Huang Zhenhua, Li Gentao, Wang Xue, Xu Hu, Zhang Youcai, Gao Qingzhi
School of Pharmaceutical Science and Technology , Tianjin University , Tianjin 300072 , P. R. China . Email:
Department of Biochemistry , Gudui BioPharma Technology Inc. , 5 Lanyuan Road , Huayuan Industrial Park , Tianjin 300384 , P. R. China.
Medchemcomm. 2017 Jun 12;8(7):1542-1552. doi: 10.1039/c7md00246g. eCollection 2017 Jul 1.
Cellular uptake and transport mechanisms directly correlate with the drug-like profiles of lead compounds. To decipher the molecular origin of the toxicity of combretastatin A4 (CA4), an important microtubule targeting agent, we investigated the interactions between CA4 and six key drug transporters, namely hOAT1, hOAT3, hOCT1, hOCT2, hOATP1B3, and hOATP2B1. Three combretastatin-based glycoconjugates, namely , , and with glucose, mannose, and galactose respectively, were synthesized and their and biological characteristics were evaluated. CA4 exhibited significant inhibition against hOAT3 and hOATP2B1, moderate inhibition of hOAT1 and hOCT2, and weak inhibitory effects on hOCT1 and hOATP1B3. Compared to CA4, the inhibitory activities of on the six transporters were minimal. The glycoconjugates were found to have a superior safety profile with their maximum tolerated dose (MTD) values exhibiting a 16-34-fold increase compared to CA4. Given the drawbacks of CA4, the enhanced solubility and safety profiles of CA4 glycoconjugates augur well for further investigation into these intriguing candidates' efficacy.
细胞摄取和转运机制与先导化合物的类药性质直接相关。为了解释重要的微管靶向剂康普瑞汀A4（CA4）毒性的分子起源，我们研究了CA4与六种关键药物转运蛋白之间的相互作用，这六种转运蛋白分别是hOAT1、hOAT3、hOCT1、hOCT2、hOATP1B3和hOATP2B1。我们合成了三种分别与葡萄糖、甘露糖和半乳糖结合的基于康普瑞汀的糖缀合物，并评估了它们的体外和体内生物学特性。CA4对hOAT3和hOATP2B1表现出显著抑制作用，对hOAT1和hOCT2有中度抑制作用，对hOCT1和hOATP1B3有较弱的抑制作用。与CA4相比，[此处原文缺失糖缀合物名称]对这六种转运蛋白的抑制活性极小。发现这些糖缀合物具有更好的安全性，其最大耐受剂量（MTD）值比CA4增加了16至34倍。鉴于CA4的缺点，CA4糖缀合物增强的溶解性和安全性为进一步研究这些有趣候选物的疗效带来了良好的前景。
