Tag: M.W=350-400

Mesches, Michael H. published the artcileSulindac improves memory and increases NMDA receptor subunits in aged Fischer 344 rats, Safety of Sulindac sulfone, the publication is Neurobiology of Aging (2004), 25(3), 315-324, database is CAplus and MEDLINE.

Inflammatory processes in the central nervous system are thought to contribute to Alzheimer’s disease (AD). Chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of Alzheimer’s disease. There are very few studies, however, on the cognitive impact of chronic NSAID administration. The N-methyl-D-aspartate (NMDA) receptor is implicated in learning and memory, and age-related decreases in the NMDA NR2B subunit correlate with memory deficits. Sulindac, an NSAID that is a nonselective cyclooxygenase (COX) inhibitor was chronically administered to aged Fischer 344 rats for 2 mo. Sulindac, but not its non-COX active metabolite, attenuated age-related deficits in learning and memory as assessed in the radial arm water maze and contextual fear conditioning tasks. Sulindac treatment also attenuated an age-related decrease in the NR1 and NR2B NMDA receptor subunits and prevented an age-related increase in the pro-inflammatory cytokine, interleukin 1β (IL-1β), in the hippocampus. These findings support the inflammation hypothesis of aging and have important implications for potential cognitive enhancing effects of NSAIDs in the elderly.

Neurobiology of Aging 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, Safety of Sulindac sulfone.

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

Liou, Jun-Yang published the artcileNonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3ε, Category: naphthyridine, the publication is Cancer Research (2007), 67(7), 3185-3191, database is CAplus and MEDLINE.

To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3ε protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3ε proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 μmol/L inhibited 14-3-3ε protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3ε promoter activity. As 14-3-3ε promoter activation is mediated by peroxisome proliferator-activated receptor δ (PPARδ), we determined the correlation between 14-3-3ε inhibition and PPARδ suppression by NSAIDs. Sulindac sulfide inhibited PPARδ protein expression and PPARδ transcriptional activity. Overexpression of PPARδ by adenoviral transfer rescued 14-3-3ε proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3ε suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARδ transduction. Stable expression of 14-3-3ε in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARδ/14-3-3ε transcriptional pathway. These results suggest that 14-3-3ε is a target for the prevention and therapy of colorectal cancer.

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, Category: naphthyridine.

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

Ribeiro, Marta F. T. published the artcileA multipumping flow system for in vitro screening of peroxynitrite scavengers, Computed Properties of 59973-80-7, the publication is Journal of Biomolecular Screening (2007), 12(6), 875-880, database is CAplus and MEDLINE.

Peroxynitrite anion is a reactive nitrogen species formed in vivo by the rapid, controlled diffusion reaction between nitric oxide and superoxide radicals. By reacting with several biol. mols., peroxynitrite may cause important cellular and tissue deleterious effects, which have been associated with many diseases. An automated flow-based procedure for the in vitro generation of peroxynitrite and subsequent screening of the scavenging activity of selected compounds is developed. This procedure involves a multipumping flow system (MPFS) and exploits the ability of compounds such as lipoic acid, dihydrolipoic acid, cysteine, reduced glutathione, oxidized glutathione, sulindac, and sulindac sulfone to inhibit the chemiluminescent reaction of luminol with peroxynitrite under physiol. simulated conditions. Peroxynitrite was generated in the MPFS by the online reaction of acidified hydrogen peroxide with nitrite, followed by a subsequent stabilization by merging with a sodium hydroxide solution to rapidly quench the developing reaction. The pulsed flow and the timed synchronized insertion of sample and reagent solutions provided by the MPFS ensure the establishment of the reaction zone only inside the flow cell, thus allowing maximum chemiluminescence emission detection. The results obtained for the assayed compounds show that, with the exception of oxidized glutathione, all are highly potent scavengers of peroxynitrite at the studied concentrations

Journal of Biomolecular Screening 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

Whitehead, Clark M. published the artcileExisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival, Computed Properties of 59973-80-7, the publication is Molecular Cancer Therapeutics (2003), 2(5), 479-488, database is CAplus and MEDLINE.

