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Anti-cancer Agents in Medicinal... 2018Berberine (BBR), an isoquinoline plant alkaloid isolated from plants such as Coptis chinensis and Hydrastis canadensis, own multiple pharmacological activities.
BACKGROUND
Berberine (BBR), an isoquinoline plant alkaloid isolated from plants such as Coptis chinensis and Hydrastis canadensis, own multiple pharmacological activities.
OBJECTIVE
In this study, seven BBR derivatives were synthesized and their anticancer activity against HeLa cervical and A549 human lung cancer cell lines were evaluated in vitro.
METHODS
The anti-cancer activity was measured by MTT assay, and apoptosis was demonstrated by the annexin V-FITC/PI staining assay. The intracellular oxidative stress was investigated through DCFH-DA assay. The molecular docking study was carried out in molecular operating environment (MOE).
RESULTS
Compound B3 and B5 showed enhanced anti-cancer activity compared with BBR, the IC50 for compound B3 and B5 were significantly lower than BBR, and compound B3 at the concentration of 64 or 128 µM induced apoptosis in HeLa and A549 cell lines. The reactive oxygen species (ROS) was generated in both cell lines when treated with 100 µM of all the compounds, and compound B3 and B5 induced higher activity in the generation of ROS, while compound B3 exhibited the highest activity, these results are in accordance with the cytotoxicity results, indicating the cytotoxicity were mostly generated from the oxidative stress. In addition, molecular docking analysis showed that compound B3 had the greatest affinity with Hsp90. Upon binding, the protective function of Hsp90 was lost, which might explain its higher cytotoxicity from molecular interaction aspect.
CONCLUSION
All the results demonstrated that compound B3 and B5 showed significantly higher anti-cancer ability than BBR, and compound B3 is a promising anticancer drug candidate.
Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Berberine; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Molecular Structure; Pyrazoles; Reactive Oxygen Species; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 30014806
DOI: 10.2174/1871520618666180717121208 -
European Journal of Medicinal Chemistry May 2016The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the... (Review)
Review
The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.
Topics: Chemistry, Pharmaceutical; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazolidines
PubMed: 26922234
DOI: 10.1016/j.ejmech.2016.02.030 -
Zeitschrift Fur Naturforschung. C,... Jul 2022Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties....
Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties. 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one were reacted with α-hydroxy aldehyde or α-hydroxy ketone derivatives to obtain nine novel pyrazolone derivatives. Structures were successfully elucidated by H NMR, C NMR, IR and HRMS. Enzyme inhibitory activity was measured on cyclooxygenases (COXs) as considered to address anti-inflammatory activity. Compound showed the highest activity on both COX-1 and COX-2 subtypes with 12.0 μM and 8.0 μM IC, respectively. This activity was found close to indomethacin COX-2 inhibition measured as 7.4 μM IC. Rest of the compounds (, -) showed 10.4-28.1 μM IC on COX-2 and 17.0-35.6 μM IC on COX-1 (Compound has no activity on COX-1). Tested compounds () showed activity on NO production. Only compound was the , which showed a low inhibition on IL-6 levels. Cell viability was up to 60% at 100 μM for all compounds (-) on RAW 264.7 and NIH3T3 cell lines, thus compounds were reported to be noncytotoxic.
Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Dose-Response Relationship, Drug; Mice; Molecular Docking Simulation; Molecular Structure; NIH 3T3 Cells; Pyrazoles; Pyrazolones; Structure-Activity Relationship
PubMed: 34902233
DOI: 10.1515/znc-2021-0217 -
Molecular Diversity May 20173-phenol-1H-pyrazoles (2), 4-halogeno-3-phenol-1H-pyrazoles (3) and 2-(1-phenol-1H-pyrazol-5-yl)phenols (4) were prepared by the condensation of...
3-phenol-1H-pyrazoles (2), 4-halogeno-3-phenol-1H-pyrazoles (3) and 2-(1-phenol-1H-pyrazol-5-yl)phenols (4) were prepared by the condensation of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-ones and hydrazine hydrate or phenylhydrazine in good yields. They were evaluated against five phytopathogens fungi, namely Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani and Fusarium solani in vitro. Most of the above-mentioned compounds exhibited activities. For example, 4-chloro-2-(1H-pyrazol-3-yl)phenol (3k) and 4-bromo-3-phenol-1H-pyrazole (3b) showed good and broad-spectrum antifungal properties against Cytospora sp., C. gloeosporioides, Botrytis cinerea, Alternaria solani and F. Solani with [Formula: see text] values ranging from 4.66 to 12.47 [Formula: see text]g/mL. The results showed that pyrazoles with one aryl group at 3-position (2 and 3) exhibited better antibacterial activity than those with two aryl substituents (4). In addition, the existence of an electron-withdrawing group, a substituent on the ortho-position of phenol ring or a halogen atom at the 4-position of the pyrazole enhanced the antifungal activity of pyrazoles 2 and 3. A series of arylpyrazole derivatives was facilely prepared and was evaluated against five phytopathogens fungi including Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani in vitro. Most of those compounds exhibited remarkable antifungal activities and were superior to the positive control hymexazol.
