Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design, Synthesis, and Biological Evaluation of Pyrano[2,3-c]-pyrazole-Based RalA Inhibitors Against Hepatocellular Carcinoma.

ABSTRACT: The activation of Ras small GTPases, including RalA and RalB, plays an important role in carcinogenesis, tumor progress, and metastasis. In the current study, we report the discovery of a series of 6-sulfonylamide-pyrano [2,3-c]-pyrazole derivatives as novel RalA inhibitors. ELISA-based biochemical assay results indicated that compounds 4k-4r suppressed RalA/B binding capacities to their substrates. Cellular proliferation assays indicated that these RalA inhibitors potently inhibited the proliferation of HCC cell lines, including HepG2, SMMC-7721, Hep3B, and Huh-7 cells. Among the evaluated compounds, 4p displayed good inhibitory capacities on RalA (IC₅₀ = 0.22 μM) and HepG2 cells (IC₅₀ = 2.28 μM). Overall, our results suggested that a novel small-molecule RalA inhibitor with a 6-sulfonylamide-pyrano [2, 3-c]-pyrazole scaffold suppressed autophagy and cell proliferation in hepatocellular carcinoma, and that it has potential for HCC-targeted therapy.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8634879 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives.

Project description:Widespread resistance of Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug-drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

| S-EPMC8622706 | biostudies-literature

6-Amino-3,4-dimethyl-4-phenyl-2H,4H-pyrano[2,3-c]pyrazole-5-carbonitrile.

Project description:In the title compound, C(15)H(14)N(4)O, the pyrazole ring is aligned at 88.23?(4)° with respect to the aromatic ring and at 3.75?(4)° with respect to the pyran ring. In the crystal, N-H?N hydrogen bonds link adjacent mol-ecules into a linear chain motif. C-H?N inter-actions are also observed.

| S-EPMC3099764 | biostudies-literature

Design, Synthesis, Biological Evaluation and In Silico Studies of Pyrazole-Based NH<sub>2</sub>-Acyl Oseltamivir Analogues as Potent Neuraminidase Inhibitors.

Project description:Oseltamivir represents one of the most successful neuraminidase (NA) inhibitors in the current anti-influenza therapy. The 150-cavity of NA was identified as an additional binding pocket, and novel NA inhibitors have been designed to occupy the 150-cavity based on the structure information of oseltamivir carboxylate (OC) in complex with NA. In this study, a series of C-5-NH2-acyl derivatives of OC containing the pyrazole moiety were synthesized. Several derivatives exhibited substantial inhibitory activity against NA. Moreover, in silico ADME evaluation indicated that the derivatives were drug-like with higher oral absorption rates and greater cell permeability than OC. Additionally, molecular docking studies revealed that the derivatives interacted with both the NA enzyme active site and 150-cavity as expected. The results provided useful information for further structural optimization of OC.

| S-EPMC8073777 | biostudies-literature

Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1H)-pyrazole Derivatives as JAKs Inhibitors.

Project description:Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1H)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from in vitro protein kinase inhibition experiments indicated that compounds 3a-f and 11b are potent JAKs inhibitors. For example, the IC50 values of compound 3f against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound 3f showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound 11b showed selective cytotoxicity at submicromolar levels against HEL (IC50: 0.35 ?M) and K562 (IC50: 0.37 ?M) cell lines. It is worth noting that both 3f and 11b showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib.

| S-EPMC5066150 | biostudies-literature

Design, synthesis and molecular modelling studies of some pyrazole derivatives as carbonic anhydrase inhibitors.

Project description:In this study, newly synthesised compounds 6, 8, 10 and other compounds (1-5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1-10 showed effective inhibition profiles with KI values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.

| S-EPMC6896446 | biostudies-literature

Design, Synthesis, and Biological Activities of Novel Pyrazole Oxime Compounds Containing a Substituted Pyridyl Moiety.

