Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and Agonistic Activity at the GPR35 of 5,6-Dihydroxyindole-2-carboxylic Acid Analogues.

ABSTRACT: 5,6-Dihydroxyindole-2-carboxylic acid (DHICA), an intermediate of melanin synthesis and an eumelanin building block, was recently discovered to be a GPR35 agonist with moderate potency. Here, we report the synthesis and pharmacological characterization of a series of DHICA analogues against GPR35 using both label-free dynamic mass redistribution and Tango ?-arrestin translocation assays. This led to identification of novel GPR35 agonists with improved potency and/or having biased agonism.

SUBMITTER: Deng H

PROVIDER: S-EPMC4030800 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Synthesis and Agonistic Activity at the GPR35 of 5,6-Dihydroxyindole-2-carboxylic Acid Analogues.

Deng Huayun H Fang Ye Y

ACS medicinal chemistry letters 20120606 7

5,6-Dihydroxyindole-2-carboxylic acid (DHICA), an intermediate of melanin synthesis and an eumelanin building block, was recently discovered to be a GPR35 agonist with moderate potency. Here, we report the synthesis and pharmacological characterization of a series of DHICA analogues against GPR35 using both label-free dynamic mass redistribution and Tango β-arrestin translocation assays. This led to identification of novel GPR35 agonists with improved potency and/or having biased agonism. ...[more]

PMID: 24900508

Similar Datasets

The 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidase activity of human tyrosinase.

Project description:Melanin synthesis in mammals is catalysed by at least three enzymic proteins, tyrosinase (monophenol dihydroxyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1) and tyrosinase-related proteins (tyrps) 1 and 2, whose genes map to the albino, brown and slaty loci in mice, respectively. Tyrosinase catalyses the rate-limiting generation of L-dopaquinone from L-tyrosine and is also able to oxidize L-dopa to L-dopaquinone. Conversely, mouse tyrp1, but not tyrosinase, catalyses the oxidation of the indolic intermediate 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into the corresponding 5,6-indolequinone-2-carboxylic acid, thus promoting the incorporation of DHICA units into eumelanin. The catalytic activities of the human melanogenic enzymes are still debated. TYRP1 has been reported to lack DHICA oxidase activity, whereas tyrosinase appears to accelerate DHICA consumption, thus raising the question of DHICA metabolism in human melanocytes. Here we have used two different approaches, comparison of the catalytic activities of human melanocytic cell lines expressing the full set of melanogenic enzymes or deficient in TYRP1, and transient expression of TYR and tyr genes in COS7 cells, to demonstrate that human tyrosinase actually functions as a DHICA oxidase, as opposed to the mouse enzyme. Therefore, human tyrosinase displays a broader substrate specificity than its mouse counterpart, and might be at least partially responsible for the incorporation of DHICA units into human eumelanins.

| S-EPMC1221637 | biostudies-other

Synthesis, antifungal activity and QSAR of some novel carboxylic acid amides.

Project description:A series of novel aromatic carboxylic acid amides were synthesized and tested for their activities against six phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to good activity. Among them N-(2-(1H-indazol-1-yl)phenyl)-2-(trifluoromethyl)benzamide (3c) exhibited the highest antifungal activity against Pythium aphanidermatum (EC50 = 16.75 µg/mL) and Rhizoctonia solani (EC50 = 19.19 µg/mL), compared to the reference compound boscalid with EC50 values of 10.68 and 14.47 µg/mL, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were employed to develop a three-dimensional quantitative structure-activity relationship model for the activity of the compounds. In the molecular docking, a fluorine atom and the carbonyl oxygen atom of 3c formed hydrogen bonds toward the hydroxyl hydrogens of TYR58 and TRP173.

| S-EPMC6272411 | biostudies-literature

Design, synthesis and biological activity of hydroxybenzoic acid ester conjugates of phenazine-1-carboxylic acid.

Project description:We prepared 16 novel hydroxybenzoic acid ester conjugates of phenazine-1-carboxylic acid (PCA) and investigated their biological activity. Most of the synthesized conjugates displayed some level of fungicidal activities in vitro against five phytopathogenic fungi. Nine conjugates 5b, 5c, 5d, 5e, 5h, 5i, 5m, 5n and 5o (EC50 between 3.2 μg/mL and 14.1 μg/mL) were more active than PCA (EC50 18.6 μg/mL) against Rhizoctonia solani. Especially conjugate 5c showed the higher fungicidal activity against Rhizoctonia solani which is 6.5-fold than PCA. And the results of the bioassay indicated that the fungicidal activity of conjugates was associated with their LogP, and the optimal LogP values of the more potent fungicidal activities within these conjugates ranged from 4.42 to 5.08. The systemic acquired resistance induced by PCA-SA ester conjugate 5c against rice sheath blight disease in rice seedlings was evaluated. The results revealed that PCA-SA ester conjugate 5c retained the resistance induction activity of SA against rice sheath blight.

| S-EPMC6768031 | biostudies-literature

5,6-Dihydroxyindole-2-carboxylic acid is incorporated in mammalian melanin.

