Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design and Synthesis of 4-(4-Benzoylaminophenoxy)phenol Derivatives As Androgen Receptor Antagonists.

ABSTRACT: We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 ?M), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 ?M), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 ?M). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.

SUBMITTER: Yamada A

PROVIDER: S-EPMC4027134 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Design and Synthesis of 4-(4-Benzoylaminophenoxy)phenol Derivatives As Androgen Receptor Antagonists.

Yamada Ayumi A Fujii Shinya S Mori Shuichi S Kagechika Hiroyuki H

ACS medicinal chemistry letters 20130819 10

We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 μM), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 μM), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 μM). Structure-acti ...[more]

PMID: 24900588

Similar Datasets

Design, synthesis and biological evaluation of novel piperazine derivatives as CCR5 antagonists.

Project description:By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC(50) values in low micromolar level. Among evaluated compounds, 23 h was found to be a CCR5 antagonist with an IC(50) value of 6.29 µM and an anti-HIV-1 inhibitor with an IC(50) value of 0.44 µM.

| S-EPMC3538727 | biostudies-literature

Design, Synthesis and Bioactivities of Novel Dichloro-Allyloxy-Phenol-Containing Pyrazole Oxime Derivatives.

Project description:In this study, in order to find novel biologically active pyrazole oxime compounds, a number of dichloro-allyloxy-phenol-containing pyrazole oximes were designed and synthesized according to the method of active group combination. All of the target compounds were confirmed by ¹H-NMR, (13)C-NMR and elemental analysis. In addition, bioassays showed that all of the newly synthesized compounds had no acaricidal activity against Tetranychus cinnabarinus and low insecticidal activity against Aphis craccivora at tested concentrations. However, most of them displayed excellent insecticidal activity against Oriental armyworm at a concentration of 500 μg/mL, and some designed compounds still exhibited potent insecticidal activity against Oriental armyworm even at the dose of 20 μg/mL, especially compounds 7f, 7n and 7p had 100%, 90% and 90% inhibition rates, respectively, which were comparable to that of the control pyridalyl.

| S-EPMC6332197 | biostudies-literature

14-O-Heterocyclic-substituted naltrexone derivatives as non-peptide mu opioid receptor selective antagonists: design, synthesis, and biological studies.

Project description:Mu opioid receptor antagonists have clinical utility and are important research tools. To develop non-peptide and highly selective mu opioid receptor antagonist, a series of 14-O-heterocyclic-substituted naltrexone derivatives were designed, synthesized, and evaluated. These compounds showed subnanomolar-to-nanomolar binding affinity for the mu opioid receptor. Among them, compound 1 exhibited the highest selectivity for the mu opioid receptor over the delta and kappa receptors. These results implicated an alternative 'address' domain in the extracellular loops of the mu opioid receptor.

| S-EPMC2802822 | biostudies-literature

Design, Synthesis, and Biological Activity Studies of Istradefylline Derivatives Based on Adenine as A<sub>2A</sub> Receptor Antagonists.

Project description:Due to its double bond, istradefylline rapidly isomerizes to Z-istradefylline when exposed to normal daylight in dilute solution. To solve the poor photostability of the istradefylline solution, a series of istradefylline derivatives (in total 17 compounds, including II-1 and II-2 series) were designed and synthesized, and their biological activity in inhibiting cAMP was evaluated. The IC50 values of compounds II-1-3, II-2-1, II-2-2, II-2-3, II-2-4, and II-2-6 were 7.71, 6.52, 6.16, 7.23, 7.96, and 9.68 ?g/mL, respectively, which had the same order of activity as that of istradefylline (IC50 value was 1.94 ?g/mL). The preliminary structure-activity relationship suggested that the 6-amino in adenine played an important role in binding an A2A receptor. The results of photostability experiments showed that the photostability of the target compounds of II-1 and II-2 series was improved when compared with that of istradefylline.

| S-EPMC7906590 | biostudies-literature

Design, synthesis, and biological evaluation of 6alpha- and 6beta-N-heterocyclic substituted naltrexamine derivatives as mu opioid receptor selective antagonists.