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochem. mechanisms responsible for the increased survival by an anal. of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochem. was used to determine cGMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatog. and the pharmacol. sensitivity to exisulind, and addnl. known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.

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 C6H12O2, Computed Properties of 59973-80-7.

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

Nortcliffe, Andrew published the artcileSynthesis and biological evaluation of nitric oxide-donating analogues of sulindac for prostate cancer treatment, Safety of Sulindac sulfone, the publication is Bioorganic & Medicinal Chemistry (2014), 22(2), 756-761, database is CAplus and MEDLINE.

A series of analogs of the non-steroidal anti-inflammatory drug (NSAID) sulindac were synthesized tethered to nitric oxide (NO) donating functional groups. Sulindac shows antiproliferative effects against immortal PC3 cell lines. It was previously demonstrated that the effect can be enhanced when tethered to NO releasing groups such as nitrate esters, furoxans and sydnonimines. To explore this approach further, a number of sulindac-NO analogs were prepared and they were evaluated as NO-releasing cytotoxic agents against prostate cancer (PCa) cell lines. Compounds (I) and (II) exhibited significant cytotoxic with IC₅₀ values of 6.1±4.1 and 12.1±3.2 μM, resp., coupled with observed nitric oxide release.

Bioorganic & 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, Safety of Sulindac sulfone.

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

Sinibaldi, Victoria J. published the artcilePhase II evaluation of docetaxel plus exisulind in patients with androgen independent prostate carcinoma, Quality Control of 59973-80-7, the publication is American Journal of Clinical Oncology (2006), 29(4), 395-398, database is CAplus and MEDLINE.

Objectives: In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind. Methods: Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 wk, followed by 2 wk of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously. Results: All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted â‰? wk; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 mo. Docetaxel pharmacokinetics for 11 patients demonstrated mean ± SD clearance values that were similar during week 1 and week 3 when exisulind had been added. Conclusions: Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

American Journal of Clinical Oncology 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 C10H10O2, Quality Control of 59973-80-7.

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

Chang, Wen-Chi L. published the artcileSulindac sulfone is most effective in modulating β-catenine-mediated transcription in cells with mutant APC, Application of Sulindac sulfone, the publication is Annals of the New York Academy of Sciences (2005), 41-55, database is CAplus and MEDLINE.

Sulindac sulfone (FGN-1, Aptosyn), a metabolite of the nonsteroidal anti-inflammatory drug sulindac, lacks cyclooxygenase inhibitory activity. Although its ability to inhibit tumorigenesis in both carcinogen-treated animals and patients with familial adenomatous polyposis has been attributed to the induction of apoptosis, its complete mechanism of action remains unclear. The purpose of the present study was to determine the ability of sulindac metabolites to regulate cellular levels of β-catenin and downstream targets of the adenomatous polyposis coli (APC)/β-catenin pathway in vitro. Sulindac sulfone was consistently more potent than the sulfide metabolite in all analyses, significantly decreasing the expression of total cellular β-catenin (50% of control), pro-caspase 3 (49%), cyclin D1 (51%), and PPARδ (65%) in SW480 cells. No significant alteration in pro-caspase 3 or β-catenin expression was found in HCA7, LS174, or Caco-2 cells treated with sulindac sulfone. A dose-dependent reduction in TCF-mediated transcriptional activity was also observed in SW480 cells. These data demonstrate that sulindac sulfone can modulate the APC/β-catenin pathway in vitro and that its efficacy is dependent upon the mutational status of APC and β-catenin.

Annals of the New York Academy of Sciences 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, Application of Sulindac sulfone.

