Tag: M.W=400-450

Ma, Tonghui published the artcileThiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion, Recommanded Product: 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, the publication is Journal of Clinical Investigation (2002), 110(11), 1651-1658, database is CAplus and MEDLINE.

Secretory diarrhea is the leading cause of infant death in developing countries and a major cause of morbidity in adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is required for fluid secretion in the intestine and airways and, when defective, causes the lethal genetic disease cystic fibrosis. We screened 50,000 chem. diverse compounds for inhibition of cAMP/flavone-stimulated Cl^– transport in epithelial cells expressing CFTR. Six CFTR inhibitors of the 2-thioxo-4-thiazolidinone chem. class were identified. The most potent compound discovered by screening of structural analogs, CFTR_inh-172, reversibly inhibited CFTR short-circuit current in less than 2 min in a voltage-independent manner with K₁ approx. 300 nM. CFTR_inh-172 was nontoxic at high concentrations in cell culture and mouse models. At concentrations fully inhibiting CFTR, CFTR_inh-172 did not prevent elevation of cellular cAMP or inhibit non-CFTR Cl^– channels, multidrug resistance protein-1 (MDR-1), ATP-sensitive K⁺ channels, or a series of other transporters. A single i.p. injection of CFTR_inh-172 (250 μg/kg) in mice reduced by more than 90% cholera toxin-induced fluid secretion in the small intestine over 6 h. Thiazolidinone CFTR inhibitors may be useful in developing large-animal models of cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas.

Journal of Clinical Investigation published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, Recommanded Product: 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Armirotti, Andrea published the artcileBioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity, Recommanded Product: 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, the publication is Scientific Reports (2019), 9(1), 1-13, database is CAplus and MEDLINE.

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Ta-1) was proposed as a single mol.-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Ta-1 changes induced by DMSO are fully reversible and that Ta-1 peptides prepared from different stock solutions have equivalent biol. activity. Considering the neg. results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Ta-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin a-1, they do not support its utility as a corrector of F508del-CFTR.

Scientific Reports published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, Recommanded Product: 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Kelly, Mairead published the artcileCystic fibrosis transmembrane regulator inhibitors CFTR_inh-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition, HPLC of Formula: 307510-92-5, the publication is Journal of Pharmacology and Experimental Therapeutics (2010), 333(1), 60-69, database is CAplus and MEDLINE.

Two highly potent and selective cystic fibrosis (CF) transmembrane regulator (CFTR) inhibitors have been identified by high-throughput screening: the thiazolidinone CFTR_inh-172 [3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone] and the glycine hydrazide GlyH-101 [N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide]. Inhibition of the CFTR chloride channel by these compounds has been suggested to be of pharmacol. interest in the treatment of secretory diarrheas and polycystic kidney disease. In addition, functional inhibition of CFTR by CFTR_inh-172 has been proposed to be sufficient to mimic the CF inflammatory profile. In the present study, we investigated the effects of the two compounds on reactive oxygen species (ROS) production and mitochondrial membrane potential in several cell lines: the CFTR-deficient human lung epithelial IB3-1 (expressing the heterozygous F508del/W1282X mutation), the isogenic CFTR-corrected C38, and HeLa and A549 as non-CFTR-expressing controls. Both inhibitors were able to induce a rapid increase in ROS levels and depolarize mitochondria in the four cell types, suggesting that these effects are independent of CFTR inhibition. In HeLa cells, these events were associated with a decrease in the rate of oxygen consumption, with GlyH-101 demonstrating a higher potency than CFTR_inh-172. The impact of CFTR inhibitors on inflammatory parameters was also tested in HeLa cells. CFTR_inh-172, but not GlyH-101, induced nuclear translocation of nuclear factor-κB (NF-κB). CFTR_inh-172 slightly decreased interleukin-8 secretion, whereas GlyH-101 induced a slight increase. These results support the conclusion that CFTR inhibitors may exert nonspecific effects regarding ROS production, mitochondrial failure, and activation of the NF-κB signaling pathway, independently of CFTR inhibition.

