殖和促凋亡活性。同时，其口服药代动力学性质也得到改善。消除半衰期(T1/2)从10.78小时延长至22.29小时，最大血浆浓度(C)增加2倍，血浆药物浓度-时间曲线下面积(AUC)增加3倍。在结肠癌异种移植小鼠模型中，的肿瘤抑制率为53.7%，优于(34.7%)。此外，HE染色结果表明对其他器官无明显毒性作用和副作用，表明其安全。
本研究表明具有优异的药代动力学性质、抗结肠癌疗效和安全性，为结肠癌治疗提供了一个有前景的候选药物。
