Tag: M.W=350-400

Kim, Kenneth P. published the artcileCombinatorial chemoprevention: Efficacy of lovostatin and exisulind on the formation and progression of aberrant crypt foci, Application In Synthesis of 59973-80-7, the publication is Anticancer Research (2004), 24(3A), 1805-1811, database is CAplus.

Background: There are several advantages to combinatorial chemoprevention strategies over monotherapeutic approaches. Both the HMG-CoA reductase inhibitor (HRI) lovastatin (LOV) and the selective apoptotic antineoplastic drug (SAAND) exisulind (EXS) have shown remarkable chemopreventive effects in previous studies, in cell lines and limited studies in rodents. Here, experiments were designed to assess the potential use of these two compounds in combinatorial chemoprevention therapy, using two bio-assays in which inhibition of the carcinogen-induced preneoplastic lesions, aberrant crypt foci (ACF), was used to quantitate efficacy. Materials and Methods: ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly i.p. injections at a dose of 15 mg/kg. F344 rats were fed seven exptl. diets containing LOV @ 50 ppm (ppm), EXS @ 100, 250 and 1000 ppm and combination diets containing EXS at 100, 250 and 1000 ppm, each combined with LOV @ 50 ppm. Quantification of ACF number and type (singlet, doublet, triplet and four or more) was performed on whole mounts of rat colons stained with 1.0% methylene blue. Results: During the initiation protocol, administration of LOV @ 50 ppm alone and the combination of LOV @ 50 ppm with EXS @ 1000 ppm significantly decreased the mean number of ACF when compared to the pos. control by 49% and 47%, resp.; however EXS @ 250 ppm displayed tumor promoting effects by significantly increasing the mean number of ACF by 64%. The post-initiation protocol administration of EXS @ 100, 250 and 1000 ppm and the combinations of LOV @ 50 ppm with EXS @ 100 and 250 ppm significantly increased the mean number of ACF when compared to the pos. control by 44%, 48%, 55%, 49% and 40%, resp. Conclusion: LOV shows greater promise than EXS in fulfilling the role as a supplemental chemopreventive agent in combinatorial chemopreventive strategies for cancers such as colon cancer. EXS did not augment this activity, failing to enhance chemopreventive therapy in this animal model.

Anticancer 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, Application In Synthesis of 59973-80-7.

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

Salter, E. A. published the artcileHomology models of the catalytic sites of phosphodiesterase 5A and 10A and molecular docking of selective apoptotic antineoplastic drugs (SAANDs), Formula: C20H17FO4S, the publication is International Journal of Quantum Chemistry (2004), 96(4), 402-410, database is CAplus.

Achieving selective inhibition for individual gene families of cyclic nucleotide phosphodiesterases (CNPDE) isoenzymes has become an important pharmacol. goal now that the diversity of these hydrolases has been recognized. Selective apoptotic antineoplastic drugs (SAANDs) induce apoptosis in neoplastic cells and not in normal cells by a mechanism involving inhibition of overexpressed PDEs that hydrolyze cyclic GMP. SAANDs, although not selective, show a preference for PDE5 and PDE10. However, highly selective PDE5 inhibitors do not induce apoptosis. To study differences in PDE inhibitors, we constructed homol. models of the target catalytic domains of PDE5A and PDE10A based upon the X-ray crystal structure of the catalytic domain of PDE4B. Mol. mechanics docking is planned to define new SAANDs vs. ineffective agents. We investigated the binding of exisulind (Aptosyn) and other analogs to PDE4, 5, and 10 isoforms using our mol. models and compared the resultant estimated binding energies with exptl. IC₅₀ values. Proposed binding orientations for CP 248, a higher-affinity and more selective inhibitor of PDE5 and PDE10 than exisulind, are presented. The modeling studies described here allowed us to identify some differing structural features of the catalytic pockets that may be helpful in the development of active and more selective drugs to treat tumors found in different tissues while maintaining minimal side effects.

International Journal of Quantum 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, Formula: C20H17FO4S.

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

Sheng, Huaming published the artcileIdentification of the sulfoxide functionality in protonated analytes via ion/molecule reactions in linear quadrupole ion trap mass spectrometry, Recommanded Product: Sulindac sulfone, the publication is Analyst (Cambridge, United Kingdom) (2014), 139(17), 4296-4302, database is CAplus and MEDLINE.

A mass spectrometric method using gas-phase ion/mol. reactions of 2-methoxypropene (MOP) has been developed for the identification of the sulfoxide functionality in protonated analytes in a LQIT mass spectrometer. Protonated sulfoxide analytes react with MOP to yield an abundant addition product (corresponding to 37-99% of the product ions), which is accompanied by a much slower proton transfer. The total efficiency (percent of gas-phase collisions leading to products) of the reaction is moderate (3-14%). A variety of compounds with different functional groups, including sulfone, hydroxylamino, N-oxide, aniline, phenol, keto, ester, amino and hydroxy, were examined to probe the selectivity of this reaction. Most of the protonated compounds with proton affinities lower than that of MOP react mainly via proton transfer to MOP. The formation of adduct-MeOH ions is characteristic for secondary N-hydroxylamines. N-Oxides formed abundant MOP adducts just like sulfoxides, but sulfoxides can be differentiated from N-oxides based on their high reaction efficiencies. The reaction was tested by using the antiinflammatory drug sulindac (a sulfoxide) and its metabolite sulindac sulfone. The presence of a sulfoxide functionality in the drug but a sulfone functionality in the metabolite was readily demonstrated. The presence of other functionalities in addition to sulfoxide in the analytes was found not to influence the diagnostic reactivity.

