Folate pro-drug of cystamine as an enhanced treatment for nephropathic cystinosis

Omran, Ziad; Kay, Graeme; Hector, Emma E.; Knott, Rachel M.; Cairns, Donald

doi:10.1016/j.bmcl.2011.02.048

Cited by 10 publications

(9 citation statements)

References 10 publications

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“…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]. In addition, folate, glutaric acid, succinic acid, and pegylate derivates of cystamine, the disulfide derivative of cysteamine, were shown to deplete cystine levels in vitro with higher efficiency than cysteamine and with no significant toxicity [69][70][71]. The potential use of these analogs needs further investigation.…”

Section: New Emerging Therapiesmentioning

confidence: 99%

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Jamalpoor

Othman

Levtchenko

et al. 2021

Trends in Molecular Medicine

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Section: New Emerging Therapiesmentioning

confidence: 99%

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Jamalpoor

Othman

Levtchenko

et al. 2021

Trends in Molecular Medicine

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“…Cysteamine enters the lysosome via an unknown transport mechanism where it breaks the disulfide bond in cystine, leading to the formation of cysteine and cysteine-cysteamine disulfide [13], and the resulting mixed disulfide leaves the lysosome possibly via the lysine transporter [7]. Several cysteamine derivatives or prodrugs have been reported to have favorable activity profiles, shown to be as, or even more, effective than cysteamine in depleting intralysosomal cystine [5,6,11,19,[22][23][24]28].…”

Section: Discussionmentioning

confidence: 99%

“…Lysosomal cystine was converted to cysteine, adapted from works by de Graf-Hess et al [9], further refined by McCaughan et al [19], and successfully utilized by Omran et al [22][23][24] (Fig. 2).…”

Section: Cystine-depleting Activity Of Naca and Dinacamentioning

confidence: 99%

Evaluation of NACA and diNACA in human cystinosis fibroblast cell cultures as potential treatments for cystinosis

Hector

Cairns

Wall³

2022

Orphanet J Rare Dis

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Background Cystinosis is a rare autosomal recessive lysosomal storage disease, associated with high morbidity and mortality. Mutations in the CTNS gene disable a membrane protein responsible for the transport of cystine out of the lysosome. Loss of transporter function leads to intralysosomal cystine accumulation and long-term damage to various tissues and organs, including the kidneys, eyes, liver, muscles, pancreas, and brain. The only cystine-depletion therapy for treatment of cystinosis is cysteamine which requires frequent administration of high doses and often causes gastrointestinal pain as well as pungent sulfurous odor in patients. The current in vitro study evaluated antioxidants, N-acetylcysteine amide (NACA; NPI-001) and (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA; NPI-002), as potential treatments for cystinosis. Methods Cytotoxicity of cysteamine, NACA and diNACA was evaluated in cultured human cystinotic fibroblasts (HCFs). HCFs were cultured in 96 well plates incubated for 0–72 h in the presence of 25, 50 or 75 μM each of either cysteamine, NACA or diNACA along with an untreated control. Media was removed and cell viability assessed. Next, cystine-depleting activities of cysteamine, NACA and diNACA were screened in HCFs cell culture utilizing an inexpensive, proven colorimetric assay. HCFs were seeded and allowed to reach approximately 80% confluence before the addition of the test articles: 50 μM of either cysteamine, NACA or diNACA in media along with an untreated control. HCFs were incubated, harvested, and cystine was reduced to cysteine, the concentration of which was then determined per quantity of protein compared to a cysteine standard. Statistically significant cystine depletion was determined by paired t-test versus untreated control (p < 0.05). Results Neither cysteamine, NACA nor diNACA at 25, 50 or 75 μM caused cytotoxicity in HCFs. Treatment with all tested concentrations (25, 50 or 75 µM) of either NACA or diNACA at 48 or 72 h resulted in statistically significant increases in cell viability, relative to untreated control, whereas the higher concentrations (50 or 75 µM) of cysteamine achieved statistical significance at both timepoints but not the lowest concentration (25 µM). All test articles depleted cystine from HCFs compared to control. NACA depletion of cystine was statistically superior to cysteamine at 6, 24 and 48 h and numerically greater at 72 h. DiNACA depletion of cystine was statistically superior to cysteamine at 6 and 48 h, slightly numerically greater at 24 h and slightly less at 72 h. Conclusions NACA and diNACA were non cytotoxic to HCFs and significantly increased cell viability. Cystine reduction was determined as percent of control after incubation with 50 µM of NACA, diNACA or cysteamine in HCFs cell culture for 6, 24, 48 and 72 h. Of the three test articles, NACA exhibited most rapid and greatest potency in cystine reduction. Rank order potency for cystine reduction over time was observed, NACA > diNACA ≥ cysteamine. Therefore, further study of NACA and diNACA as potential treatments for cystinosis is warranted.

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“…The presence of resorufin was quantified by measuring fluorescence Ex -555 nm, Em -585 nm (protocol for Cell viability assay "CellTiter-Blue" fluorescence in SoftMaxPro (Molecular devices)). 21,22) Water solubility, log D and PAMPA-BBB were evaluated using the protocols we previously descried. 23)…”

Section: Isoquinoline (3)mentioning

confidence: 99%

Boronic Analogues of (<i>R</i>)-6-<i>O</i>-Desmethylantofine as Anticancer Agents

Omran

Abdalla

Ibrahim

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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Phenanthroindolizidines are naturally occurring alkaloids mainly isolated from different species of Asclepiadaceae. These alkaloids are characterized by an excellent anticancer activity against a very wide range of cancerous cell lines including those who are multi drug resistant. Nevertheless, phenanthroindolizidines are associated with sever neurotoxicity that prevented any candidate from this family to pass the clinical trials. A number of boron-based analogues of (R)-6-O-desmethylantofine have been synthesised. Their physochemical properties were evaluated, same as their in-vitro antiproliferative activity. The pinacol boronate ester derivative (3) showed interesting cytotoxicity against a panel of cancerous cell lines attested by a cancer cell growth-inhibitory potency (GI 50) as low as 30 nM.

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Folate pro-drug of cystamine as an enhanced treatment for nephropathic cystinosis

Cited by 10 publications

References 10 publications

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Evaluation of NACA and diNACA in human cystinosis fibroblast cell cultures as potential treatments for cystinosis

Boronic Analogues of (<i>R</i>)-6-<i>O</i>-Desmethylantofine as Anticancer Agents

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