Topics: Antifungal Agents; Chemistry Techniques, Synthetic; Fungi; Microbial Sensitivity Tests; Plants; Pyrazoles
PubMed: 28247170
DOI: 10.1007/s11030-017-9727-x -
Bioorganic Chemistry Jun 2022The methods of fighting cancer are far from ideal, therefore it is necessary to search for innovative and effective drugs. In our work, we present pyrazole derivatives...
The methods of fighting cancer are far from ideal, therefore it is necessary to search for innovative and effective drugs. In our work, we present pyrazole derivatives and their modifications with polymer microspheres as potential anticancer agents. Molecular and crystal structures of pyrazole derivatives were determined an X-ray analysis and characterized by theoretical calculations. Modifications of cross-linked polymer microspheres with pyrazole derivatives were made on the basis of divinylbenzene and glycidyl methacrylate. The in vitro antiproliferative activity of the pyrazole derivatives and their modified microspheres was assessed against a normal cell line, namely monkey epithelial renal cells (GMK) and cancer cell lines, such as human hepatocellular carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) as well as human lung adenocarcinoma cell line (A549), using the MTT assay. All the tested pyrazole derivatives and the polymer microspheres modified by them showed antiproliferative activity in vitro. Two of the modified substances showed the greatest ability to inhibit divisions of all cancer cells. In order to determine a potential target, molecular docking was performed. In silico studies carried out with the use of the human EphB1 receptor revealed that the analyzed compounds bound to the EphB1 binding site, and the compounds with the highest antiproliferative activity showed a better fit to the active site.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Microspheres; Molecular Docking Simulation; Molecular Structure; Neoplasms; Polymers; Pyrazoles; Structure-Activity Relationship
PubMed: 35427940
DOI: 10.1016/j.bioorg.2022.105765 -
Molecules (Basel, Switzerland) Oct 2021Microwave irradiation has become a popular heating technique in organic synthesis, mainly due to its short reaction times, solventless reactions, and, sometimes, higher... (Review)
Review
Microwave irradiation has become a popular heating technique in organic synthesis, mainly due to its short reaction times, solventless reactions, and, sometimes, higher yields. Additionally, microwave irradiation lowers energy consumption and, consequently, is ideal for optimization processes. Moreover, there is evidence that microwave irradiation can improve the regioselectivity and stereoselectivity aspects of vital importance in synthesizing bioactive compounds. These crucial features of microwave irradiation contribute to its inclusion in green chemistry procedures. Since 2003, the use of microwave-assisted organic synthesis has become common in our laboratory, making our group one of the first Portuguese research groups to implement this heating source in organic synthesis. Our achievements in the transformation of heterocyclic compounds, such as (/)-3-styryl-4-chromen-4-ones, ()-3-(2-hydroxyphenyl)-4-styryl-1-pyrazole, ()-2-(4-arylbut-1-en-3-yn-1-yl)-4-chromen-4-ones, or ()-2-[2-(5-aryl-2-methyl-2-1,2,3-triazol-4-yl)vinyl]-4-chromen-4-ones, will be discussed in this review, highlighting the benefits of microwave irradiation use in organic synthesis.
Topics: Chemistry, Pharmaceutical; Chromones; Combinatorial Chemistry Techniques; Enzyme Inhibitors; Heating; Humans; Microwaves; Molecular Structure; Pyrazoles; Quinolones
PubMed: 34684877
DOI: 10.3390/molecules26206293 -
Anti-inflammatory & Anti-allergy Agents... 20172, 4-Thiazolidinedione (TZD), pyrazole and thiazole heterocyclic rings exhibit a wide range of pharmacological activities. Medicinal chemists use these heterocyclic...
BACKGROUND
2, 4-Thiazolidinedione (TZD), pyrazole and thiazole heterocyclic rings exhibit a wide range of pharmacological activities. Medicinal chemists use these heterocyclic moieties as scaffolds in drug designing and discovery. The existing medicaments, celecoxib and meloxicam, used for treating inflammation and pain are having, pyrazole and thiazole, respectively as key scaffolds. Pyrazoles coupled with 2, 4-thiazolidinediones may display enhanced anti-inflammatory activity. With this hope the bench work was carried out.
METHODS
Heterocyclic aldehydes, 3-(4-methyl-2-substituted thiazol-5-yl)-1-phenyl-1Hpyrazole- 4- carbaldehydes (4a-b) have been allowed to undergo Knoevenagel condensation with N-substituted 2,4-thiazolidinediones (5a-e) in PEG-400 in the presence of L-proline at 110°C and obtained the condensed products (6a-j). COX-2 evaluation of the titled product has been carried out using in vitro COX-2 ELISA Kit. Antibacterial activity of these compounds (6a-j) has also been determined.
RESULTS
On the basis of 1H NMR, 13C NMR and Mass spectral data of the condensed products the structures have been assigned to (Z)-5-((3-(4-methyl-2-substituted thiazol-5-yl)-1- phenyl-1H-pyrazol-4-yl)methylene) 3-substituted thiazolidine-2,4-diones (6a-j). Among the evaluated compounds (6a-j), 6f, 6g, 6h, 6i and 6j have shown notable COX-2 inhibitory activity.