Project description:The role of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) in the biosynthesis of melanins has been studied by using the incorporation of specifically radiolabelled melanogenic precursors into melanins formed by melanocytes growing in vitro and in vivo. Extracts of mouse melanocytes and intact viable melanocytes were found to incorporate into melanin from 25% to more than 60% of [1-14C]tyrosine. Melanins from melanoma tumours grown in mice were radiolabelled with 3,4-dihydroxy[1-14C]phenylalanine, purified and chemoselectively decarboxylated. Determination of the 14CO2 evolved showed that at least 20% of the precursor incorporated in vivo retains the label in the form of non-aminoacidic aromatic-type carboxyl groups. These results provide the first unambiguous demonstration that DHICA is incorporated in physiologically relevant amounts in mammalian melanins.

| S-EPMC1132924 | biostudies-other

Synthesis and enzyme-based evaluation of analogues <i>L</i>-tyrosine thiol carboxylic acid inhibitor of metallo-β-lactamase IMP-1.

Project description:The emergence of drug-resistant pathogenic bacteria is occurring due to the global overuse and misuse of β-lactam antibiotics. Infections caused by some bacteria which secrete metallo-β-lactamases (enzymes that inactivate β-lactam antibiotics) are increasingly prevalent and have become a major worldwide threat to human health. These bacteria are resistant to β-lactam antibiotics and MBL-inhibitor/β-lactam antibiotic combination therapy can be a strategy to overcome this problem. So far, no clinically available inhibitors of metallo-β-lactamases (MBLs) have been reported. In this study, L-benzyl tyrosine thiol carboxylic acid analogues (2a-2k) were synthesized after the study of computational simulation by adding of methyl, chloro, bromo and nitro groups to the benzyl ring for investigation of SAR analysis. Although the synthesized molecules 2a-k shows the potent inhibitory effects against metallo-β-lactamase (IMP-1) with the range of Kic values of 1.04-4.77 µM, they are not as potent as the candidate inhibitor.

| S-EPMC8853707 | biostudies-literature

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid Amides.

Project description:A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

| S-EPMC6272562 | biostudies-literature

Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

Project description:BackgroundSpecies selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models.MethodsAnalogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts.ResultsMono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems.ConclusionXanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds.

| S-EPMC3619269 | biostudies-literature

Design, <i>in silico</i> studies, and synthesis of new 1,8-naphthyridine-3-carboxylic acid analogues and evaluation of their H1R antagonism effects.

Project description:New 1,8-naphthyridine-3-carboxylic acid derivatives were designed, synthesized and evaluated for their in vivo antihistaminic activity on guinea pig trachea by using chlorpheniramine as the standard drug. It was found that compound 5a1 displayed a promising bronchorelaxant effect in conscious guinea pigs using the in vivo model. A molecular docking study was performed to understand the molecular interaction and binding mode of the compounds in the active site of the H1 receptor. Furthermore, in silico computational studies were also performed to predict the binding modes and pharmacokinetic parameters of these derivatives. Prior to the start of experimental lab work, PASS software was used to predict the biological activities of these compounds. An in silico PASS, Swiss ADME assisted docking approach was found to be suitable to derive and synthesize effective antihistaminic agents for the present study.

| S-EPMC9051541 | biostudies-literature

Synthesis of 1-(5-Chloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives and Their Antioxidant Activity.

Project description:A series of novel 1-(5-chloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives containing chloro, hydroxyl, isopropyl, nitro, nitroso, and amino substituents at benzene ring and 1-(5-chloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carbohydrazide derivatives bearing heterocyclic moieties were synthesized. Antioxidant activity of the synthesized compounds was screened by DPPH radical scavenging method and reducing power assay. A number of compounds were identified as potent antioxidants. Antioxidant activity of 1-(5-chloro-2-hydroxyphenyl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one has been tested to be 1.5 times higher than that of a well-known antioxidant ascorbic acid. 1-(5-Chloro-2-hydroxyphenyl)-4-(4-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-one has shown 1.35 times higher antioxidant activity than that of vitamin C by DPPH radical scavenging method and optical density value of 1.149 in reducing power assay. The structure of 1-(5-chloro-2-hydroxyphenyl)-N-(1,3-dioxoisoindolin-2-yl)-5-oxopyrrolidine-3-carboxamide was unambiguously assigned by means of X-ray diffraction analysis data.

| S-EPMC6429199 | biostudies-literature

The Chemotherapeutic Agent, 5,6-Dimethylxanthenone-4-Acetic Acid,

Project description:Vascular disrupting agents (VDA) represent a novel approach to the treatment of cancer, resulting in collapse of tumor vasculature and tumor death. 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced Phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. The data presented herein demonstrate that DMXAA is a novel and specific activator of the TBK1-IRF-3 signaling pathway. DMXAA treatment of primary murine macrophages resulted in robust IRF-3 activation, a ~750-fold increase in IFN-beta mRNA and, in contrast to the potent Toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal NF-kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3, but MyD88-, TRIF-, IPS-1/MAVS-, and IKKbeta-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of murine macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid (SA). These findings detail a novel pathway for TBK-1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. Keywords: DMXAA, IRF-3, TBK1, IFN-beta, Salicylic acid, TLR

2007-03-08 | GSE7194 | GEO

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