M.W=350-400 | Page 9 of 14 | Heterocyclic Building Blocks-Naphthyridine

Jones, Suzanne F.’s team published research in Clinical Lung Cancer in 6 | CAS: 59973-80-7

Clinical Lung 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, Synthetic Route of 59973-80-7.

Jones, Suzanne F. published the artcileA phase I/II study of exisulind in combination with docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer, Synthetic Route of 59973-80-7, the publication is Clinical Lung Cancer (2005), 6(6), 361-366, database is CAplus and MEDLINE.

Exisulind is a sulfone derivative of sulindac that induces apoptosis and demonstrates synergy with docetaxel in lung cancer models. This study evaluated the safety, efficacy, and pharmacokinetic interactions of exisulind and docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer (NSCLC). Fifty-seven patients received 218 cycles of docetaxel (75 mg/m²) and carboplatin (area under the curve, 5.0) in combination with exisulind (125-250 mg orally twice daily). Two complete responses and 9 partial responses were observed among the 47 patients assessable for response (overall response rate, 23%). The median duration of response was 5.9 mo and median survival was 9.4 mo. The 1- and 2-yr survival rates are 35% and 14%, resp. The hematol. toxicities were consistent with those previously reported with docetaxel/carboplatin. The most common nonhematol. toxicities were mild to moderate fatigue, anorexia, nausea, and vomiting. The addition of exisulind to the chemotherapy regimen did not interfere with the metabolism or elimination of docetaxel and vice versa, and docetaxel did not interfere with the pharmacokinetic parameters of exisulind. This trial did not allow direct comparison of patients receiving docetaxel/carboplatin with and without exisulind, but when compared with historical data of docetaxel/carboplatin alone, the addition of exisulind does not appear to enhance antitumor activity, duration of response, or survival. Although preclin. data demonstrate increased apoptosis and prolonged survival for the combination of exisulind and docetaxel, multiple clin. trials do not support further clin. development of this combination regimen in patients with advanced NSCLC.

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

Frahm, Silke’s team published research in Cancer Cell International in 4 | CAS: 59973-80-7

Cancer Cell International 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, HPLC of Formula: 59973-80-7.

Frahm, Silke published the artcileSulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients, HPLC of Formula: 59973-80-7, the publication is Cancer Cell International (2004), No pp. given, database is CAplus.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone (Exisulind) are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients. Results: Exisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 渭M, and 63 渭M, resp. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 渭M Exisulind and 125 渭M Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1/2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen. Conclusions: Our results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST.

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

Giladi, Nis’s team published research in Expert Opinion on Investigational Drugs in 19 | CAS: 59973-80-7

Expert Opinion on Investigational Drugs 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.

Giladi, Nis published the artcileCurcumin potentiates the pro-apoptotic effects of sulindac sulfone in colorectal cancer, Related Products of naphthyridine, the publication is Expert Opinion on Investigational Drugs (2010), 19(S1), S117-S124, database is CAplus and MEDLINE.

Objective: The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment. Methods: HT-29 CRC cells were exposed to SFN (200 – 400 microM), curcumin (5 – 10 microM) or their combination. The cytotoxic effects of the drugs were evaluated using growth inhibition assays. Annexin V/PI and cell cycle anal. were employed to study the mechanism of action of the drugs. The therapeutic efficacy of the drugs in vivo was examined using the aberrant crypt foci (ACF) model. The treatment groups included eight rats/group. Results: Treatment of cells with curcumin and SFN resulted in a synergistic inhibitory effect of 50 – 90% (p < 0.005) on cell growth. Growth inhibition was associated with inhibition of proliferation, G2/M arrest and induction of apoptosis. Administration of curcumin (0.6%) and SFN (0.06%) to 1, 2-dimethylhydrazine treated rats significantly reduced (by 75%, p < 0.01) the number of ACF. Conclusions: Curcumin augments the therapeutic effects of SFN. This may be clin. important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC.