CONCLUSION
Compounds, 6a, 6b, 6c, 6d, 6e and 6f have inhibited the growth of the Bacillus cereus NCIM 2106, Bacillus subtilis NCIM 2063, Pseudomonas aeruginosa NCIM 2074, Salmonella typhimurium NCIM 2501 and Staphylococcus aureus NCIM 2079. However, compound 6f has emerged as a suitable candidate with dual properties i.e. COX-2 inhibitory and antibacterial in the present study.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Bacteria; Cell Survival; Cyclooxygenase 2; Mice; Pyrazoles; RAW 264.7 Cells; Thiazolidinediones
PubMed: 28618987
DOI: 10.2174/1871523016666170616120346 -
Molecules (Basel, Switzerland) Feb 2021Coinage metal(I)···metal(I) interactions are widely of interest in fields such as supramolecular assembly and unique luminescent properties, etc. Only two types of...
Coinage metal(I)···metal(I) interactions are widely of interest in fields such as supramolecular assembly and unique luminescent properties, etc. Only two types of polynuclear silver(I) pyrazolato complexes have been reported, however, and no detailed spectroscopic characterizations have been reported. An unexpected synthetic method yielded a polynuclear silver(I) complex (L1Clpz = 4-chloride-3,5-diisopropyl-1-pyrazolate anion) by the reaction of {[Ag(μ-L1Clpz)]} with (BuN)[Ag(CN)]. The obtained structure was compared with the known hexanuclear silver(I) complex {[Ag(μ-L1Clpz)]}. The Ag···Ag distances in are slightly shorter than twice Bondi's van der Waals radius, indicating some Ag···Ag argentophilic interactions. Two Ag-N distances in were found: 2.0760(13) and 2.0716(13) Å, and their N-Ag-N bond angles of 180.00(7)° and 179.83(5)° indicate that each silver(I) ion is coordinated by two pyrazolyl nitrogen atoms with an almost linear coordination. Every five pyrazoles point in the same direction to form a 1-D zig-zag structure. Some spectroscopic properties of in the solid-state are different from those of {[Ag(μ-L1Clpz)]} (especially in the absorption and emission spectra), presumably attributable to this zig-zag structure having longer but differently arranged intramolecular Ag···Ag interactions of 3.39171(17) Å. This result clearly demonstrates the different physicochemical properties in the solid-state between 1-D coordination polymer and metalacyclic trinuclear (hexanuclear) or tetranuclear silver(I) pyrazolate complexes.
Topics: Crystallography, X-Ray; Luminescence; Molecular Conformation; Polymers; Pyrazoles; Silver; Spectrophotometry, Ultraviolet; Temperature
PubMed: 33671921
DOI: 10.3390/molecules26041015 -
Biochemical and Biophysical Research... Nov 2022Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug...
Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug target for nephritis and cancers, while CK2α2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2α1 and CK2α2 make it difficult to design CK2α1-specific inhibitors. Herein, the crystal structures of CK2α1 and CK2α2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein-inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2α1, but not to CK2α2, at the CK2β protein-protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2α1 inhibitors.
Topics: Adenosine Triphosphate; Casein Kinase II; Isoenzymes; Protein Kinase Inhibitors; Pyrazoles
PubMed: 36130444
DOI: 10.1016/j.bbrc.2022.09.040 -
Bioorganic Chemistry Jun 2020Heterocyclic compounds with nitrogen atom play a key role in the normal life cycle of a cell. Pyrazolopyrimidine is a privileged class of nitrogen containing fused... (Review)
Review
Heterocyclic compounds with nitrogen atom play a key role in the normal life cycle of a cell. Pyrazolopyrimidine is a privileged class of nitrogen containing fused heterocyclic compound contributing to a major portion of all lead molecules in medicinal chemistry. The thumbprint of pyrazolopyrimidine as a pharmacophore is always noticeable due to its analogy with the adenine base in DNA. Pyrazolopyrimidines are divided into five types [I, II, III, IV, V] based on the mechanism of action on the specific target conferring a wide scope of research which has accelerated the interest of researchers to investigate its biological profile. In 1956, the anti-cancer activity of pyrazolopyrimidine was evaluated for the first time with appreciable results. Since then, medicinal chemists centered their work on various methods of synthesis and evaluating the biological profile of pyrazolopyrimidine isomers. This report consists of novel methodologies followed to synthesize pyrazolopyrimidine isomers along with a note on their biological significance. To the best of our knowledge, this review article will be first of its kind to encompass different synthetic procedures along with anti-cancer, kinase inhibition, phosphodiesterase inhibition and receptor blocking activity of pyrazolopyrimidine moieties. IC values of potent compounds are added wherever necessary to understand the suitability of pyrazolopyrimidine skeletons for a specific biological activity.
Topics: Antineoplastic Agents; Cell Proliferation; Humans; Molecular Structure; Neoplasms; Phosphotransferases; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 32278206
DOI: 10.1016/j.bioorg.2020.103801