Journal of Pharmacology and Experimental Therapeutics published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, HPLC of Formula: 307510-92-5.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Sonawane, N. D. published the artcileThiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis, HPLC of Formula: 307510-92-5, the publication is Bioorganic & Medicinal Chemistry (2008), 16(17), 8187-8195, database is CAplus and MEDLINE.

The thiazolidinone 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTR_inh-172) inhibits cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel conductance with submicromolar affinity and blocks cholera toxin-induced intestinal fluid secretion. Fifty-eight CFTR_inh-172 analogs were synthesized to identify CFTR inhibitors with improved water solubility, exploring modifications in its two Ph rings, thiazolidinone core, and core-Ph connectors. Greatest CFTR inhibition potency was found for 3-CF₃ and polar group-substituted-Ph rings, and a thiazolidinone core. Two compounds with ∼1 μM CFTR inhibition potency and solubility >180 μM (>10-fold more than CFTR_inh-172) were identified: Tetrazolo-172, containing 4-tetrazolophenyl in place of 4-carboxyphenyl, and Oxo-172, containing thiazolidinedione in place of the thiazolidinone core. These water soluble thiazolidinone analogs had low cellular toxicity. The improved water solubility of Tetrazolo- and Oxo-172 make them potential lead candidates for therapy of secretory diarrheas and polycystic kidney disease.

Bioorganic & Medicinal Chemistry published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C19H36BNO2Si, HPLC of Formula: 307510-92-5.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Talbi, Khaoula published the artcileCalmodulin-Dependent Regulation of Overexpressed but Not Endogenous TMEM16A Expressed in Airway Epithelial Cells, Category: thiazolidine, the publication is Membranes (Basel, Switzerland) (2021), 11(9), 723, database is CAplus and MEDLINE.

Regulation of the Ca2+-activated Cl- channel TMEM16A by Ca²⁺/calmodulin (CAM) is discussed controversially. In the present study, we compared regulation of TMEM16A by Ca²⁺/calmodulin (holo-CAM), CAM-dependent kinase (CAMKII), and CAM-dependent phosphatase calcineurin in TMEM16A-overexpressing HEK293 cells and TMEM16A expressed endogenously in airway and colonic epithelial cells. The activator of the Ca²⁺/CAM-regulated K⁺ channel KCNN4, 1-EBIO, activated TMEM16A in overexpressing cells, but not in cells with endogenous expression of TMEM16A. Evidence is provided that CAM-interaction with TMEM16A modulates the Ca²⁺ sensitivity of the Cl- channel. Enhanced Ca²⁺ sensitivity of overexpressed TMEM16A explains its activity at basal (non-elevated) intracellular Ca²⁺ levels. The present results correspond well to a recent report that demonstrates a Ca²⁺-unbound form of CAM (apo-CAM) that is pre-associated with TMEM16A and mediates a Ca²⁺-dependent sensitization of activation (and inactivation). However, when using activators or inhibitors for holo-CAM, CAMKII, or calcineurin, we were unable to detect a significant impact of CAM, and limit evidence for regulation by CAM-dependent regulatory proteins on receptor-mediated activation of endogenous TMEM16A in airway or colonic epithelial cells. We propose that regulatory properties of TMEM16A and other members of the TMEM16 family as detected in overexpression studies, should be validated for endogenous TMEM16A and physiol. stimuli such as activation of phospholipase C (PLC)-coupled receptors.

Membranes (Basel, Switzerland) published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C8H8O3, Category: thiazolidine.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Ferreira, Vera F. C. published the artcileTargeting of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein with a Technetium-99m Imaging Probe, SDS of cas: 307510-92-5, the publication is ChemMedChem (2018), 13(14), 1469-1478, database is CAplus and MEDLINE.

Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to almost total absence of CFTR at the plasma membrane, a defect potentially corrected via drug-based therapies. Herein, we report the first proof-of-principle study of a noninvasive imaging probe able to detect CFTR at the plasma membrane. We radiolabeled the CFTR inhibitor, CFTR_inh-172a, with technetium-99m via a pyrazolyl-diamine chelating unit, yielding a novel ^99mTc(CO)₃ complex. A non-radioactive surrogate showed that the structural modifications introduced in the inhibitor did not affect its activity. The radioactive complex was able to detect plasma membrane CFTR, shown by its significantly higher uptake in wild-type vs. mutated cells. Furthermore, assessment of F508del CFTR pharmacol. correction in human cells using the radioactive complex revealed differences in corrector vs. control uptake, recapitulating the biochem. correction observed for the protein.

ChemMedChem published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, SDS of cas: 307510-92-5.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Sonawane, N. D. published the artcileIn vivo pharmacology and antidiarrheal efficacy of a thiazolidinone CFTR inhibitor in rodents, Category: thiazolidine, the publication is Journal of Pharmaceutical Sciences (2005), 94(1), 134-143, database is CAplus and MEDLINE.

A small-mol. inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR), 3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone (CFTR_inh-172), reduces enterotoxin-induced intestinal fluid secretion in rodents. Here, we study CFTR_inh-172 pharmacol. and antidiarrheal efficacy in rodents using ¹⁴C-labeled CFTR_inh-172, liquid chromatog./mass spectrometry, and a closed intestinal loop model of fluid secretion. CFTR_inh-172 was cleared primarily by renal glomerular filtration without chem. modification. CFTR_inh-172 accumulated in liver within 5 min after i.v. infusion in mice, and was concentrated fivefold in bile over blood. At 30-240 min, CFTR_inh-172 was found mainly in liver, intestine, and kidney, with little detectable in the brain, heart, skeletal muscle, or lung. Pharmacokinetic anal. in rats following i.v. bolus infusion showed a distribution volume of 770 mL with redistribution and elimination half-times of 0.14 h and 10.3 h, resp. CFTR_inh-172 was stable in hepatic microsomes. Closed-loop studies in mice indicated that a single i.p. injection of 20 μg CFTR_inh-172 inhibited fluid accumulation at 6 h after cholera toxin by >90% in duodenum and jejunum, ∼60% in ileum and <10% in colon. No toxicity was seen after high-dose CFTR_inh-172 administration (3 mg/kg/day in two daily doses) in mice over the first 6 wk of life. The metabolic stability, enterohepatic recirculation, slow renal elimination, and intestinal accumulation of CFTR_inh-172 account for its efficacy as an antidiarrheal.

Journal of Pharmaceutical Sciences published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C24H26ClNO4, Category: thiazolidine.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Laselva, Onofrio published the artcileRescue of multiple class II CFTR mutations by elexacaftor + tezacaftor + ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator, Synthetic Route of 307510-92-5, the publication is European Respiratory Journal (2021), 57(6), 2002774, database is CAplus and MEDLINE.

Pos. results in pre-clin. studies of the triple combination of elexacaftor, tezacaftor and ivacaftor, performed in airway epithelial cell cultures obtained from patients harbouring the class II cystic fibrosis transmembrane conductance regulator (CFTR) mutation F508del-CFTR, translated to impressive clin. outcomes for subjects carrying this mutation in clin. trials and approval of Trikafta. Encouraged by this correlation, we were prompted to evaluate the effect of the elexacaftor, tezacaftor and ivacaftor triple combination on primary nasal epithelial cultures obtained from individuals with rare class II CF-causing mutations (G85E, M1101K and N1303K) for which Trikafta is not approved. Cultures from individuals homozygous for M1101K responded better than cultures harbouring G85E and N1303K after treatment with the triple combination with respect to improvement in regulated channel function and protein processing. A similar genotype-specific effect of the triple combination was observed when the different mutations were expressed in HEK293 cells, supporting the hypothesis that these modulators may act directly on the mutant proteins. Detailed studies in nasal cultures and HEK293 cells showed that the corrector, elexacaftor, exhibited dual activity as both corrector and potentiator, and suggested that the potentiator activity contributes to its pharmacol. activity. These pre-clin. studies using nasal epithelial cultures identified mutation genotypes for which elexacaftor, tezacaftor and ivacaftor may produce clin. responses that are comparable to, or inferior to, those observed for F508del-CFTR.

