Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria.
Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria.
复制标题
作为胱氨酸尿症的 L-胱氨酸结晶抑制剂的 L-胱氨酸二酰胺的设计、合成和评估。
DOI：
10.1016/j.bmcl.2018.03.024
复制
发表时间：
2018
影响因子：
2.7
通讯作者：
Hu,Longqin
中科院分区：
文献类型：
--
作者：
Yang,Yanhui;Albanyan,Haifa;Lee,Sumi;Aloysius,Herve;Liang,Jian-Jie;Kholodovych,Vladyslav;Sahota,Amrik;Hu,Longqin
为了克服L-胱氨酸二甲酯（CDME）和L-胱氨酸甲酯（CME）的化学和代谢稳定性问题，设计、合成了一系列N α-甲基化或非N α-甲基化的L-胱氨酸二酰胺，无N α-甲基化的L-胱氨酸二酰胺2a-1是有效的L-胱氨酸结晶抑制剂，而N α-甲基化的L-胱氨酸二酰胺衍生物3b-1是有效的L-胱氨酸结晶抑制剂。对L-胱氨酸结晶没有任何抑制活性。计算模型表明，N α-甲基化导致半胱氨酸二酰胺与半胱氨酸晶体表面的结合能力显著降低。L-胱氨酸双吗啉（CDMOR，LH 707，2g）和L-胱氨酸双（N′-甲基哌嗪）（CDNMP，LH 708，2 h）是抑制L-胱氨酸结晶最有效的化合物。
To overcome the chemical and metabolic stability issues ofl-cystine dimethyl ester (CDME) andl-cystine methyl ester (CME), a series ofl-cystine diamides with or withoutNα-methylation was designed, synthesized, and evaluated for their inhibitory activity ofl-cystine crystallization.l-Cystine diamides2a–iwithoutNα-methylation were found to be potent inhibitors ofl-cystine crystallization whileNα-methylation ofl-cystine diamides resulted in derivatives3b–idevoid of any inhibitory activity ofl-cystine crystallization. Computational modeling indicates thatNα-methylation leads to significant decrease in binding of thel-cystine diamides tol-cystine crystal surface. Among thel-cystine diamides2a–i,l-cystine bismorpholide (CDMOR, LH707,2g) andl-cystine bis(N′-methylpiperazide) (CDNMP, LH708,2h) are the most potent inhibitors ofl-cystine crystallization.