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

Piazza, Gary A.’s team published research in Cancer Prevention Research in 2 | CAS: 59973-80-7

Cancer Prevention 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, Name: Sulindac sulfone.

Piazza, Gary A. published the artcileA novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity, Name: Sulindac sulfone, the publication is Cancer Prevention Research (2009), 2(6), 572-580, database is CAplus and MEDLINE.

Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC₅₀ values of 2 to 5 μmol/L compared with 73 to 85 μmol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC₅₀ for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.

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

Rice, Pamela L.’s team published research in Molecular Cancer Therapeutics in 2 | CAS: 59973-80-7

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, Formula: C20H17FO4S.

Rice, Pamela L. published the artcileSulindac metabolites induce caspase- and proteasome-dependent degradation of β-catenin protein in human colon cancer cells, Formula: C20H17FO4S, the publication is Molecular Cancer Therapeutics (2003), 2(9), 885-892, database is CAplus.

Colorectal cancer (CRC) is the second leading cause of cancer death in the USA. Accumulation of β-catenin protein is nearly ubiquitous in colon adenomas and cancers, presumably due to mutations in the APC or β-catenin genes that inhibit proteasome-dependent degradation of β-catenin protein. Substantial clin., epidemiol., and animal evidence indicate that sulindac and other non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of CRC. The mechanisms by which sulindac exerts its potent growth inhibitory effects against colon tumor cells are incompletely understood, but down-regulation of β-catenin was suggested as one potential mechanism. The goal of this study was to determine the mechanism of β-catenin protein down-regulation by sulindac metabolites. Treatment of human colon cancer cell lines with apoptotic concentrations of sulindac metabolites (sulindac sulfide, sulindac sulfone) induced a dose- and time-dependent inhibition of β-catenin protein expression. Inhibition of proteasome activity with MG-132 partially blocked the ability of sulindac sulfide and sulindac sulfone to inhibit β-catenin protein expression. Pretreatment with the caspase inhibitor z-VAD-fmk blocked morphol. signs of apoptosis as well as caspase cleavage, and also partially prevented β-catenin degradation by sulindac metabolites. These effects occurred in cells with bi-allelic APC mutation (SW480), with wild-type APC but mono-allelic β-catenin mutation (HCT116) and in cells that lack expression of either COX-1 or -2 (HCT15). These results indicate that loss of β-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of β-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis.

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

Ayyanathan, Kasirajan’s team published research in PLoS One in 7 | CAS: 59973-80-7

PLoS One 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.

Ayyanathan, Kasirajan published the artcileCombination of sulindac and dichloroacetate kills cancer cells via oxidative damage, Formula: C20H17FO4S, the publication is PLoS One (2012), 7(7), e39949, database is CAplus and MEDLINE.

Sulindac is an FDA-approved non-steroidal anti-inflammatory drug with documented anticancer activities. Our recent studies showed that sulindac selectively enhanced the killing of cancer cells exposed to oxidizing agents via production of reactive oxygen species (ROS) resulting in mitochondrial dysfunction. This effect of sulindac and oxidative stress on cancer cells could be related to the defect in respiration in cancer cells, first described by Warburg 50 years ago, known as the Warburg effect. We postulated that sulindac might enhance the selective killing of cancer cells when combined with any compound that alters mitochondrial respiration. To test this hypothesis we have used dichloroacetate (DCA), which is known to shift pyruvate metabolism away from lactic acid formation to respiration. One might expect that DCA, since it stimulates aerobic metabolism, could stress mitochondrial respiration in cancer cells, which would result in enhanced killing in the presence of sulindac. In this study, we have shown that the combination of sulindac and DCA enhances the selective killing of A549 and SCC25 cancer cells under the conditions used. As predicted, the mechanism of killing involves ROS production, mitochondrial dysfunction, JNK signaling and death by apoptosis. Our results suggest that the sulindac-DCA drug combination may provide an effective cancer therapy.

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

Lim, Jin T. E.’s team published research in Clinical Cancer Research in 12 | CAS: 59973-80-7

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, SDS of cas: 59973-80-7.

