Category: 59973-80-7

Santos, Fernando published the artcileInteractions of sulindac and its metabolites with phospholipid membranes: An explanation for the peroxidation protective effect of the bioactive metabolite, Synthetic Route of 59973-80-7, the publication is Free Radical Research (2008), 42(7), 639-650, database is CAplus and MEDLINE.

Non-steroidal anti-inflammatory drugs (NSAIDs) treat inflammatory processes by inhibition of cyclooxygenase (COX). However, their action against lipid peroxidation can be an alternative pathway to COX inhibition. Since inflammation and lipid peroxidation are cell-surface phenomena, the effects of NSAIDs on membrane models were investigated. Peroxidation was induced by peroxyl radical (ROO^·) derived from AAPH and assessed in aqueous or lipid media using fluorescence probes with distinct lipophilic properties: fluorescein; HDAF and DPH-PA. The antioxidant effect of Sulindac and its metabolites was tested and related with their membrane interactions. Drug-membrane interactions included the study of: drug location by fluorescence quenching; drug interaction with membrane surface by zeta-potential measurements; and membrane fluidity changes by steady-state anisotropy. Results revealed that the active NSAID (sulindac sulfide) penetrates into the lipid bilayer and protects the membrane against oxy-radicals. The inactive forms (sulindac and sulindac sulfone) present weaker interactions with the membrane and are better radical scavengers in aqueous media.

Free Radical Research published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Synthetic Route of 59973-80-7.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Romeiro, Nelilma C. published the artcileNSAIDs revisited: Putative molecular basis of their interactions with peroxisome proliferator-activated gamma receptor (PPARγ), Category: naphthyridine, the publication is European Journal of Medicinal Chemistry (2008), 43(9), 1918-1925, database is CAplus and MEDLINE.

This paper describes mol. docking studies of a series of classical NSAIDs with PPARγ receptor, which has been pointed as a new target for the design of anticancer and antiinflammatory drugs, and has been found to be responsible for some of the already established pharmacol. effects observed for marketed drugs. The results show the mol. basis of PPARγ activation by non-selective COX inhibitors.

European Journal of Medicinal Chemistry published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Category: naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Brunell, David published the artcileStudies on the metabolism and biological activity of the epimers of Sulindac, Category: naphthyridine, the publication is Drug Metabolism and Disposition (2011), 39(6), 1014-1021, database is CAplus and MEDLINE.

Sulindac is a nonsteroidal, anti-inflammatory drug (NSAID) that was also studied for its anticancer activity. Recent studies suggest that sulindac and its metabolites act by sensitizing cancer cells to oxidizing agents and drugs that affect mitochondrial function, resulting in the production of reactive oxygen species and death by apoptosis. In contrast, normal cells are not killed under these conditions and, in some instances, are protected against oxidative stress. Sulindac has a Me sulfoxide moiety with a chiral center and was used in all of the previous studies as a mixture of the R- and S-epimers. Because epimers of a compound can have very different chem. and biol. properties, we have separated the R- and S-epimers of sulindac, studied their individual metabolism, and performed preliminary experiments on their effect on normal and lung cancer cells exposed to oxidative stress. Previous results had indicated that the reduction of (S)-sulindac to sulindac sulfide, the active NSAID, was catalyzed by methionine sulfoxide reductase (Msr) A. In the present study, we purified an enzyme that reduces (R)-sulindac and resembles MsrB in its substrate specificity. The oxidation of both epimers to sulindac sulfone is catalyzed primarily by the microsomal cytochrome P 450 (P 450) system, and the individual enzymes responsible have been identified. (S)-Sulindac increases the activity of the P 450 system better than (R)-sulindac, but both epimers increase primarily the enzymes that oxidize (R)-sulindac. Both epimers can protect normal lung cells against oxidative damage and enhance the killing of lung cancer cells exposed to oxidative stress.

Drug Metabolism and Disposition published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Category: naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Gasparini, Laura published the artcileModulation of β-amyloid metabolism by non-steroidal anti-inflammatory drugs in neuronal cell cultures, Related Products of naphthyridine, the publication is Journal of Neurochemistry (2004), 88(2), 337-348, database is CAplus and MEDLINE.

Alzheimer disease (AD) is characterized by cerebral deposits of β-amyloid (Aβ) peptides, which are surrounded by neuroinflammatory cells. Epidemiol. studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD. In addition, biol. data indicate that certain NSAIDs specifically lower Aβ42 levels in cultures of peripheral cells independently of cyclooxygenase (COX) activity and reduce cerebral Aβ levels in AD transgenic mice. Whether other NSAIDs, including COX-selective compounds, modulate Aβ levels in neuronal cells remains unexploited. Here, we investigated the effects of compounds from every chem. class of NSAIDs on Aβ40 and Aβ42 secretion using both Neuro-2a cells and rat primary cortical neurons. Among non-selective NSAIDs, flurbiprofen and sulindac sulfide concentration-dependently reduced the secretion not only of Aβ42 but also of Aβ40. Surprisingly, both COX-2 (celecoxib; s.c.-125) or COX-1 (s.c.-560) selective compounds significantly increased Aβ42 secretion, and either did not alter (s.c.-560; s.c.-125) or reduced (celecoxib) Aβ40 levels. The levels of βAPP C-terminal fragments and Notch cleavage were not altered by any of the NSAIDs, indicating that γ-secretase activity was not overall changed by these drugs. The present findings show that only a few non-selective NSAIDs possess Aβ-lowering properties and therefore have a profile potentially relevant to their clin. use in AD.

