59587-09-6Relevant articles and documents
Preclinical Characterization of 3β-(N-Acetyl l -cysteine methyl ester)-2aβ,3-dihydrogaliellalactone (GPA512), a Prodrug of a Direct STAT3 Inhibitor for the Treatment of Prostate Cancer
Escobar, Zilma,Bjartell, Anders,Canesin, Giacomo,Evans-Axelsson, Susan,Sterner, Olov,Hellsten, Rebecka,Johansson, Martin H.
, p. 4551 - 4562 (2016)
The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPA512, Johansson, M.; Sterner, O. Patent WO 2015/132396 A1, 2015), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the prodrug was rapidly absorbed and converted to 1 with a tmax of 15 min. Oral administration of 6 in mice increased the plasma exposure of the active parent compound 20-fold compared to when 1 was dosed orally. 6 treated mice bearing DU145 xenograft tumors had significantly reduced tumor growth compared to untreated mice. The favorable druglike properties and safety profile of 6 warrant further studies of 6 for the treatment of castration-resistant prostate cancer.
Superior properties of N-acetylcysteine ethyl ester over n-acetyl cysteine to prevent retinal pigment epithelial cells oxidative damage
Tosi, Gian Marco,Giustarini, Daniela,Franci, Lorenzo,Minetti, Alberto,Imperatore, Francesco,Caldi, Elena,Fiorenzani, Paolo,Aloisi, Anna Maria,Sparatore, Anna,Rossi, Ranieri,Chiariello, Mario,Orlandini, Maurizio,Galvagni, Federico
, p. 1 - 12 (2021)
Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats’ eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.
COMPOUNDS AND IMPLANTS FOR TREATING OCULAR DISORDERS
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Paragraph 0215, (2021/05/15)
The present disclosure relates to therapeutic compositions and therapies for use in the treatment of diseases and disorders of the eye. The present disclosure relates to curved, multilayer controlled-release ocular implant devices which include the therapeutic compositions of the present disclosure. The present disclosure related to methods for delivery of the therapeutic agents to the eye and the treatment of diseases and disorders of the eye.
Catalytic Hydrogenation of Thioesters, Thiocarbamates, and Thioamides
Luo, Jie,Rauch, Michael,Avram, Liat,Ben-David, Yehoshoa,Milstein, David
supporting information, p. 21628 - 21633 (2021/01/11)
Direct hydrogenation of thioesters with H2 provides a facile and waste-free method to access alcohols and thiols. However, no report of this reaction is documented, possibly because of the incompatibility of the generated thiol with typical hydrogenation catalysts. Here, we report an efficient and selective hydrogenation of thioesters. The reaction is catalyzed by an acridine-based ruthenium complex without additives. Various thioesters were fully hydrogenated to the corresponding alcohols and thiols with excellent tolerance for amide, ester, and carboxylic acid groups. Thiocarbamates and thioamides also undergo hydrogenation under similar conditions, substantially extending the application of hydrogenation of organosulfur compounds.
Synthesis of the 4-aza cyclopentenone analogue of Δ12,14-15-deoxy-PGJ2 and S-cysteine adducts
Conway, Lorna,Riccio, Anna,Santoro, M. Gabriella,Evans, Paul
supporting information, (2020/05/18)
The synthesis of a series of 4-aza cross-conjugated cyclopentenones, inspired by the natural prostaglandin Δ12,14-15-deoxy-PGJ2 (5) is described. Using the 4-aza cyclopentenone 7, the installation of the α-side chain was performed using N-functionalisation, following a Boc-deprotection. The ω-side chain was then installed through a Baylis-Hillman type aldol reaction with trans-2-octenal. This afforded 11, the aza-analogue of 5. With this prostaglandin analogue in hand, a series of thiol adducts (14–16) were prepared. Included are activities for compounds 11 and 14–16 in relation to inhibition of the transcription factor NF-κB.
Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs
Bulumulla, Chandima,Catchpole, Timothy,Christie, Abigail,Csaky, Karl G.,Kularatne, Ruvanthi N.,Stefan, Mihaela C.,Takacs, Alison
, p. 386 - 394 (2020/04/17)
Age-related macular degeneration (AMD) is one of the major causes of vision loss in the elderly in most developed countries. Among other causes, oxidative stress in the retinal pigment epithelium (RPE) has been hypothesized to be a major driving force of AMD pathology. Oxidative stress could be treated by antioxidant administration into the RPE cells. However, to achieve high in-vivo efficacy of an antioxidant, it is imperative that the agent be able to penetrate the tissues and cells. Evidence suggests that lipophilicity governs cellular penetrance. Out of many antioxidant candidates, N-acetyl-L-cysteine (a prodrug of L-cysteine) (NAC) is a potent antioxidant as the bioavailability of the parent drug, L-cysteine, determines the production of glutathione; the universal antioxidant that regulates ROS. To increase the lipophilicity, four ester derivatives of N-acetylcysteine: N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester, N-acetylcysteine propyl ester, and N-acetylcysteine butyl ester were synthesized. To mimic in vitro AMD conditions, hydroquinone, a component of cigarette smoke, was used as the oxidative insult. Cytosolic and mitochondrial protection against oxidative stress were tested using cytosolic and mitochondrial specific assays. The results provide evidence that these lipophilic cysteine prodrugs provide increased protection against oxidative stress in human RPE cells compared with NAC.
Visible-Light-Mediated S?H Bond Insertion Reactions of Diazoalkanes with Cysteine Residues in Batch and Flow
Chen, Lin,Cui, Yu-Sheng,Duan, Xiu,Guo, Kai,Qin, Long-Zhou,Qiu, Jiang-Kai,Sun, Qi,Yuan, Xin,Zhuang, Kai-Qiang
supporting information, p. 5093 - 5104 (2020/09/23)
We describe the application of S?H bond insertion reactions of aryl diazoacetates with cysteine residues that enabled metal-free, S?H functionalization under visible-light conditions. Moreover, this process could be intensified by a continuous-flow photomicroreactor on the acceleration of the reaction (6.5 min residence time). The batch and flow protocols described were applied to obtain a wide range of functionalized cysteine derivatives and cysteine-containing dipeptides, thus providing a straightforward and general platform for their functionalizations in mild conditions. (Figure presented.).
Synthesis and cytotoxicity studies of novel NHC?-gold(I) complexes derived from lepidiline A
Curran, Danielle,Dada, Oyinlola,Müller-Bunz, Helge,Rothemund, Matthias,Sánchez-Sanz, Goar,Schobert, Rainer,Zhu, Xiangming,Tacke, Matthias
, (2018/09/26)
Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC?-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3-5), p-mercaptobenzoate derivatives (12-14) and N-acetyl-L-cysteine derivatives (15-17). All complexes were synthesised in good yields of 57-78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116-/- colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 μM ± 0.03 μM. Complexes incorporating a Au-S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6-311++G(2df,p) computational level, show that NHC? is the more favourable ligand for Au(I)-Cl when compared to PPh3.
PROTECTED FUMARIC ACID-BASED METABOLITES FOR THE TREATMENT OF AUTOIMMUNE DISEASES
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, (2017/08/01)
The present invention provides novel cell-permeable fumarate acyl mercaptoethylamines (FAMs) which have cellular effects including induction of Nrf2 and inhibition of the NFkB pathway. These compounds have utility in medicine including their use in treatment of diseases such as Multiple sclerosis, Non-alcoholic Steatohepatitis, Psoriasis, Inflammatory Arthritis, Inflammatory Bowel Disease, Asthma, Chronic Obstructive Pulmonary Disease, Cancer, Parkinson's Disease, Alzheimer's Disease, Huntington's Disease and Amyotrophic Lateral Sclerosis.
GOLD (I)-PHOSPHINE COMPOUNDS AS ANTI-BACTERIAL AGENTS
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Page/Page column 36, (2015/12/17)
A compound of formula (I): for use in the prevention or treatment of a bacterial infection wherein: A is either S or Se; RA is selected from: wherein: each of Y1, Y2, Y3, Y4 and Y9 is independently selected from CH or N, wherein at least three of Y1, Y2, Y3, Y4 and Y9 is CH; V is selected from O, CH-OR01, N-CO2-RC2 or N-RN2; one of Y5, Y6, Y7 and Y8 is selected from CH and N, and the others are CH; X is selected from NH, S or O; RC1 is selected from O-RO2 or NHRN1; RO1 is selected from H and C1-3 unbranched alkyl; RO2 is C1-3 unbranched alkyl; RN1 is selected from H and C1-3 unbranched alkyl; RN2 is C1-3 unbranched alkyl; RC2 is either C1-3 unbranched alkyl or C3-4 branched alkyl; RC3 is selected from C1-3 unbranched alkyl and C2H4CO2H; RC4 is either H or Me; RC5 is either H or Me; RC6 represents one or two optional methyl substituents; and n is an integer from 2 to 8.
