Identification of Diarylsulfone Sulfonamides as Secreted Frizzled Related Protein-1 (sFRP-1) Inhibitors

Gopalsamy, Ariamala; Shi, Mengxiao; Stauffer, Barbara; Bahat, Ramesh; Billiard, Julia; Ponce-de-Leon, Helga; Seestaller-Wehr, Laura; Fukayama, Shoichi; Mangine, Annamarie; Moran, Robert A.; Krishnamurthy, Girija; Bodine, Peter V.N.

doi:10.1021/jm801069w

Cited by 45 publications

(24 citation statements)

References 16 publications

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“…Analogues of 8 were synthesized to understand the significance of the two chlorine atoms and to study the tolerance of the sulfonamide moiety to N substitution. Friedel–Crafts sulfonylation of appropriately substituted aromatic compounds 17 – 19 using phenylsulfonyl chloride provided diarylsulfones 20 – 22 (Scheme ) 17. Regioselective chlorosulfonylation of 20 – 22 furnished 23 – 25 in moderate yields ranging from 50 to 55 % over two steps.…”

Section: Resultsmentioning

confidence: 99%

Inhibitors of the Salicylate Synthase (MbtI) from Mycobacterium tuberculosis Discovered by High‐Throughput Screening

et al. 2010

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A simple steady-state kinetic high-throughput assay was developed for the salicylate synthase MbtI from Mycobacterium tuberculosis, which catalyzes the first committed step of mycobactin biosynthesis. The mycobactins are small-molecule iron chelators produced by M. tuberculosis, and their biosynthesis has been identified as a promising target for the development of new antitubercular agents. The assay was miniaturized to a 384-well plate format and high-throughput screening was performed at the National Screening Laboratory for the Regional Centers of Excellence in Biodefense and Emerging Infectious Diseases (NSRB). Three classes of compounds were identified comprising the benzisothiazolones (class I), diarylsulfones (class II), and benzimidazole-2-thiones (class III). Each of these compound series was further pursued to investigate their biochemical mechanism and structure-activity relationships. Benzimidazole-2-thione 4 emerged as the most promising inhibitor owing to its potent reversible inhibition.

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Section: Resultsmentioning

confidence: 99%

Inhibitors of the Salicylate Synthase (MbtI) from Mycobacterium tuberculosis Discovered by High‐Throughput Screening

et al. 2010

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“…It harbors two distinct structural domains, namely netrin domain and CRD domain. CRD domain is homologous to the frizzled receptors [16,21]. Studies show that SFRP1 is an antagonist of the Wnt signaling pathway, and can bind to Wnt proteins via its CRD domain in a competitive manner with the transmembrane frizzled receptor, leading to the inhibition of the Wnt signaling pathway [22–25].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Value of SFRP1 as a Favorable Predictive and Prognostic Biomarker in Patients with Prostate Cancer

et al. 2015

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Growing genetic and molecular biological evidence suggests that the disruption of balance between Secreted Frizzled-Related Protein-1 (SFRP1) and β-catenin plays an important role in the initiation and development of multiple cancers. The aim of this study was to examine whether the expression of SFRP1 and β-catenin is associated with the clinical-pathologic features of patients with prostate cancer (PCa), and to evaluate their potential roles as predictive and prognostic biomarkers. In this study, a total of 61 patients with PCa and 10 patients with benign prostatic hyperplasia were included, and we showed that the expression of SFRP1 and β-catenin was correlated with the Gleason score, survival rate and response for endocrine therapy of PCa. The survival rates of PCa patients with low SFRP1 expression (P = 0.016) or high β-catenin expression (P = 0.004) were significantly poorer. A negative correlation (r = -0.275, P = 0.032) between SFRP1 and β-catenin was observed by Chi-square test. Multivariate analysis suggested that SFRP1 (hazard ratio, 0.429; 95% confidence intervals, 0.227–0.812; P = 0.009) may serve as an independent predictive and prognostic factor for PCa. We also showed that the protein and mRNA levels of SFRP1 in androgen-dependent PCa cell line LNCaP were significantly higher than those in androgen-independent PCa cell lines DU145 and PC3. However, the protein level of β-catenin in LNCaP cells was significantly lower than that in DU145 and PC3 cells, and no significant difference of β-catenin mRNA level was observed in LNCaP, DU145 and PC3 cells. Bisulfite sequencing PCR assay revealed significantly lower methylation level of SFRP1 promoter in LNCaP cells than that in DU145 and PC3 cells. Taken together, these findings suggest that SFRP1, which expression inversely correlates with that of β-catenin, is a favorable predictive and prognostic biomarker.

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“…WAY-316606 (MCE, HY-10858) is a cell-permeable small-molecule compound that selectively inhibits the activity of the secreted protein Sfrp1, and also activates the Wnt signaling pathway (Moore et al, 2009;Bodine et al, 2009;Gopalsamy et al, 2008). 12.5-day mice were anesthetized with isoflurane gas for 30 min before the procedure.…”

Section: In Utero Injectionmentioning

confidence: 99%

Sonic hedgehog regulates the pathfinding of descending serotonergic axons in hindbrain in collaboration with Wnt5a and secreted frizzled‐related protein 1

Xie

Zhao

Liu

2017

Intl J of Devlp Neuroscience

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Previous studies have demonstrated that both Wnt5a and Sonic hedgehog (Shh) are involved in regulating the pathfinding of descending serotonergic (5-HT, 5-hydroxytryptamine) axons in an opposite manner in the brainstem. Shh and Wnt signaling pathways interact to guide post-crossing commissural axons, where Shh acts as a repellent directly and shaping the Wnt gradient indirectly by regulating the gradient expression of the frizzled-related protein 1 (Sfrp1). Whether such a mechanism functions in descending 5-HT axon guidance remains unknown. Here, we found that the core components of the Shh and Wnt planar cell polarity signaling pathways are expressed in caudal 5-HT neurons, and the expression gradients of Shh, Sfrp1, and Wnt5a exist simultaneously in hindbrain. Dunn chamber assays revealed that Sfrp1 suppressed the attractive Wnt gradient. Moreover, we found that Shh overexpression led to pathfinding defects in 5-HT axon descending, and the axonal pathfinding defects could be partially rescued by administration of an Sfrp1 antagonist in vivo. Biochemical evidence showed Shh overexpression upregulated the expression of the Sfrp1 gene and interrupted Wnt5a binding to Frizzled-3. Taken together, our results indicate that Shh, Sfrp1, and Wnt5a collaborate to direct the pathfinding of descending 5-HT axons in the brainstem.

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Identification of Diarylsulfone Sulfonamides as Secreted Frizzled Related Protein-1 (sFRP-1) Inhibitors

Cited by 45 publications

References 16 publications

Inhibitors of the Salicylate Synthase (MbtI) from Mycobacterium tuberculosis Discovered by High‐Throughput Screening

Inhibitors of the Salicylate Synthase (MbtI) from Mycobacterium tuberculosis Discovered by High‐Throughput Screening

Diagnostic Value of SFRP1 as a Favorable Predictive and Prognostic Biomarker in Patients with Prostate Cancer

Sonic hedgehog regulates the pathfinding of descending serotonergic axons in hindbrain in collaboration with Wnt5a and secreted frizzled‐related protein 1

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