STAT3抑制剂napabucasin亚砜亚胺衍生物的前药研究

Studies on the prodrugs of STAT3 inhibitor napabucasin sulfoximine derivative

目的改善napabucasin亚砜亚胺衍生物(2)的溶解性和成药性。方法基于前药策略,在化合物(2)的4,9位引入水溶性侧链,形成氨基甲酸酯和甲酸酯;在不同的pH条件下评价其前药的稳定性,在pH 7.4的磷酸盐缓冲溶液中评价前药释放化合物场2的能力,按照中国药典方法测定其溶解度,选择适当的模型对优秀的前药进行体外抗肿瘤活性评价。结果与结论设计合成了4种化合物2的前药(3a-3d);与前体药2相比,4种前药的溶解度都得到了显著提高(>10 mg·mL^-1);在酸性条件下,氨基甲酸酯类前药的稳定性很好,优于甲酸酯类前药;在中性和碱性条件下,两类前药均不稳定;在pH 7.4的磷酸盐缓冲溶液中,3种氨基甲酸酯类前药能够以一定速率释放出化合物2;前药3a的体外抗肿瘤活性与化合物2相当。综合评价,前药3a具有很好的成药性,值得进一步研究。

Napabucasin is one of the few STAT3 inhibitors entering clinical research,but its disadvantages of poor solubility,large oral dose and low bioavailability have become urgent problems to be solved.Napabucasin sulfoximine derivative(2),identified by our group,had improved antitumor activity and the solubility.However,the solubility needs to be further improved.Thus,four prodrugs(3a-3d)were designed and synthesized through the reduction of 4,9-position carbonyl groups in compound 2 and introduction of the water-soluble side chains by forming formate or carbamate.The properties of prodrugs were evaluated and the results showed that all of them have excellent solubility(>10 mg·mL^-1).In acidic buffer solution(pH 3.0 and pH 1.2),the stability of carbamate prodrugs(3a,3c and 3d)were very well,which is superior to that of formate prodrug(3b).All prodrugs were unstable in neutral and alkaline solutions.Carbamate prodrugs(3a,3c and 3d)could release the compound 2 at a certain speed in the phosphate buffer solution of pH 7.4.Moreover,prodrug 3 a showed comparable antitumor activities with compound 2.Comprehensive consideration,3a is a suitable prodrug worthy of further study.