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JCO Precision Oncology May 2023
Topics: Humans; Pyrazoles; Receptor, trkA; Protein Kinase Inhibitors; Mutation
PubMed: 37262390
DOI: 10.1200/PO.22.00697 -
Scientific Reports Jun 2020The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel...
The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel cascade reaction features an intramolecular N2-arylation of pyrazoles with allenes at the C-β position of triple bond. Screening in the colorectal cancer cell lines HCT116 and SW620 validated the feasibility of the methodology for generating bioactive compounds. The lead compound 7h which is active against HCT116 and SW620 with IC of 1.3 and 1.8 µM, respectively, can be synthesized and purified in a gram process synthetic scale in 7 hours. The mechanical studies indicated that compound 7h can induce cell cycle arrest in the G2/M phase and inhibit proliferation and viability in human colon cancer cells. Overall, compound 7h is represented as a promising starting point for the development of new anti-colorectal cancer drugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Humans; Pyrazines; Pyrazoles; Structure-Activity Relationship
PubMed: 32518332
DOI: 10.1038/s41598-020-66137-z -
Angewandte Chemie (International Ed. in... Mar 2021Selective alkylation of pyrazoles could solve a challenge in chemistry and streamline synthesis of important molecules. Here we report catalyst-controlled pyrazole...
Selective alkylation of pyrazoles could solve a challenge in chemistry and streamline synthesis of important molecules. Here we report catalyst-controlled pyrazole alkylation by a cyclic two-enzyme cascade. In this enzymatic system, a promiscuous enzyme uses haloalkanes as precursors to generate non-natural analogs of the common cosubstrate S-adenosyl-l-methionine. A second engineered enzyme transfers the alkyl group in highly selective C-N bond formations to the pyrazole substrate. The cosubstrate is recycled and only used in catalytic amounts. Key is a computational enzyme-library design tool that converted a promiscuous methyltransferase into a small enzyme family of pyrazole-alkylating enzymes in one round of mutagenesis and screening. With this enzymatic system, pyrazole alkylation (methylation, ethylation, propylation) was achieved with unprecedented regioselectivity (>99 %), regiodivergence, and in a first example on preparative scale.
Topics: Alkyl and Aryl Transferases; Alkylation; Aspergillus; Fungal Proteins; Humans; Hydrocarbons, Halogenated; Methyltransferases; Proof of Concept Study; Protein Engineering; Pyrazoles; Substrate Specificity
PubMed: 33300646
DOI: 10.1002/anie.202014239 -
International Journal of Molecular... May 2023Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer...
Some new Bis-pyrazoline hybrids with dual EGFR and BRAF inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds , , and demonstrated strong antiproliferative activity with GI values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAF. Compounds , , and inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound is the most potent inhibitor of cancer cell proliferation and BRAF. Compounds and induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds , , and have the potential to be dual EGFR/BRAF inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, and , were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.
Topics: Humans; Apoptosis; Cell Line; Cell Proliferation; Cell Survival; Density Functional Theory; Drug Design; ErbB Receptors; Molecular Docking Simulation; Proto-Oncogene Proteins B-raf; Pyrazoles; Static Electricity; Structure-Activity Relationship; Antineoplastic Agents
PubMed: 37240450
DOI: 10.3390/ijms24109104 -
Journal of Enzyme Inhibition and... Dec 2023Design and synthesis of three novel series of aryl enaminones (- and -) and pyrazole () linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid...
Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity.
Design and synthesis of three novel series of aryl enaminones (- and -) and pyrazole () linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO hydrase assay. Enaminone sulphonamide derivatives (-) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds and were further screened for their cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC = 4.918 and 12.27 µM, respectively) and hypoxic (IC = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.
Topics: Humans; Carbonic Anhydrases; Carbonic Anhydrase IX; Sulfaguanidine; Structure-Activity Relationship; Carboxylic Acids; Sulfonamides; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Pyrazoles; Molecular Structure
PubMed: 37078174
DOI: 10.1080/14756366.2023.2201403 -
Methods (San Diego, Calif.) Jun 2023Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics....
Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity.