Lim, Jin T. E. published the artcileSulindac Sulfide and Exisulind Inhibit Expression of the Estrogen and Progesterone Receptors in Human Breast Cancer Cells, SDS of cas: 59973-80-7, the publication is Clinical Cancer Research (2006), 12(11), 3478-3484, database is CAplus and MEDLINE.

In previous studies, we found that sulindac sulfide and exisulind (sulindac sulfone, Aptosyn) cause growth inhibition, arrest cells in the G₁ phase of the cell cycle, and induce apoptosis in human breast cancer cell lines. These effects were associated with decreased expression of cyclin D1. The present study focuses on the effects of sulindac sulfide and exisulind on hormone signaling components in breast cancer cells. We found that estrogen receptor (ER)-pos. and progesterone receptor (PR)-pos. T47D breast cancer cells were somewhat more sensitive to growth inhibition by sulindac sulfide or exisulind than ER-neg. PR-neg. MB-MDA-468 breast cancer cells. Further studies indicated that sulindac sulfide and exisulind caused marked down-regulation of expression of the ER and PR-A and PR-B in T47D cells. However, neither compound caused a major change in expression of the retinoic acid receptor α (RARα), RAR{szligbeta}, or RARα in T47D cells. Sulindac sulfide and exisulind also caused a decrease in expression of the ER in estrogen-responsive MCF-7 breast cancer cells. Both compounds also markedly inhibited estrogen-stimulated activation of an estrogen-responsive promoter in transient transfection reporter assays. Treatment of T47D cells with specific protein kinase G (PKG) activators did not cause a decrease in ER or PR expression. Therefore, although sulindac sulfide and exisulind can cause activation of PKG, the inhibitory effects of these two compounds on ER and PR expression does not seem to be mediated by PKG. Our findings suggest that the growth inhibition by sulindac sulfide and exisulind in ER-pos. and PR-pos. human breast cancer cells may be mediated, in part, by inhibition of ER and PR signaling. Thus, these and related compounds may provide a novel approach to the prevention and treatment of human breast cancers, especially those that are ER pos.

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

Chen, Yen-Ling’s team published research in Journal of Chromatography A in 1119 | CAS: 59973-80-7

Journal of Chromatography A 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, Quality Control of 59973-80-7.

Chen, Yen-Ling published the artcileCapillary electrophoresis combining field-amplified sample stacking and electroosmotic flow suppressant for analysis of sulindac and its two metabolites in plasma, Quality Control of 59973-80-7, the publication is Journal of Chromatography A (2006), 1119(1-2), 176-182, database is CAplus and MEDLINE.

Field-amplified sample stacking with electroosmotic flow (EOF) suppressant in capillary electrophoresis was used to determine the concentration of sulindac (SU) and its two active metabolites, sulindac sulfide (SI) and sulindac sulfone (SO), in human plasma. After acidification, the analytes were extracted from the plasma with dichloromethane. Before sample loading, a water plug (0.5 psi, 3 s) was injected to contain sample anions and to permit field-amplified stacking. Electrokinetic injection at a reversed voltage (-6 kV, 99.9 s) was then used to introduce anions. Separation was performed using phosphate buffer (80 mM, pH 6.0) containing 2,6-di-O-methyl-β-cyclodextrin (0.75 mM), and poly(ethylene oxide) (0.01%) as an EOF suppressant. The separation was performed at -30 kV and 200 nm. During method validation, calibration plots were linear (r > 0.994) over a range of 0.3-30.0 μM for SU and SO, and 0.5-30.0 μM for SI. During intra- and inter-day anal., relative standard deviations (RSD) and relative errors (RE) were all less than 16%. The limits of detection were 0.1 μM for SU and SO, and 0.3 μM for SI (S/N = 4, sampling 99.9 s at -6 kV). This method was feasible for determining SU and its metabolites in plasma. One female volunteer (27 years, 42 kg) was orally administered one SU tablet (Clinoril, 200 mg/tab), and blood samples were drawn at regular intervals over an 8 h period. After pretreatment and anal., the plasma levels of SU, SI and SO were monitored. The pharmacokinetic profile of SU was also investigated.