European Respiratory Journal published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, Synthetic Route of 307510-92-5.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Srivastava, Jitendra Kumar published the artcilePharmacological evaluation of hybrid thiazolidin-4-one-1,3,5-triazines for NF-κB, biofilm and CFTR activity, Name: 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, the publication is RSC Advances (2015), 5(108), 88710-88718, database is CAplus.

Cystic fibrosis (CF) is a monogenetic disease caused mostly by the F508del mutation, a deletion of phenylalanine at position 508 of the CF transmembrane conductance regulator (CFTR) protein, which causes improper localization and functioning of this chloride channel in lung, pancreas, and intestine by affecting the normal fluid homeostasis. In CF the lungs are the most affected organ due to the accumulation of thick mucus, which results into heavy bacterial load and associated chronic inflammation. Therefore, novel state-of-the-art therapies are needed to circumvent this problem. To address this, a series of compounds (thiazolidin-4-one-1,3,5-triazines) was tested for the inhibition of NF-κB, and compounds SP6 and SP5 showed most significant activity (resp. with relative NF-κB activity: 1.82 ± 1.87 and 1.96 ± 1.56). Docking studies of the active compounds in the DNA binding surface of the N-terminal domains of NF-κB were also carried out to identify which structural motifs are vital for activity. These compounds were also tested for antibiofilm activity against P. aeruginosa and S. aureus where they showed MIC ranges from 7.81-125 μg mL^-1. The most active compound – SP6 was further assayed by micro-Ussing chamber experiments to determine its CFTR inhibitory properties, given its structural similarity to CFTR Inh₁₇₂. Results suggest that SP6 does not inhibit CFTR alone or in combination with Inh₁₇₂.

RSC Advances published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C11H8O3, Name: 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com

Lopes-Pacheco, Miqueias published the artcileCombination of Correctors Rescue ΔF508-CFTR by Reducing Its Association with Hsp40 and Hsp27*, COA of Formula: C18H10F3NO3S2, the publication is Journal of Biological Chemistry (2015), 290(42), 25636-25645, database is CAplus and MEDLINE.

Correcting the processing of ΔF508-CFTR, the most common mutation in cystic fibrosis, is the major goal in the development of new therapies for this disease. Here, we determined whether ΔF508 could be rescued by a combination of small-mol. correctors, and identified the mechanism by which correctors rescue the trafficking mutant of cystic fibrosis transmembrane conductance regulator (CFTR). We transfected COS-7 cells with ΔF508, created HEK-293 stably expressing ΔF508, and utilized CFBE41o- cell lines stably transduced with ΔF508. As shown previously, ΔF508 expressed less protein, was unstable at physiol. temperature, and rapidly degraded. When the cells were treated with the combination C18 + C4 the mature C-band was expressed at the cell surface. After treatment with C18 + C4, we saw a lower rate of protein disappearance after translation was stopped with cycloheximide. To understand how this rescue occurs, we evaluated the change in the binding of proteins involved in endoplasmic reticulum-associated degradation, such as Hsp27 (HspB1) and Hsp40 (DnaJ). We saw a dramatic reduction in binding to heat shock proteins 27 and 40 following combined corrector therapy. The siRNA experiments confirmed that a reduction in Hsp27 or Hsp40 rescued CFTR in the ΔF508 mutant, but the rescue was not additive or synergistic with C4 + 18 treatment, indicating these correctors shared a common pathway for rescue involving a network of endoplasmic reticulum-associated degradation proteins.

Journal of Biological Chemistry published new progress about 307510-92-5. 307510-92-5 belongs to thiazolidine, auxiliary class Membrane Transporter/Ion Channel,CFTR, name is 4-((4-Oxo-2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-5-ylidene)methyl)benzoic acid, and the molecular formula is C18H10F3NO3S2, COA of Formula: C18H10F3NO3S2.

Referemce:
https://en.wikipedia.org/wiki/Thiazolidine,
Thiazolidine – ScienceDirect.com