Topics: alpha-Synuclein; Pyrazoles; Benzodioxoles; Magnetic Resonance Spectroscopy; Protein Aggregates
PubMed: 37037308
DOI: 10.1016/j.ymeth.2023.04.002 -
Database : the Journal of Biological... Sep 2023The present article describes the building of a small-molecule web server, CBPDdb, employing R-shiny. For the generation of the web server, three compounds were chosen,...
The present article describes the building of a small-molecule web server, CBPDdb, employing R-shiny. For the generation of the web server, three compounds were chosen, namely coumarin, benzothiazole and pyrazole, and their derivatives were curated from the literature. The two-dimensional (2D) structures were drawn using ChemDraw, and the .sdf file was created employing Discovery Studio Visualizer v2017. These compounds were read on the R-shiny app using ChemmineR, and the dataframe consisting of a total of 1146 compounds was generated and manipulated employing the dplyr package. The web server is provided with JSME 2D sketcher. The descriptors of the compounds are obtained using propOB with a filter. The users can download the filtered data in the .csv and .sdf formats, and the entire dataset of a compound can be downloaded in .sdf format. This web server facilitates the researchers to screen plausible inhibitors for different diseases. Additionally, the method used in building the web server can be adapted for developing other small-molecule databases (web servers) in RStudio. Database URL: https://srampogu.shinyapps.io/CBPDdb_Revised/.
Topics: Benzothiazoles; Coumarins; Databases, Factual; Pyrazoles
PubMed: 37702993
DOI: 10.1093/database/baad062 -
Molecules (Basel, Switzerland) Feb 2020Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the...
Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure-activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets.
Topics: Anti-Inflammatory Agents; Blood Platelets; Cell Survival; Chemotaxis; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Male; Neutrophils; Oxidation-Reduction; Phosphodiesterase 4 Inhibitors; Platelet Aggregation; Pyrazoles; Reactive Oxygen Species; Structure-Activity Relationship
PubMed: 32085423
DOI: 10.3390/molecules25040899 -
Food and Chemical Toxicology : An... Dec 2023Tartrazine (E102, FD&C Yellow 5) is a vibrant yellow azo dye added to many processed foods. The safety of this ubiquitous chemical has not been fully elucidated, and it...
Tartrazine (E102, FD&C Yellow 5) is a vibrant yellow azo dye added to many processed foods. The safety of this ubiquitous chemical has not been fully elucidated, and it has been linked to allergic reactions and ADHD in some individuals. In our study, bacterial species isolated from human stool decolourised tartrazine and, upon exposure to air, a purple compound formed. Tartrazine is known to undergo reduction in the gut to sulfanilic acid and 4-amino-3-carboxy-5-hydroxy-1-(4-sulfophenyl)pyrazole (SCAP). These metabolites and their derivatives are relevant to the toxicology of tartrazine. The toxicity of sulfanilic acid has been studied before, but the oxidative instability of SCAP has previously prevented full characterisation. We have verified the chemical identity of SCAP and confirmed that the purple-coloured oxidation derivative is 4-(3-carboxy-5-hydroxy-1-(4-sulfophenyl)-1H-pyrazol-4-yl)imino-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (purpurazoic acid, PPA), as proposed by Westöö in 1965. A yellow derivative of SCAP is proposed to be the hydrolysed oxidation product, 4,5-dioxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid. SCAP and PPA are moderately toxic to human cells (IC 89 and 78 μM against HEK-293, respectively), but had no apparent effect on Escherichia coli and Bacillus subtilis bacteria. These results prompt further analyses of the toxicology of tartrazine and its derivatives.
Topics: Humans; Tartrazine; Azo Compounds; HEK293 Cells; Oxidation-Reduction; Carboxylic Acids; Pyrazoles
PubMed: 37980979
DOI: 10.1016/j.fct.2023.114193 -
Molecules (Basel, Switzerland) Dec 2019Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex... (Review)
Review
Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.
Topics: Chemistry, Pharmaceutical; Molecular Structure; Pyrazoles; Pyrimidines; Structure-Activity Relationship
PubMed: 31877672
DOI: 10.3390/molecules25010042