Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues.

ABSTRACT: (5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding.

SUBMITTER: Fakhouri L

PROVIDER: S-EPMC4661079 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Isolation, semisynthesis, covalent docking and transforming growth factor beta-activated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues.

Fakhouri Lara L El-Elimat Tamam T Hurst Dow P DP Reggio Patricia H PH Pearce Cedric J CJ Oberlies Nicholas H NH Croatt Mitchell P MP

Bioorganic & medicinal chemistry 20150925 21

(5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK1 inhibitors. Seven analogues were synthesized and more than a score of natural products isolated that examined the role that different areas of the molecule contribute to TAK1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK1 inhibition. Covalent docking fo ...[more]

PMID: 26481152

Similar Datasets

TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.

Project description:Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-?B activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-?B activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox- and VP16-induced NF-?B activation and enhanced Dox- and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.

| S-EPMC3778057 | biostudies-literature

Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.

Project description:Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.

| S-EPMC5484535 | biostudies-literature

Rhodomycin analogues from Streptomyces purpurascens: isolation, characterization and biological activities.

Project description:During a screening program for bioactive natural products, a potential Streptomyces sp was isolated from soil. On the basis of biochemical, cultural, physiological and 16S rRNA gene analysis, it was identified as Streptomyces purpurascens. The isolate was grown in liquid medium and the crude antibiotic complex was obtained by ethyl acetate extraction. Seven purified fractions were obtained by preparative Thin Layer Chromatography (TLC). Acid hydrolysis of each fraction and subsequent TLC led to the identification of aglycones and sugars indicating these compounds to be Rhodomycin and its analogues. The identity of these compounds was established on the basis of UV-visible and FT-IR spectra and comparison with published data. The compounds were active against Gram-positive bacteria. Compound E, identified as Rhodomycin B, was found to be the most potent compound with an MIC of 2 ?g/ml against Bacillus subtilis. Compounds A and F identified as ?2-Rhodomycin II and Obelmycin respectively, and Compound E exhibited an IC50 of 8.8 ?g/ml against HeLa cell line but no cytotoxicity was found against L929.

| S-EPMC3667366 | biostudies-literature

Structure-guided development of covalent TAK1 inhibitors.

Project description:TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.

| S-EPMC5484537 | biostudies-literature

Novel 2,4-Diarylaminopyrimidine Analogues (DAAPalogues) Showing Potent c-Met/ALK Multikinase Inhibitory Activities.

Project description:By repurposing a typical dopamine D1/D5 receptor agonist motif, C1-substituted-N3-benzazepine or benzazecine, into the classical RTK inhibitor 2,4-diaminopyrimidine skeleton, a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) were developed. Compounds 7 and 8a were identified possessing high potency against both c-Met and ALK kinases. Compound 8a displayed appreciable antitumor efficacy at the dose of 1 mg/kg in the ALK-driven BF3/EML4-ALK xenograft mice model.

| S-EPMC4027579 | biostudies-literature

Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies.

Project description:Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives with various substituents on the phenyl ring using Ellman's colorimetric method. Compound 2e with a 2,4-dichloro electron-withdrawing substituent on the phenyl ring exhibited the strongest inhibition effect against AChE, with an IC50 value of 77.15 µM. Overall, the adamantyl-based ester with the mono-substituent at position 3 of the phenyl ring exhibited good AChE inhibition effects with an ascending order for the substituents: Cl < NO? < CH? < OCH?. Furthermore, compounds with electron-withdrawing groups (Cl and NO?) substituted at position 3 on their phenyl rings demonstrated stronger AChE inhibition effects, in comparison to their respective positional isomers. On the other hand, compound 2j with a 3-methoxyphenyl ring showed the highest inhibition effect against BChE, with an IC50 value of 223.30 µM. Molecular docking analyses were conducted for potential AChE and BChE inhibitors, and the results demonstrated that the peripheral anionic sites of target proteins were predominant binding sites for these compounds through hydrogen bonds and halogen interactions instead of hydrophobic interactions in the catalytic active site.

| S-EPMC6152672 | biostudies-literature

Semisynthesis and Biological Evaluation of Platensimycin Analogues with Varying Aminobenzoic Acids.

Project description:Platensimycin (PTM) is an excellent natural product drug lead against various gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. In this study, twenty PTM derivatives with varying aminobenzoic acids were semisynthesized. In contrast to all the previous reported inactive aminobenzaote analogues, a few of them showed moderate antibacterial activities against S. aureus. Our study suggested that modification of the conserved aminobenzoic acid remains a viable approach to diversify the PTM scaffold.

| S-EPMC7105086 | biostudies-literature

Synthesis, in vitro urease inhibitory potential and molecular docking study of benzofuran-based-thiazoldinone analogues.

Project description:In continuation of our work on enzyme inhibition, the benzofuran-based-thiazoldinone analogues (1-14) were synthesized, characterized by HREI-MS, 1H and 13CNMR and evaluated for urease inhibition. Compounds 1-14 exhibited a varying degree of urease inhibitory activity with IC50 values between 1.2 ± 0.01 to 23.50 ± 0.70 µM when compared with standard drug thiourea having IC50 value 21.40 ± 0.21 µM. Compound 1, 3, 5 and 8 showed significant inhibitory effects with IC50 values 1.2 ± 0.01, 2.20 ± 0.01, 1.40 ± 0.01 and 2.90 ± 0.01 µM respectively, better than the rest of the series. A structure activity relationship (SAR) of this series has been established based on electronic effects and position of different substituents present on phenyl ring. Molecular docking studies were performed to understand the binding interaction of the compounds.

| S-EPMC7326984 | biostudies-literature

Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues.

Project description:This article reports on the design, synthesis, and pharmacological activity of a new series of hybrid pyrazole analogues: 5a-5u. Among the series 5a-5u, the compounds 5u and 5s exhibited potent anti-inflammatory activity of 80.63% and 78.09% and inhibition of 80.87% and 76.56% compared with the standard drug ibuprofen, which showed 81.32% and 79.23% inhibition after 3 and 4 hours, respectively. On the basis of in vivo studies, 12 compounds were selected for assessment of their in vitro inhibitory action against COX1/2 and TNF?. The compounds 5u and 5s showed high COX2-inhibitory activity, with half-maximal inhibitory concentrations of 1.79 and 2.51 ?M and selectivity index values of 72.73 and 65.75, respectively, comparable to celecoxib (selectivity index =78.06). These selected compounds were also tested for TNF?, cytotoxicity, and ulcerogenicity. Docking studies were also carried out to determine possible interactions of the potent compounds (5u and 5s), which also showed high docking scores of -12.907 and -12.24 compared to celecoxib, with a -9.924 docking score. These selective COX2 inhibitors were docked into the active site of COX2, and showed the same orientation and binding mode to that of celecoxib (selective COX2 inhibitor). Docking studies also showed that the SO2NH2 of 5u and 5s is inserted deep inside the selective pocket of the COX2-active site and formed a hydrogen-bond interaction with His90, Arg513, Phe518, Ser353, Gln192, and Ile517, which was further validated by superimposed docked pose with celecoxib.

| S-EPMC5096746 | biostudies-literature

Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities.

Project description:Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.

| S-EPMC4687028 | 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