Analyst (Cambridge, United Kingdom) 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 C8H11NO, Recommanded Product: Sulindac sulfone.

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

Sheng, Huaming published the artcileIdentification of the Sulfone Functionality in Protonated Analytes via Ion/Molecule Reactions in a Linear Quadrupole Ion Trap Mass Spectrometer, Safety of Sulindac sulfone, the publication is Journal of Organic Chemistry (2014), 79(7), 2883-2889, database is CAplus and MEDLINE.

A tandem mass spectrometric method is presented for the rapid identification of drug metabolites that contain the sulfone functional group. This method is based on a gas-phase ion/mol. reaction of protonated sulfone analytes with tri-Me borate (TMB) that yields a diagnostic product ion, adduct-Me₂O, at high reaction efficiency. A variety of compounds with different functional groups, such as sulfoxides, hydroxylamines, N-oxides, anilines, phenol, an aliphatic amine, and an aliphatic alc., were examined to probe the selectivity of this reaction. Except for protonated sulfones, most of the protonated compounds react very slowly or not at all with TMB. Most importantly, none of them give the adduct-Me₂O product. A mechanism that explains the observed selectivity is proposed for the diagnostic reaction and is supported by quantum chem. calculations The reaction was tested with the anti-inflammatory drug sulindac and its metabolite, sulindac sulfone, which were readily distinguished. The presence of other functionalities in addition to sulfone was found not to influence the diagnostic reactivity.

Journal of Organic 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 C20H28B2O4S2, Safety of Sulindac sulfone.

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

Cheng, Ka Wing published the artcileAerosol Administration of Phospho-Sulindac Inhibits Lung Tumorigenesis, Category: naphthyridine, the publication is Molecular Cancer Therapeutics (2013), 12(8), 1417-1428, database is CAplus and MEDLINE.

Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation. Mol Cancer Ther; 12(8); 1417-28. ©2013 AACR.

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 C20H17FO4S, Category: naphthyridine.

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

Cheng, Ka-Wing published the artcileCurcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics, Recommanded Product: Sulindac sulfone, the publication is International Journal of Oncology (2013), 43(3), 895-902, database is CAplus and MEDLINE.

Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tvveen-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse s.c. xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

International Journal of 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 C20H17FO4S, Recommanded Product: Sulindac sulfone.

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

Xie, Gang published the artcileRegioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety, Quality Control of 59973-80-7, the publication is British Journal of Pharmacology (2012), 167(1), 222-232, database is CAplus and MEDLINE.

Background and Purpose Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT-328) are highly effective in cancer and arthritis treatment in preclin. models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs). Exptl. Approach The CYP/FMO-catalyzed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modeling and a direct exptl. approach. Key Results The CYP isoforms catalyze the oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac resp. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho-sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho-sulindac may be due to their greater lipophilicity, a key parameter for CYP binding. Conclusions and Implications CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety.

British Journal of Pharmacology 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 C8H8BNO3, Quality Control of 59973-80-7.

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

Duncan, Kristal published the artcileNSAIDs induce apoptosis in nonproliferating ovarian cancer cells and inhibit tumor growth in vivo, COA of Formula: C20H17FO4S, the publication is IUBMB Life (2012), 64(7), 636-643, database is CAplus and MEDLINE.

Ovarian cancer (OC) is one of the most lethal gynaecol. cancers, which usually has a poor prognosis due to late diagnosis. A large percentage of the OC cell population is in a nonproliferating and quiescent stage, which poses a barrier to success when using most chemotherapeutic agents. Recent studies have shown that several nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of OC. Furthermore, we have previously described the mol. mechanisms of NSAIDs’ induction of cancer apoptosis. In this report, we evaluated various structurally distinct NSAIDs for their efficacies in inducing apoptosis in nonproliferating OC cells. Although several NSAIDs-induced apoptosis, Flufenamic Acid, Flurbiprofen, Finasteride, Celocoxib, and Ibuprofen were the most potent NSAIDs inducing apoptosis. A combination of these agents resulted in an enhanced effect. Furthermore, we demonstrate that the combination of Flurbiprofen, which targets nonproliferative cells, and Sulindac Sulfide, that affects proliferative cells, strongly reduced tumor growth when compared with a single agent treatment. Our data strongly support the hypothesis that drug treatment regimens that target nonproliferating and proliferating cells may have significant efficacy against OC. These results also provide a rationale for employing compounds or even chem. modified NSAIDs, which selectively and efficiently induce apoptosis in cells during different stages of the cell cycle, to design more potent anticancer drugs. © 2012 IUBMB IUBMB Life, 2012.

IUBMB Life 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

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

Ge, Yiyue published the artcileAn integrative drug repositioning framework discovered a potential therapeutic agent targeting COVID-19, Formula: C20H17FO4S, the publication is Signal Transduction and Targeted Therapy (2021), 6(1), 165, database is CAplus and MEDLINE.

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical anal. approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clin. trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathol. induced by SARS-CoV-2 infection.

Signal Transduction and Targeted 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, Formula: C20H17FO4S.

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