Browse
Submit Data
Databases
API
Help

Dataset Information

41 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Asymmetrically Substituted m-Terphenyl Phosphates Inhibit the Transcription Factor STAT5a.

ABSTRACT: We recently presented Stafia-1 as the first chemical entity that inhibits the transcription factor STAT5a with selectivity over the highly homologous STAT5b. Stafia-1, which was identified from a series of symmetrically substituted m-terphenyl phosphates, binds to the interface between the SH2 domain and the linker domain of STAT5a. Here, we outline a synthetic strategy for the synthesis of asymmetrically substituted m-terphenyl phosphates, which can be tailored to address their asymmetric STAT5a binding site in a more specific manner. The asymmetrically substituted m-terphenyl phosphate with the highest activity against STAT5a was converted to a phosphatase-stable monofluoromethylene phosphonate. The synthetic methodology and activity analysis described here provide first insights into the structure-activity relationships of m-terphenyl phosphates for use as selective STAT5a inhibitors.

SUBMITTER: Muller-Klieser D

PROVIDER: S-EPMC9303812 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Asymmetrically Substituted m-Terphenyl Phosphates Inhibit the Transcription Factor STAT5a.

Müller-Klieser Daniel D Berg Thorsten T

Chembiochem : a European journal of chemical biology 20211229 4

We recently presented Stafia-1 as the first chemical entity that inhibits the transcription factor STAT5a with selectivity over the highly homologous STAT5b. Stafia-1, which was identified from a series of symmetrically substituted m-terphenyl phosphates, binds to the interface between the SH2 domain and the linker domain of STAT5a. Here, we outline a synthetic strategy for the synthesis of asymmetrically substituted m-terphenyl phosphates, which can be tailored to address their asymmetric STAT5 ...[more]

PMID: 34905258

Similar Datasets

Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a.

Project description:Src homology?2 (SH2) domains play a central role in signal transduction. Although many SH2 domains have been validated as drug targets, their structural similarity makes development of specific inhibitors difficult. The cancer-relevant transcription factors STAT5a and STAT5b are particularly challenging small-molecule targets because their SH2 domains are 93% identical on the amino acid level. Here we present the natural product-inspired development of the low-nanomolar inhibitor Stafib-1, as the first small molecule which inhibits the STAT5b SH2 domain (K(i)=44?nM) with more than 50-fold selectivity over STAT5a. The binding site of the core moiety of Stafib-1 was validated by functional analysis of point mutants. A prodrug of Stafib-1 was shown to inhibit STAT5b with high selectivity over STAT5a in tumor cells. Stafib-1 provides the first demonstration that naturally occurring SH2 domains with more than 90% sequence identity can be selectively targeted with small organic molecules.

| S-EPMC4471549 | biostudies-literature

Improved synthesis of symmetrically & asymmetrically N-substituted pyridinophane derivatives.

Project description:The N,N'-di(toluenesulfonyl)-2,11-diaza[3,3](2,6)pyridinophane (TsN4) precursor was sought after as a starting point for the preparation of various symmetric and asymmetric pyridinophane-derived ligands. Various procedures to synthesize TsN4 had been published, but the crucial problem had been the purification of TsN4 from the larger 18- and 24-membered azamacrocycles. Most commonly, column chromatography or other laborious methods have been utilized for this separation, yet we have found an alternate selective dissolution method upon protonation which allows for multi-gram scale output of TsN4·HCl. This optimized synthesis of TsN4 also led to the development of symmetric RN4 derivatives as well as the asymmetric derivative N-(tosyl)-2,11-diaza[3,3](2,6)pyridinophane (TsHN4). Using this TsHN4 precursor, different N-substituents can be added to create a library of asymmetric RR'N4 macrocyclic ligands. These asymmetric RR'N4 derivatives expand the utility of the RN4 framework in coordination chemistry and the ability to study the electronic, steric, and denticity effects of these pyridinophane ligands on the metal center.

| S-EPMC7716245 | biostudies-literature

Asymmetrically Substituted Phospholes as Ligands for Coinage Metal Complexes.

Project description:A series of coinage metal complexes asymmetrically substituted 2,5-diaryl phosphole ligands is reported. Structure, identity, and purity of all obtained complexes were corroborated with state-of-the-art techniques (multinuclear NMR, mass spectrometry, elemental analysis, X-ray diffraction) in solution and solid state. All complexes obtained feature luminescence in solution as well as in the solid state. Additionally, DOSY-MW NMR estimation experiments were performed to achieve information about the aggregation behavior of the complexes in solution allowing a direct comparison with their structures observed in the solid state.

| S-EPMC9182544 | biostudies-literature

Asymmetrically Substituted s-Triazine Phosphonates by One-Step Synthesis.

Project description:Asymmetrically substituted s-triazine phosphonates with up to three different phosphonate groups C3 N3 RR'R" with R, R', R"=PO(OR"') and R"'=for example, methyl, ethyl, isopropyl or n-butyl are interesting as polymer additives like flame retardants. Typically, these compounds are obtained by multiple synthesis steps. However, this leads to high production costs, which are a disadvantage for commercial use. Here we report the one-step synthesis of mixtures of asymmetrical s-triazine phosphonates which is an easy way to adjust the thermal behaviour and other properties such as viscosities of the compounds. The synthesis is based on a Michaelis-Arbuzov reaction. A complete conversion of the reactants to the target compounds is observed which was proofed by detailed 1 H, 13 C and 31 P NMR investigations and elemental analysis. The thermal behaviour was compared with thermogravimetric analysis (TGA).

| S-EPMC10509391 | biostudies-literature

Solid-phase synthesis of asymmetrically substituted "AB3-type" phthalocyanines.