Journal of Neurochemistry published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Related Products of naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Cousido-Siah, Alexandra published the artcileStructural analysis of sulindac as an inhibitor of aldose reductase and AKR1B10, Product Details of C20H17FO4S, the publication is Chemico-Biological Interactions (2015), 290-296, database is CAplus and MEDLINE.

Aldose reductase (AR, AKR1B1) and AKR1B10 are enzymes implicated in important pathologies (diabetes and cancer) and therefore they have been proposed as suitable targets for drug development. Sulindac is the metabolic precursor of the potent non-steroidal anti-inflammatory drug (NSAID) sulindac sulfide, which suppresses prostaglandin production by inhibition of cyclooxygenases (COX). In addition, sulindac has been found to be one of the NSAIDs with higher antitumoral activity, presumably through COX inhibition. However, sulindac anticancer activity could be partially mediated through COX-independent mechanisms, including the participation of AR and AKR1B10. Previously, it had been shown that sulindac and sulindac sulfone were good AR inhibitors and the structure of the ternary complex with NADP⁺ and sulindac was described (PDB ID 3U2C). In this work, we determined the three-dimensional structure of AKR1B10 with sulindac and established structure-activity relationships (SAR) of sulindac and their derivatives with AR and AKR1B10. The difference in the IC₅₀ values for sulindac between AR (0.36 μM) and AKR1B10 (2.7 μM) might be explained by the different positioning and stacking interaction given by Phe122/Phe123, and by the presence of two buried and ordered water mols. in AKR1B10 but not in AR. Moreover, SAR anal. shows that the substitution of the sulfinyl group is structurally allowed in sulindac derivatives Hence, sulindac and its derivatives emerge as lead compounds for the design of more potent and selective AR and AKR1B10 inhibitors.

Chemico-Biological Interactions published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Product Details of C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Bravi, Luca published the artcileSulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice, Recommanded Product: Sulindac sulfone, the publication is Proceedings of the National Academy of Sciences of the United States of America (2015), 112(27), 8421-8426, database is CAplus and MEDLINE.

Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurol. consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacol. treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacol. therapy of intracranial vascular cavernomas.

Proceedings of the National Academy of Sciences of the United States of America published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Recommanded Product: Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Narayanan, Bhagavathi A. published the artcileExisulind in combination with Celecoxib modulates epidermal growth factor receptor, cyclooxygenase-2, and cyclin D1 against prostate carcinogenesis: in vivo evidence, Computed Properties of 59973-80-7, the publication is Clinical Cancer Research (2007), 13(19), 5965-5973, database is CAplus and MEDLINE.

Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer. We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 wk. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochem. and Western blot anal. were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E₂ and tumor necrosis factor-α levels were determined using enzyme immunoassay/ELISA assays. The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E₂, and tumor necrosis factor-α indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr⁹⁹² and Tyr⁸⁴⁵) and Akt (Ser⁴⁷³) was significant in rats given with these agents in combination. In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key mol. events.

Clinical Cancer Research published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Computed Properties of 59973-80-7.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Li, Han published the artcileβ-Catenin signaling: therapeutic strategies in oncology, COA of Formula: C20H17FO4S, the publication is Cancer Biology & Therapy (2002), 1(6), 621-625, database is CAplus and MEDLINE.

A review. Activated Wnt signaling pathways have been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. As a result, β-catenin is accumulated and becomes transcriptionally active for proliferative genes and oncogenes. Wnt pathway mutations result in biochem. mechanisms yielding inefficient phosphorylation of β-catenin by glycogen synthase kinase 3β (GSK3β) due to APC, β-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/β-catenin/Lef/Tcf signals. Exisulind and analogs are inhibitors of cyclic GMP phosphodiesterases (PDE) that have been shown to activate and induce protein kinase G. The data show PKG regulation of β-catenin in Wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or β-catenin mutations. Exisulind and analogs reduce β-catenin via a novel, GSK3β independent processing mechanism. Activated PKG directly phosphorylate β-catenin at its C-terminal domain and causes proteasome dependent degradation of the protein. Since this pathway is independent of APC and GSK3β, exisulind and analogs provide a superior approach to circumvent the mol. defects of Wnt signaling pathway and to treat cancers with such defects.