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

Mlynarska-Cieslak, Agnieszka published the artcileFluorinated Phosphoadenosine 5′-Phosphosulfate Analogs for Continuous Sulfotransferase Activity Monitoring and Inhibitor Screening by ¹⁹F NMR Spectroscopy, Computed Properties of 59973-80-7, the publication is ACS Chemical Biology (2022), 17(3), 661-669, database is CAplus and MEDLINE.

Sulfotransferases (STs) are ubiquitous enzymes that participate in a vast number of biol. processes involving sulfuryl group (SO₃) transfer. 3′-phosphoadenosine 5′-phosphosulfate (PAPS) is the universal ST cofactor, serving as the “active sulfate” source in cells. Herein, we report the synthesis of three fluorinated PAPS analogs that bear fluorine or trifluoromethyl substituents at the C2 or C8 positions of adenine and their evaluation as substitute cofactors that enable ST activity to be quantified and real-time-monitored by fluorine-19 NMR (¹⁹F NMR) spectroscopy. Using plant AtSOT18 and human SULT1A3 as two model enzymes, we reveal that the fluorinated PAPS analogs show complementary properties with regard to recognition by enzymes and the working ¹⁹F NMR pH range and are attractive versatile tools for studying STs. Finally, we developed an ¹⁹F NMR assay for screening potential inhibitors against SULT1A3, thereby highlighting the possible use of fluorinated PAPS analogs for the discovery of drugs for ST-related diseases.

ACS Chemical Biology 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

Beher, Dirk published the artcileSelected Non-steroidal Anti-inflammatory Drugs and Their Derivatives Target γ-Secretase at a Novel Site: Evidence for an allosteric mechanism, Application In Synthesis of 59973-80-7, the publication is Journal of Biological Chemistry (2004), 279(42), 43419-43426, database is CAplus and MEDLINE.

γ-Secretase is a multi-component enzyme complex that performs an intramembranous cleavage, releasing amyloid-β (Aβ) peptides from processing intermediates of the β-amyloid precursor protein. Because Aβ peptides are thought to be causative for Alzheimer’s disease, inhibiting γ-secretase represents a potential treatment for this neurodegenerative condition. Whereas inhibitors directed at the active center of γ-secretase inhibit the cleavage of all its substrates, certain non-steroidal antiinflammatory drugs (NSAIDs) have been shown to selectively reduce the production of the more amyloidogenic Aβ(1-42) peptide without inhibiting alternative cleavages. In contrast to the majority of previous studies, however, we demonstrate that in cell-free systems the mode of action of selected NSAIDs and their derivatives, depending on the concentrations used, can either be classified as modulatory or inhibitory. At modulatory concentrations, a selective and, with respect to the substrate, noncompetitive inhibition of Aβ(1-42) production was observed At inhibitory concentrations, on the other hand, biochem. readouts reminiscent of a nonselective γ-secretase inhibition were obtained. When these compounds were analyzed for their ability to displace a radiolabeled, transition-state analog inhibitor from solubilized enzyme, noncompetitive antagonism was observed The allosteric nature of radioligand displacement suggests that NSAID-like inhibitors change the conformation of the γ-secretase enzyme complex by binding to a novel site, which is discrete from the binding site for transition-state analogs and therefore distinct from the catalytic center. Consequently, drug discovery efforts aimed at this site may identify novel allosteric inhibitors that could benefit from a wider window for inhibition of γ (42)-cleavage over alternative cleavages in the β-amyloid precursor protein and, more importantly, alternative substrates.

Journal of Biological 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, Application In Synthesis of 59973-80-7.

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

Dell’Omo, Giulia published the artcileInhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs, COA of Formula: C20H17FO4S, the publication is British Journal of Cancer (2019), 120(5), 537-546, database is CAplus and MEDLINE.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumors; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clin. application. Mol. biol., in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochem. assays, were applied to identify and characterize the COX-independent anti-cancer mechanism of NSAIDs. Here, we show that tumor-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumor suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clin. interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival. Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumor-protective drugs.

British Journal of Cancer 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