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

Santiesteban, Oscar J.’s team published research in Small in 10 | CAS: 59973-80-7

Small 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.

Santiesteban, Oscar J. published the artcileIdentification of toxin inhibitors using a magnetic nanosensor-based assay, Safety of Sulindac sulfone, the publication is Small (2014), 10(6), 1202-1211, database is CAplus and MEDLINE.

A magnetic nanosensor-based method is described to screen a library of drugs for potential binding to toxins. Screening is performed by measuring changes in the magnetic relaxation signal of the nanosensors (bMR nanosensors) in aqueous suspension upon addition of the toxin. The Anthrax lethal factor (ALF) is selected as a model toxin to test the ability of our bMR nanosensor-based screening method to identify potential inhibitors of the toxin. Out of 30 mols. screened, sulindac, naproxen and fusaric acid are found to bind LF, with dissociation constants in the low micromolar range. Further biol. anal. of the free mols. in solution indicate that sulindac and its metabolic products inhibited LF cytotoxicity to macrophages with IC₅₀ values in the micromolar range. Meanwhile, fusaric acid is found to be less effective at inhibiting LF cytotoxicity, while naproxen does not inhibit LF toxicity. Most importantly, when the sulindac and fusaric acid-bMR nanosensors themselves are tested as LF inhibitors, as opposed to the corresponding free mols., they are stronger inhibitors of LF with IC₅₀ values in the nanomolar range. Taken together, these studies show that a bMR nanosensors-based assay can be used to screen known drugs and other small mols. for inhibitor of toxins. The method can be easily modified to screen for inhibitors of other mol. interactions and not only the selected free mol. can be study as potential inhibitors but also the bMR nanosensors themselves achieving greater inhibitory potential.

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

Nixon, J. B.’s team published research in Prostaglandins, Leukotrienes and Essential Fatty Acids in 68 | CAS: 59973-80-7

Prostaglandins, Leukotrienes and Essential Fatty Acids 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.

Nixon, J. B. published the artcileEvaluation of eicosanoids and NSAIDs as PPARγ ligands in colorectal carcinoma cells, Related Products of naphthyridine, the publication is Prostaglandins, Leukotrienes and Essential Fatty Acids (2003), 68(5), 323-330, database is CAplus and MEDLINE.

The activation of peroxisome proliferator activated receptor γ (PPARγ) may play a role in the control of colorectal carcinogenesis. The expression of PPARγ was examined by Western blotting in human colorectal tumors and matched normal adjacent tissues, as well as in various colorectal carcinoma cell lines. In the tissues, the expression of PPARγ was elevated in tumors relative to the adjacent normal tissues. Each colorectal carcinoma cell line expressed PPARγ. The ability of various eicosanoids to bind PPARγ in colorectal carcinoma cells was investigated using luciferase reporter assays. The well-known PPARγ ligands, troglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂ strongly induced PPARγ binding activity. Products of lipoxygenases displayed moderate binding activity, while other prostaglandins and fatty acids displayed little or no reporter activation. The activation of PPARγ by 13(S)-HODE, the major metabolite of 15-lipoxygenase-1 from linoleic acid, was concentration dependent reaching maximum at 10 μM (35-fold activation). The endogenous production of 13(S)-HODE by expression of 15-LO-1 did not activate PPARγ. The ability of various nonsteroidal anti-inflammatory drugs (NSAIDs) to induce PPARγ activation was also evaluated. The conventional NSAIDs that inhibit both cyclooxygenases (COX-1 and COX-2) also induced PPARγ binding activity. In general, however, neither COX-1- nor COX-2-specific inhibitors induced the activation of PPARγ. Taken together, the metabolites of 15-lipoxygenase and the conventional NSAIDs were confirmed as exogenous ligands for PPARγ in colorectal carcinoma cells.

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