Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors.

ABSTRACT: Sirtuins are a family of NAD(+)-dependent protein deacetylases that play critical roles in epigenetic regulation, stress responses, and cellular aging in eukaryotic cells. In an effort to identify small molecule inhibitors of sirtuins for potential use as chemotherapeutics as well as tools to modulate sirtuin activity, we previously identified a nonselective sirtuin inhibitor called cambinol (IC50 ≈ 50 μM for SIRT1 and SIRT2) with in vitro and in vivo antilymphoma activity. In the current study, we used saturation transfer difference (STD) NMR experiments with recombinant SIRT1 and 20 to map parts of the inhibitor that interacted with the protein. Our ongoing efforts to optimize cambinol analogues for potency and selectivity have resulted in the identification of isoform selective analogues: 17 with >7.8-fold selectivity for SIRT1, 24 with >15.4-fold selectivity for SIRT2, and 8 with 6.8- and 5.3-fold selectivity for SIRT3 versus SIRT1 and SIRT2, respectively. In vitro cytotoxicity studies with these compounds as well as EX527, a potent and selective SIRT1 inhibitor, suggest that antilymphoma activity of this compound class may be predominantly due to SIRT2 inhibition.

SUBMITTER: Mahajan SS

PROVIDER: S-EPMC4002067 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors.

Project description:Human neutrophil elastase (HNE) is an important target for the development of novel and selective inhibitors to treat inflammatory diseases, especially pulmonary pathologies. Here, we report the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with an isoxazol-5(2H)-one scaffold. The most potent compound (2o) had a good balance between HNE inhibitory activity (IC50 value =20 nM) and chemical stability in aqueous buffer (t1/2=8.9 h). Analysis of reaction kinetics revealed that the most potent isoxazolone derivatives were reversible competitive inhibitors of HNE. Furthermore, since compounds 2o and 2s contain two carbonyl groups (2-N-CO and 5-CO) as possible points of attack for Ser195, the amino acid of the active site responsible for the nucleophilic attack, docking studies allowed us to clarify the different roles played by these groups.

| S-EPMC5927774 | biostudies-literature

Structure-based development of novel sirtuin inhibitors.

Project description:Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins they deacetylate. The physiological roles of Sirtuins and their potential use as therapeutic targets for metabolic and aging-related diseases have spurred interest in the development of small-molecule Sirtuin modulators. Here, we describe an approach exploiting the structures available for four human Sirtuins for the development of isoform-specific inhibitors. Virtual docking of a compound library into the peptide binding pockets of crystal structures of Sirt2, 3, 5 and 6 yielded compounds potentially discriminating between these isoforms. Further characterization in activity assays revealed several inhibitory compounds with little isoform specificity, but also two compounds with micromolar potency and high specificity for Sirt2. Structure comparison and the predicted, shared binding mode of the Sirt2-specific compounds indicate a pocket extending from the peptide-binding groove as target side enabling isoform specificity. Our family-wide structure-based approach thus identified potent, Sirt2-specific inhibitors as well as lead structures and a target site for the development of compounds specific for other Sirtuin isoform, constituting an important step toward the identification of a complete panel of isoform-specific Sirtuin inhibitors.

| S-EPMC3227451 | biostudies-literature

Development of Anthraquinone Analogues as Phosphoglycerate Mutase 1 Inhibitors.

Project description:Phosphoglycerate mutase 1 (PGAM1) coordinates glycolysis and biosynthesis to promote cancer cell proliferation, and is believed to be a promising target for cancer therapy. Herein, based on the anthraquinone scaffold, we synthesized 31 anthraquinone derivatives and investigated the structure-activity relationship (SAR). The 3-substitient of sulfonamide on the anthraquinone scaffold was essential for maintaining potency and the modifications of the hydroxyl of alizarin would cause a sharp decrease in potency. In the meantime, we determined the co-crystal structure of PGAM1 and one of the anthraquinone inhibitors 9i with IC50 value of 0.27 ?M. The co-crystal structure revealed that F22, K100 and R116 of PGAM1 were critical residues for the binding of inhibitors which further validated the SAR. Consistent with the crystal structure, a competitive assay illustrated that compound 9i was a noncompetitive inhibitor. In addition, compound 9i effectively restrained different lung cancer cells proliferation in vitro. Taken together, this work provides reliable guide for future development of PGAM1 inhibitors and compound 9i may act as a new leading compound for further optimization.

| S-EPMC6429356 | biostudies-literature

4-(2-Hydroxy-benzyl-idene)-3-methyl-isoxazol-5(4H)-one.

Project description:The mol-ecular skeleton of the title mol-ecule, C(11)H(9)NO(3), is approximately planar (r.m.s. deviation = 0.0056?Å); the two rings form a dihedral angle of 6.5?(1)°. In the crystal structure, inter-molecular O-H?N hydrogen bonds involving the H atom of the hydr-oxy group and the N atom of the isoxazole ring link mol-ecules into chains running along the c axis.

| S-EPMC2972172 | biostudies-literature

Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors.

Project description:A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.

| S-EPMC3426190 | biostudies-literature

Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors.

Project description:Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that ?-? interactions between the compound and Smoothened play a key role in stabilizing the bound analogues.

| S-EPMC6358021 | biostudies-literature

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds.

Project description:NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents.

| S-EPMC8949162 | biostudies-literature

(Z)-4-Benzyl-idene-3-methyl-isoxazol-5(4H)-one.

Project description:In the title compound C(11)H(9)NO(2), the phenyl and isoxazole rings are almost coplanar, making a dihedral angle of 1.14?(9)°. This planarity is also assisted by an intra-molecular C-H?O hydrogen bond between the phenyl ring and the carbonyl O atom. In the crystal, weak C-H?O inter-actions generate a layered structure parallel to the ac plane.

| S-EPMC3515194 | biostudies-other

Development of Simplified Heterocyclic Acetogenin Analogues as Potent and Selective Trypanosoma brucei Inhibitors.

Project description:Neglected tropical diseases caused by parasitic infections are an ongoing and increasing concern. They are a burden to human and animal health, having the most devastating effect on the world's poorest countries. Building upon our previously reported triazole analogues, in this study we describe the synthesis and biological testing of other novel heterocyclic acetogenin-inspired derivatives, namely 3,5-isoxazoles, furoxans, and furazans. Several of these compounds maintain low-micromolar levels of inhibition against Trypanosoma brucei, whilst having no observable inhibitory effect on mammalian cells, leading to the possibility of novel lead compounds for selective treatment.

| S-EPMC5111590 | biostudies-literature

Sirtuin activators and inhibitors: Promises, achievements, and challenges.

Project description:The NAD+-dependent protein lysine deacylases of the Sirtuin family regulate various physiological functions, from energy metabolism to stress responses. The human Sirtuin isoforms, SIRT1-7, are considered attractive therapeutic targets for aging-related diseases, such as type 2 diabetes, inflammatory diseases and neurodegenerative disorders. We review the status of Sirtuin-targeted drug discovery and development. Potent and selective pharmacological Sirt1 activators and inhibitors are available, and initial clinical trials have been carried out. Several promising inhibitors and activators have also been described for other isoforms. Progress in understanding the mechanisms of Sirtuin modulation by such compounds provides a rational basis for further drug development.

| S-EPMC6342514 | 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