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

Yang, Yanhui; Albanyan, Haifa; Lee, Sumi; Aloysius, Herve; Liang, Jing; Kholodovych, Vladyslav; Sahota, Amrik

doi:10.1016/j.bmcl.2018.03.024

Cited by 20 publications

(16 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To overcome the chemical and metabolic stability issues of L-CDME and L-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. 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 (67).…”

Section: Bucillaminementioning

confidence: 99%

Update on cystine stones: current and future concepts in treatment

Moussa

Papatsoris

Chakra

et al. 2020

IRDR

View full text Add to dashboard Cite

cystinuria, urolithiasis, novel therapy, cystine stone, tiopronin, D-penicillamine Cystine stones are relatively uncommon compared with other stone compositions, constituting just 1% to 2% of adult urinary tract stone diseases, and accounting for up to 10% of pediatric stone diseases. Two responsible genes of cystinuria have been identified, the SLC3A1 and the SLC7A9. Cystinuria is diagnosed by family history, stone analysis, or by measurement of urine cystine excretion. Current treatments for cystinuria include increased fluid intake to increase cystine solubility by maintaining daily urine volume of greater than 3 Liter (L). Limiting sodium and protein intake can decrease cystine excretion. When conservative therapy fails, then pharmacologic therapy may be effective. Alkaline urine pH in the 7.0-7.5 range will reduce cystine solubility and can be achieved by the addition of alkali therapy. If these measures fail, cystine-binding thiol drugs such as tiopronin and D-penicillamine are considered. These compounds bind cysteine and prevent the formation of less soluble cystine. These drugs, however, have poor patient compliance due to adverse effects. Captopril can be useful in the treatment of cystine stones but the drug has not been tested in rigorous clinical trials. Novel potential therapies such as alpha-lipoic acid and crystal growth inhibitors (L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME)) were developed and tested in animals. Those therapies showed promising results. Compliance with treatment was associated with a lower rate of cystine stone formation. 2002; 31:951-977.

show abstract

Section: Bucillaminementioning

confidence: 99%

Update on cystine stones: current and future concepts in treatment

Moussa

Papatsoris

Chakra

et al. 2020

IRDR

View full text Add to dashboard Cite

show abstract

“…Measurements of residual l -cystine concentrations in solution after crystallization using a fluorescent tag protocol during bulk crystal growth revealed substantial differences (Figure B) among the inhibitors. , Here, the concentration effect of an inhibitor that elevates the supersaturation of l -cystine following crystallization is benchmarked using EC 2 x , the inhibitor concentration corresponding to an l -cystine concentration twice that of the lower plateau. l -CDMOR and l -CDNMP were superior to l -CDME with significantly lower EC 2 x values, corresponding to higher supersaturations and suggesting more effective kinetic inhibition of l -cystine growth compared to l -CDME.…”

Section: Molecular Imposters and Growth Inhibitionmentioning

confidence: 99%

“…The stereochemical specificity of molecular imposter binding to crystal sites was tested by measuring step velocities in the presence of various molecules from a library of more than 50 compounds (some examples are shown in Figure ). , This library included molecules in which the terminal hydroxyl group of l -cystine was replaced or its backbone core was modified as well as compounds based on l -cysteine. The step velocity measurements revealed that the most effective inhibitors were l -cystine diesters and diamides that retained the essential structural elements of cystine.…”

Section: Molecular Imposters and Growth Inhibitionmentioning

confidence: 99%

Disrupting Crystal Growth through Molecular Recognition: Designer Therapies for Kidney Stone Prevention

