Design,synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria |
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Authors: | Yanhui Yang Haifa Albanyan Sumi Lee Herve Aloysius Jian-Jie Liang Vladyslav Kholodovych Amrik Sahota Longqin Hu |
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Affiliation: | 1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, United States;2. Dassault Systemes BioVIA Corp, San Diego, CA 92121, United States;3. High Performance and Research Computing, Office of Advanced Research Computing, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States;4. Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, United States |
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Abstract: | To overcome the chemical and metabolic stability issues of l-cystine dimethyl ester (CDME) and l-cystine methyl ester (CME), a series of l-cystine diamides with or without Nα-methylation was designed, synthesized, and evaluated for their inhibitory activity of l-cystine crystallization. l-Cystine diamides 2a–i without Nα-methylation were found to be potent inhibitors of l-cystine crystallization while Nα-methylation of l-cystine diamides resulted in derivatives 3b–i devoid of any inhibitory activity of l-cystine crystallization. Computational modeling indicates that Nα-methylation leads to significant decrease in binding of the l-cystine diamides to l-cystine crystal surface. Among the l-cystine diamides 2a–i, l-cystine bismorpholide (CDMOR, LH707, 2g) and l-cystine bis(N′-methylpiperazide) (CDNMP, LH708, 2h) are the most potent inhibitors of l-cystine crystallization. |
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Keywords: | Cystine diamide Cystinuria Crystallization inhibition Molecular imposter |
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