Cancer Biology & Therapy published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, COA of Formula: C20H17FO4S.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Yoon, Jung-Taek published the artcileCP248, a derivative of exisulind, causes growth inhibition, mitotic arrest, and abnormalities in microtubule polymerization in glioma cells, Category: naphthyridine, the publication is Molecular Cancer Therapeutics (2002), 1(6), 393-404, database is CAplus and MEDLINE.

Exisulind (sulindac sulfone) and two potent derivatives, CP248 and CP461, have been shown previously to cause growth inhibition and apoptosis in several types of human carcinoma cell lines. These and related compounds have not been previously studied with respect to glioma cell lines. In the present study, we found that these three compounds caused marked growth inhibition in four rat glioma and eight human glioma cell lines, with IC₅₀ values of 150, 1, and 0.075 μM, resp. When studied at these concentrations exisulind and CP461 had no significant effect on the cell cycle profile of glioma cells, but CP248 caused marked arrest in mitosis. Detailed studies of CP248 in the 9L rat gliosarcoma cell line indicated that treatment with 0.075 μM CP248 caused abnormalities in the spindle apparatus and activation of the spindle assembly check point. In interphase glioma cells, CP248 stabilized microtubules (MTs) at low concentrations (0.075 μM) and depolymerized MTs at higher concentrations (0.2-0.4 μM). In NIH 3T3 fibroblasts, 0.1 μM CP248 caused extensive MT depolymerization CP248 also caused MT depolymerization when added to assembled MTs in vitro, which indicated that it can directly affect MTs, perhaps because it shares certain structural similarities with Colcemid. In glioma cells, the effects of CP248 on MTs were independent of the previously reported effects of this compound on activation of protein kinase G. Therefore, CP248 is a novel MT-active agent that may be useful in the treatment of glioblastoma, and possibly other types of cancer, because of its dual effects on protein kinase G and MTs.

Molecular Cancer Therapeutics published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C9H8BNO2, Category: naphthyridine.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem

Lee, Jin Kyung published the artcileSulindac and its metabolites inhibit multiple transport proteins in rat and human hepatocytes, Recommanded Product: Sulindac sulfone, the publication is Journal of Pharmacology and Experimental Therapeutics (2010), 334(2), 410-418, database is CAplus and MEDLINE.

Sulindac is a commonly used nonsteroidal anti-inflammatory drug. This study tested the hypothesis that sulindac-mediated drug-drug interactions and/or hepatotoxicity may be caused, in part, by inhibition of proteins responsible for the hepatic transport of drugs and/or bile acids by sulindac and/or sulindac metabolites [sulindac sulfone (S-sulfone) and sulindac sulfide (S-sulfide)]. The uptake and excretion of model substrates, [³H]taurocholate (TC), [³H]estradiol 17-β-glucuronide (E217G), and nitrofurantoin (NF), were investigated in rat and human suspended and sandwich-cultured hepatocytes (SCH). In suspended rat hepatocytes, S-sulfone and S-sulfide inhibited Na⁺-dependent TC initial uptake (IC₅₀ of 24.9 ± 6.4 and 12.5 ± 1.8 μM, resp.) and Na⁺-independent E217G initial uptake (IC₅₀ of 12.1 ± 1.6 and 6.3 ± 0.3 μM, resp.). In rat SCH, sulindac metabolites (100 μM) decreased the in vitro biliary clearance (Cl_biliary) of TC, E217G, and NF by 38 to 83%, 81 to 97%, and 33 to 57%, resp.; S-sulfone and S-sulfide also decreased the TC and NF biliary excretion index by 39 to 55%. In suspended human hepatocytes, S-sulfone and S-sulfide inhibited Na⁺-dependent TC initial uptake (IC₅₀ of 42.2 and 3.1 μM, resp.); S-sulfide also inhibited the TC Cl_biliary in human SCH. Sulindac/metabolites markedly inhibited hepatic uptake and biliary excretion of E217G by 51 to 100% in human SCH. In conclusion, sulindac and metabolites are potent inhibitors of the uptake and biliary clearance of bile acids in rat and human hepatocytes and also inhibit substrates of rat breast cancer resistance protein, rat and human organic anion-transporting polypeptides, and human multidrug resistance-associated protein 2. Inhibition of multiple hepatic transport proteins by sulindac/metabolites may play an important role in clin. significant sulindac-mediated drug-drug interactions and/or liver injury.

Journal of Pharmacology and Experimental Therapeutics published new progress about 59973-80-7. 59973-80-7 belongs to naphthyridine, auxiliary class Immunology/Inflammation,COX, name is Sulindac sulfone, and the molecular formula is C20H17FO4S, Recommanded Product: Sulindac sulfone.

Referemce:
https://en.wikipedia.org/wiki/1,8-Naphthyridine,
1,8-Naphthyridine | C8H6N2 – PubChem