Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria

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 N^α-methylation was designed, synthesized, and evaluated for their inhibitory activity of l-cystine crystallization. l-Cystine diamides 2a-i without N^α-methylation were found to be potent inhibitors of l-cystine crystallization while N^α-methylation of l-cystine diamides resulted in derivatives 3b-i devoid of any inhibitory activity of l-cystine crystallization. Computational modeling indicates that N^α-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.

Keywords: Crystallization inhibition; Cystine diamide; Cystinuria; Molecular imposter.