Search results for "Assay"
showing 10 items of 2241 documents
Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm
2020
We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability, and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N, and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions. A high-resolution crystal structure of the Y220S mutant DBD revealed a mutation-induced surface crevice similar to that of Y220C, whereas the corresponding pock…
Inhibitory effects and oxidation of 6-methylcoumarin, 7-methylcoumarin and 7-formylcoumarin via human CYP2A6 and its mouse and pig orthologous enzymes
2015
1. Information about the metabolism of compounds is essential in drug discovery and development, risk assessment of chemicals and further development of predictive methods. 2. In vitro and in silico methods were applied to evaluate the metabolic and inhibitory properties of 6-methylcoumarin, 7-methylcoumarin and 7-formylcoumarin with human CYP2A6, mouse CYP2A5 and pig CYP2A19. 3. 6-Methylcoumarin was oxidized to fluorescent 7-hydroxy-6-methylcoumarin by CYP2A6 (Km: 0.64-0.91 µM; Vmax: 0.81-0.89 min(-1)) and by CYP2A5 and CYP2A19. The reaction was almost completely inhibited at 10 µM 7-methylcoumarin in liver microsomes of human and mouse, but in pig only 40% inhibition was obtained with the…
Heterocyclic and Phenyl Double-Bond-Locked Combretastatin Analogues Possessing Potent Apoptosis-inducing activity in HL60 and in MDR Cell lines
2005
Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC501 microM) and apoptosis-inducing activity but poor antitubulin activity. The isoxazoline derivatives 18b, 20a, and 21a, demonstrated potent apoptotic activity different from that of natural CA-4. Their ability to block most cells in the G2 phase suggests…
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine
2009
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited approximately 100-f…
Amidino substituted 2-aminophenols: biologically important building blocks for the amidino-functionalization of 2-substituted benzoxazoles
2021
Unlike the closely related and widely investigated amidino-substituted benzimidazoles and benzothiazoles with a range of demonstrated biological activities, the matching benzoxazole analogues still remain a largely understudied and not systematically evaluated class of compounds. To address this challenge, we utilized the Pinner reaction to convert isomeric cyano-substituted 2- aminophenols into their amidine derivatives, which were isolated as hydrochlorides and/or zwitterions, and whose structure was confirmed by single crystal X-ray diffraction. The key step during the Pinner synthesis of the crucial carboximidate intermediates was characterized through mechanistic DFT calculations, with…
Investigation of new 2-aryl substituted Benzothiopyrano[4,3-d[pyrimidines as kinase inhibitors targeting vascular endothelial growth factor receptor 2
2015
Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on …
Synthesis, physicochemical characterization, cytotoxicity, antimicrobial, anti-inflammatory and psychotropic activity of new N-[1,3-(benzo)thiazol-2-…
2012
Abstract A series of new N-[(benzo)thiazol-2-yl]-2/3-[3,4-dihydroisoquinolin-2(1H)-yl]ethan/propanamide derivatives was synthesized and characterized by 1H, 13C NMR and IR spectroscopy and mass-spectrometry. A single crystal X-ray study of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide is reported to determine its conformational feature. The investigated compounds were found to be active in psychotropic in vivo, anti-inflammatory in vivo and cytotoxicity in vitro screening. They possess marked sedative action, reveal high anti-inflammatory activity, have selective cytotoxic effects and NO-induction ability concerning tumour cell lines. Some of the compounds synthesi…
Click chemistry-assisted bioconjugates for hapten immunodiagnostics
2020
Bioorthogonal reactions have revolutionized the way low molecular weight compounds are coupled to biomolecules. Organic chemistry, polymer science, and chemical biology are among the disciplines that are benefited the most from this breakthrough. Despite the reliability of the click chemistry concept for the efficient and chemoselective functionalization of biomacromolecules with haptens at preferred positions, the fact that azide–alkyne cycloaddition reactions originate new chemical moieties as part of the linker may have delayed their application in the immunodiagnostic field. Using the mycotoxin ochratoxin A as a model compound, we herein demonstrate for the first time that bioconjugates…
Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene
2013
Cholera toxin (CT), the causative agent of cholera, displays a pentavalent binding domain that targets the oligosaccharide of ganglioside GM1 (GM1os) on the periphery of human abdominal epithelial cells. Here, we report the first GM1os-based CT inhibitor that matches the valency of the CT binding domain (CTB). This pentavalent inhibitor contains five GM1os moieties linked to a calix[5]arene scaffold. When evaluated by an inhibition assay, it achieved a picomolar inhibition potency (IC50 = 450 pM) for CTB. This represents a significant multivalency effect, with a relative inhibitory potency of 100000 compared to a monovalent GM1os derivative, making GM1os-calix[5]arene one of the most potent…
Design, synthesis, and SAR analysis of cytotoxic sinapyl alcohol derivatives.
2005
Five series totalling 51 of sinapyl alcohol derivatives were designed and synthesized. Their cytotoxicity analyses were performed oil six human tumor cell lines Such as PC-3. CNE, KB, A549, BEL-7404, and HeLa. Certain sinapyl alcohol derivatives showed significant cytotoxic activities. Compound 14d exhibited especially potent cytotoxicity against the BEL-7404 cell line with an IC50 value of 0.7 mu M, which showed more cytotoxic activity than the positive control, cisplatin. The structure-cytotoxicity relationships were discussed and the CoMFA analysis was performed using the cytotoxic data against HeLa cells as a template. (c) 2005 Elsevier Ltd. All rights reserved.