Project description:Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible mu opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K(i) = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the delta receptor (DOR) and more than 150-fold selectivity over the kappa receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.

| S-EPMC2880636 | biostudies-literature

Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HT1A Serotonin Receptor Antagonists.

Project description:We have designed and synthesized a series of 60 new 5- and 7-hydroxycoumarin derivatives bearing the piperazine moiety with the expected binding to 5-HT1A and 5-HT2A receptors. Molecular docking of all investigated compounds revealed subnanomolar estimates of 5-HT1AR Ki for three ligands and 5-HT2AR Ki for one ligand as well as numerous low nanomolar estimates of Ki for both receptors. Intrigued by these results we synthesized all 60 new derivatives using microwave-assisted protocols. We show that three new compounds show a relatively high antagonistic activity against the 5HT1A receptor, although lower than the reference compound WAY-100635. These compounds also showed relatively low binding affinities to the 5-HT2A receptor. We also provide a detailed structure-activity analysis of this series of compounds and compare it with previously obtained results for an exhaustive series of coumarin derivatives.

| S-EPMC7996328 | biostudies-literature

Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity.

Project description:Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease, and diabetes. Recently, development of several CB1 antagonists was halted because of adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than that for rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.

| S-EPMC3319116 | biostudies-literature

Design, synthesis, and biological evaluation of novel androst-17?-amide structurally related compounds as dual 5?-reductase inhibitors and androgen receptor antagonists.

Project description:Prostate cancer (PCa) is the second leading cause of death in men. Apart from androgen receptor, 5?-reductase has also been recognized as a potential target. In this study, a series of androst-17?-amide compounds have been designed and synthesized targeting both AR and 5?-reductase. Their anti-proliferation activities were evaluated in AR?+?cell line 22RV1 and AR?-?cell line PC-3. The results indicated that most of the synthesized compounds inhibited the testosterone-stimulated cell proliferation with good selectivity and safety. Among all the compounds, androst[3,2-c]pyrazole derivatives (9a-9d) displayed the best inhibition activity comparable with flutamide. Moreover, most of the synthesized compounds displayed good 5?-reductase inhibitory activities with IC50 lower than 1??M. The docking result of 9d-AR indicated that AR was forced to expands its binding cavity and maintain an antagonistic conformation since the steric hindrance of 9d impeded H12 transposition. Overall, compound 9d can be identified as a potential dual 5?-reductase inhibitor and AR antagonist, which might be of therapeutic importance for PCa treatment.

| S-EPMC6735293 | biostudies-literature

Design, synthesis and SAR study of novel trisubstituted pyrimidine amide derivatives as CCR4 antagonists.

Project description:The design, synthesis and structure-activity relationship studies of some novel trisubstituted pyrimidine amide derivatives prepared as CCR4 antagonists are described. The activities of these compounds were evaluated by the CCR4-MDC chemotaxis inhibition assay. Compound 1, which we have previously reported as a potent antagonist of CCR4, was employed as the positive control. The results indicated that most of the synthesized compounds exhibited some chemotaxis inhibition activity against CCR4. Of these new compounds, compounds 6c, 12a and 12b, with IC?? values of 0.064, 0.077 and 0.069 ?M, respectively, showed higher or similar activity compared with compound 1 (IC?? of 0.078 ?M). These compounds provide a basis for further structural modifications. The systematic structure-activity relationship of these trisubstituted pyrimidine amide derivatives was discussed based on the obtained experimental data. The results from the SAR study may be useful for identifying more potent CCR4 antagonists.

| S-EPMC6271259 | biostudies-other

Design, Synthesis, and Optimization of Balanced Dual NK1/NK3 Receptor Antagonists.

Project description:In connection with a program directed at potent and balanced dual NK1/NK3 receptor ligands, a focused exploration of an original class of peptidomimetic derivatives was performed. The rational design and molecular hybridization of a novel phenylalanine core series was achieved to maximize the in vitro affinity and antagonism at both human NK1 and NK3 receptors. This study led to the identification of a new potent dual NK1/NK3 antagonist with pK i values of 8.6 and 8.1, respectively.

| S-EPMC4027792 | biostudies-other

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