Project description:In this paper, in order to find novel biologically active pyrazole oximes, a series of pyrazole oxime compounds bearing a substituted pyridyl unit were prepared. Bioassays showed that some target compounds were found to have good acaricidal activity against Tetranychus cinnabarinus at a concentration of 500 ?g/mL, compound 9q especially displayed potent acaricidal activity against T. cinnabarinus when the concentration was reduced to 100 ?g/mL. Interestingly, most target compounds possessed excellent insecticidal activities against Oriental armyworm at 500 ?g/mL. Moreover, some compounds were active against Aphis medicaginis and Nilaparvata lugens at 500 ?g/mL. Additionally, compounds 9b, 9g, 9l, 9p, 9q, 9r, 9s, 9t, 9u, and 9v displayed significant antiproliferative activities against HepG2 cells with IC50 values of 1.53-17.27 ?M, better than that of the control 5-fluorouracil (IC50 = 35.67 ?M).

| S-EPMC6152754 | biostudies-literature

Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors.

Project description:Oxidative stress is one of the main causes of significant severe diseases. The discovery of new potent antioxidants with high efficiency and low toxicity is a great demand in the field of medicinal chemistry. Herein, we report the design, synthesis molecular modelling and biological evaluation of novel hybrids containing pyrazole, naphthalene and pyrazoline/isoxazoline moiety. Chalcones 2a-e were synthesized efficiently and were used as starting materials for synthesis of a variety of heterocycles. A novel series of pyrazoline 3a-e, phenylpyrazoline 4a-e, isoxazoline 5a-e and pyrazoline carbothioamide derivatives 6a-e were synthesized and screened for in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide radical scavenging assay as well as 15-lipoxygenase (15-LOX) inhibition activity. Compounds 3a, 4e, 5b, 5c, 6a, 6c, and 6e showed excellent radical scavenging activity in all three methods in comparison with ascorbic acid and 15-LOX inhibition potency using quercetin as standard then were subjected to in vivo study. Catalase (CAT) activity, glutathione (GSH) and malondialdehyde (MDA) levels were assayed in liver of treated rats. Compounds 5b, 5c, and 6e showed significant in vivo antioxidant potentials compared to control group at dose of 100 mg/kg B.W. Molecular docking of compound 6a endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.

| S-EPMC7170299 | biostudies-literature

Ethyl 6-amino-5-cyano-4-phenyl-2,4-di-hydro-pyrano[2,3-c]pyrazole-3-carboxyl-ate dimethyl sulfoxide monosolvate.

Project description:In the asymmetric unit of the title compound, C16H14N4O3·C2H6OS, there are two independent main mol-ecules (A and B) and two dimethyl sulfoxide solvent mol-ecules. In mol-ecule A, the pyran ring is in a flattened sofa conformation, with the sp (3)-hydridized C atom forming the flap. In mol-ecule B, the pyran ring is in a flattened boat conformation, with the sp (3)-hydridized C atom and the O atom deviating by 0.073?(3) and 0.055?(3)?Å, respectively, from the plane of the other four atoms. The mean planes the pyrazole and phenyl rings form dihedral angles of 84.4?(2) and 84.9?(2)°, respectively, for mol-ecules A and B. In the crystal, N-H?O and N-H?N hydrogen bonds link the components of the structure into chains along [010]. In both solvent mol-ecules, the S atoms are disordered over two sites, with occupancy ratios of 0.679?(4):0.321?(4) and 0.546?(6):0.454?(6).

| S-EPMC4120557 | biostudies-literature

Design, synthesis and biological characterization of novel inhibitors of CD38.

Project description:Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca(2+) messenger molecule, cyclic ADP-ribose, from NAD(+). It is well established that this novel Ca(2+) signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD(+) complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound 1-14). A number of these compounds exhibited moderate inhibition of the NAD(+) utilizing activity of CD38, with Compound 4 showing the highest potency. The crystal structure of CD38/Compound 4 complex and computer simulation of Compound 7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds 4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development.

| S-EPMC3357394 | biostudies-literature

Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes.

Project description:The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC(50) of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the antiproliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.

| S-EPMC3466118 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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