Project description:Synthesis of phthalocyanines with asymmetrical substitution on the periphery is often difficult due the problems in purification of the phthalocyanine mixtures obtained. Using a poly(ethylene glycol) (PEG)-based support with a Wang-type linker, we have developed the synthesis of monohydroxylated, oligoethylene glycol substituted phthalocyanines utilizing an amidine-base-promoted phthalonitrile tetramerization reaction. The use of a hydrophilic support allows symmetrical phthalocyanine product formed in solution to be readily and completely removed by washing while leaving the "AB3" product on the support. Acid cleavage with 10% trifluoroacetic acid provides the pure unsymmetrically substituted Pc. This method was applied to several metallo Pcs. Additionally, methods to avoid premature reactions on-resin that give A2B2 products are provided.

| S-EPMC2525812 | biostudies-literature

Asymmetrically-substituted quadruplex-binding napththalene diimides showing potent activity in models for pancreatic cancer

Project description:Targeting quadruplexes in cancer genes and pathways by a novel class of asymmetrically-substituted napththalene diimides (SOP1812) with potent cellular and antitumour activity in models for pancreatic cancer.

2020-06-04 | GSE151741 | GEO

Structural and Electronic Studies of Substituted m-Terphenyl Group 12 Complexes

Project description:The effects of para-substitution on the structural

| S-EPMC9490839 | biostudies-literature

Antimicrobial activity of ion-substituted calcium phosphates: A systematic review.

Project description:In this systematic review, the antimicrobial effect of ion-substituted calcium phosphate biomaterials was quantitatively assessed. The literature was systematically searched up to the 6th of December 2021. Study selection and data extraction was performed in duplo by two independent reviewers with a modified version of the OHAT tool for risk of bias assessment. Any differences were resolved by consensus or by a referee. A mixed effects model was used to investigate the relation between the degree of ionic substitution and bacterial reduction. Of 1016 identified studies, 108 were included in the analysis. The methodological quality of included studies ranged from 6 to 16 out of 18 (average 11.4). Selenite, copper, zinc, rubidium, gadolinium, silver and samarium had a clear antimicrobial effect, with a log reduction in bacteria count of 0.23, 1.8, 2.1, 3.6, 5.8, 7.4 and 10 per atomic% of substitution, respectively. There was considerable between-study variation, which could partially be explained by differences in material formulation, study quality and microbial strain. Future research should focus on clinically relevant scenarios in vitro and the translation to in vivo prevention of PJI.

| S-EPMC10248076 | biostudies-literature

Transcription and Remodeling Produce Asymmetrically Unwrapped Nucleosomal Intermediates.

Project description:Nucleosomes are disrupted during transcription and other active processes, but the structural intermediates during nucleosome disruption in vivo are unknown. To identify intermediates, we mapped subnucleosomal protections in Drosophila cells using Micrococcal Nuclease followed by sequencing. At the first nucleosome position downstream of the transcription start site, we identified unwrapped intermediates, including hexasomes that lack either proximal or distal contacts. Inhibiting topoisomerases or depleting histone chaperones increased unwrapping, whereas inhibiting release of paused RNAPII or reducing RNAPII elongation decreased unwrapping. Our results indicate that positive torsion generated by elongating RNAPII causes transient loss of histone-DNA contacts. Using this mapping approach, we found that nucleosomes flanking human CTCF insulation sites are similarly disrupted. We also identified diagnostic subnucleosomal particle remnants in cell-free human DNA data as a relic of transcribed genes from apoptosing cells. Thus identification of subnucleosomal fragments from nuclease protection data represents a general strategy for structural epigenomics.

| S-EPMC6421108 | biostudies-literature

New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription.

Project description:Conventional chemotherapy remains the primary treatment option for triple-negative breast cancer (TNBC). However, the current chemotherapeutic drugs have limited effects on TNBC, and often lead to serious side effects as well as drug resistance. Thus, more effective therapeutic options are sorely needed. As c-MYC oncogene is highly expressed during TNBC pathogenesis, inhibiting c-MYC expression would be an alternative anti-TNBC strategy. In this study, we designed and synthesized a serial of quinoxaline analogs that target c-MYC promoter G-quadruplex (G4), which is believed to be a repressor of c-MYC transcription. Among them, a difluoro-substituted quinoxaline QN-1 was identified as the most promising G4-stabilizing ligand with high selectivity to c-MYC G4 over other G4s, which is distinguished from many other reported ligands. Intracellular studies indicated that QN-1 induced cell cycle arrest and apoptosis, repressed metastasis and inhibited TNBC cell growth, primarily due to the downregulation of c-MYC transcription by a G4-dependent mechanism. Notably, inhibition by QN-1 was significantly greater for c-MYC than other G4-driven genes. Cancer cells with c-MYC overexpression were more sensitive to QN-1, relative to normal cells. Furthermore, QN-1 effectively suppressed tumor growth in a TNBC mouse model. Accordingly, this work provides an alternative strategy for treating TNBC.

| S-EPMC6846596 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data