et al. 2022

Self Cite

View full text Add to dashboard Cite

Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: Aberrant crystallization within the human body can lead to several disease states or adverse outcomes, yet much remains to be understood about the critical stages leading to these events, which can include crystal nucleation and growth, crystal aggregation, and the adhesion of crystals to cells. Kidney stones, which are aggregates of single crystals with physiological origins, are particularly illustrative of pathological crystallization, with 10% of the U.S. population experiencing at least one stone occurrence in their lifetimes. The human record of kidney stones is more than 2000 years old, as noted by Hippocrates in his renowned oath and much later by Robert Hooke in his treatise Micrographia. William Hyde Wollaston, who was a physician, chemist, physicist, and crystallographer, was fascinated with stones, leading him to discover an unusual stone that he described in 1810 as cystic oxide, later corrected to cystine. Despite this long history, however, a fundamental understanding of the stages of stone formation and the rational design of therapies for stone prevention have remained elusive. This Account reviews discoveries and advances from our laboratories that have unraveled the complex crystal growth mechanisms of L-cystine, which forms L-cystine kidney stones in at least 20 000 individuals in the U.S. alone. Although L-cystine stones affect fewer individuals than common calcium oxalate stones, they are usually larger, recur more frequently, and are more likely to cause chronic kidney disease. Real-time in situ atomic force microscopy (AFM) reveals that the crystal growth of hexagonal L-cystine is characterized by a complex mechanism in which six interlaced anisotropic spirals grow synchronously, emanating from a single screw dislocation to generate a micromorphology with the appearance of stacked hexagonal islands. In contrast, proximal heterochiral dislocations produce features that appear to be spirals but actually are closed loops, akin to a Frank−Read source. These unusual and aesthetic growth patterns can be explained by the coincidence of the dislocation Burgers vector and the crystallographic 6 1 screw axis. Inhibiting L-cystine crystal growth is key to preventing stone formation. Decades of studies of "tailor-made additives", which are imposter molecules that closely resemble the solute and bind to crystal faces through molecular recognition, have demonstrated their effects on crystal properties such as morphology and polymorphism. The ability to visualize crystal growth in real time by AFM enables quantitative measurements of step velocities and, by extension, the effect of prospective inhibitors on growth rates, which can then be used to deduce inhibition mechanisms. Investigations with a wide range of prospective inhibitors revealed the importance of precise molecular recognition for binding L-cystine imposters to crystal sites, which results in step pinning and the inhibition of step advancement as well as the growth...

show abstract

“…A series of diamines, which mimic cystine and interfere with its crystallization, have shown efficacy in vitro and in a knockout mouse model. [40][41][42] The effect of these molecules is attributed to steric hindrance, where side chains prevent additional molecules of cystine from being added to crystals. No studies of these drugs in humans with cystinuria have been performed as of yet.…”

Section: Future Directionsmentioning

confidence: 99%

Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement

Eisner

Goldfarb

Baum

et al. 2020

Journal of Endourology

View full text Add to dashboard Cite

Purpose: Cystinuria is a genetic disorder with both autosomal recessive and incompletely dominant inheritance. The disorder disrupts cystine and other dibasic amino acid transport in proximal tubules of the kidney, resulting in recurrent kidney stone formation. Currently, there are no consensus guidelines on evaluation and management of this disease. This article represents the consensus of the author panel and will provide clinicians with a stepwise framework for evaluation and clinical management of patients with cystinuria based on evidence in the existing literature. Materials and Methods: A search of MEDLINE Ò /PubMed Ò and Cochrane databases was performed using the following key words: ''cystine nephrolithiasis,'' ''cystinuria,'' ''penicillamine, cystine,'' and ''tiopronin, cystine.'' In total, as of May 2018, these searches yielded 2335 articles, which were then evaluated for their relevance to the topic of evaluation and management of cystinuria. Evidence was evaluated by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results: Twenty-five articles on the topic of cystinuria or cystine nephrolithiasis were deemed suitable for inclusion in this study. The literature supports a logical evaluation process and step-wise treatment approach beginning with conservative measures: fluid intake and dietary modification. If stone formation recurs, proceed to pharmacotherapeutic options by first alkalinizing the urine and then using cystine-binding thiol drugs. Conclusions: The proposed clinical pathways provide a framework for efficient evaluation and treatment of patients with cystinuria, which should improve overall outcomes of this rare, but highly recurrent, form of nephrolithiasis.

show abstract

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

Cited by 20 publications

References 16 publications

Update on cystine stones: current and future concepts in treatment

Update on cystine stones: current and future concepts in treatment

Disrupting Crystal Growth through Molecular Recognition: Designer Therapies for Kidney Stone Prevention

Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement

Contact Info

Product

Resources

About