Evaluation of carbohydrate-cysteamine thiazolidines as pro-drugs for the treatment of cystinosis

Abstract

Cystinosis is a genetic disorder caused by malfunction of cystinosin and is characterized by accumulation of cystine. Cysteamine, the medication used in cystinosis, causes halitosis resulting in poor patient compliance. Halitosis is mainly caused by the formation of dimethylsulfide as the final product in the cysteamine metabolism pathway. We have synthesized carbohydrate-cysteamine thiazolidines, and hypothesized that the hydrolytic breakdown of cysteamine-thiazolidines can result in free cysteamine being released in target organs. To examine our hypothesis, we tested these analogs in vitro in patient-derived fibroblasts. Cystinotic fibroblasts were treated with different concentrations of arabinose-cysteamine, glucose-cysteamine and maltose-cysteamine. We demonstrated that the analogs break down into cysteamine extracellularly and might therefore not be fully taken up by the cells under the form of the pro-drug. Potential modifications of the analogs that enable their intracellular rather than extracellular breakdown, is necessary to pursue the potential of these analogs as pro-drugs.

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

“…Furthermore, the cysteamine metabolites dimethylsulfide and methanethiol result in halitosis and poor sweat odors. These adverse events might be overcome using prodrugs of cysteamine that increase metabolic stability, achieve a sustained cysteamine concentration, and guarantee on-target release [67]. Esterified γ-glutamyl-cysteamine prodrugs maintain the concentration of cysteamine at above baseline levels for at least 24 hours, indicating the potential for less frequent administration [68].…”

Thiazolidine Peracetates: Carbohydrate Derivatives that Readily Assigncis-,trans-2,3-Monosaccharides by Gas Chromatography–Mass Spectrometry Analysis

“…The thiazolidine peracetate derivatives (TPAs) were prepared from aldoses as described previously . Carbohydrate samples were dissolved in a small quantity (typically 1 mL) of saturated cysteamine hydrochloride dissolved in pyridine.…”

“…The peracetylation also has several advantages. The thiazolidine reaction is reversible via a Schiff’s base ring opening of the thiazolidine group, − but once N -acetylated on the thiazolidine amino group the reverse reaction is precluded. The peracetylation step also allows a direct assessment of the completeness of the thiazolidine reaction, since any unreacted sugars should be immediately apparent in the GC/MS analysis as peracetylated sugars.…”

Identification of novel inhibitors for Prp protein of Mycobacterium tuberculosis by structure based drug design, and molecular dynamics simulations

“…As demonstrated in Figure 1, there are several thiazolidine ring containing approved drugs available in market such as Ralitoline ( A , antiepileptic), Teneligliptin ( B , anti‐diabetic), Etozoline ( C , diuretic), Penicillins ( D , antibiotic), Epalrestat ( E , diabetic neuropathy). In addition, thiazolidines are reported as influenza neuraminidase inhibitor, 21 tyrosyl‐DNA phosphodiesterase I inhibitor, 22 S1P1 receptor antagonists, 23 prodrugs as cystinosis, 24 and also act as immuno‐stimulating agents 25 …”