Search results for " DOC"
showing 10 items of 1281 documents
Design and Synthesis of 4-Substituted Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Derivatives with Antitumor Activity
2008
New derivatives of the indolo[3,2- e][1,2,3]triazolo[1,5- a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theoretical capability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -12.76 --> -39.68 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs, whereas the side chain lies along the minor groove. Compounds, selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The mo…
N-(INDAZOLYL)BENZAMIDO DERIVATIVES AS CDK1 INHIBITORS: DESIGN, SYNTHESIS, BIOLOGICAL ACTIVITY, AND MOLECULAR DOCKING STUDIES
2009
A series of N-1H-indazole-1-carboxamides has been synthesized and their effects on both CDK1/cyclin B and the K-562 (human chronic myelogenus leukemia) cell line were evaluated. Using a computational model, we have observed that all the most active compounds 9e, f, i-n exhibited the same binding mode of purvanalol A in the ATP-binding cleft. Although they were able to moderately inhibit the leukemic cell line K-562 and to show inhibitory activity against the Cdc2-Cyclin B kinase in the low micromolar range, they turned out to be non-cytotoxic against HuDe (IZSL) primary cell cultures from human derm. These preliminary results are quite encouraging in view of the low toxicity demonstrated by…
Inside the Hsp90 inhibitors binding mode through induced fit docking
2009
Abstract During the last few decades, the development of new anticancer strategies had to face the instability of many tumors, occurring when the genetic plasticity of cells produces new drug-resistant cancers. It has been shown that a chaperone protein, heat shock protein 90 (Hsp90), is one of the fundamental factors involved in the cell response to stresses, and its role in many biochemical pathways has been demonstrated. Thus, the inhibition of Hsp90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. The natural antibiotic Geldanamycin is the first Hsp90 inhibitor that has been identified. Nevertheless, more potent and water-soluble sma…
In vitro and in silico studies of polycondensed diazine systems as anti-parasitic agents
2012
Abstract Parasitic diseases caused by protozoarian agents are still relevant today more than ever. Recently, we synthesized several polycondensed diazine derivatives by means 1,3-dipolar cycloaddition reactions. A broad selection of these compounds were submitted to in vitro biological screening against Plasmodium falciparum , Leishmania infantum , Trypanosoma brucei , and Trypanosoma cruzi , resulting active at micromolar level. Induced Fit Docking/MM-GBSA studies were performed giving interesting indications about the probable mechanism of action of the most active compounds
Development of new Coumarin-based profluorescent substrates for human cytochrome P450 enzymes
2018
Cytochrome P450 (CYP) enzymes constitute an essential xenobiotic metabolizing system that regulates the elimination of lipophilic compounds from the body. Convenient and affordable assays for CYP enzymes are important for assessing these metabolic pathways.In this study, 10 novel profluorescent coumarin derivatives with various substitutions at carbons 3, 6 and 7 were developed. Molecular modeling indicated that 3-phenylcoumarin offers an excellent scaffold for the development of selective substrate compounds for various human CYP forms, as they could be metabolized to fluorescent 7-hydroxycoumarin derivatives. Oxidation of profluorescent coumarin derivatives to fluorescent metabolites by 1…
Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-
2019
In the context of there being a limited number of clinically approved drugs for the treatment of Candida sp.-based infections, along with the rapid development of resistance to the existing antifungals, two novel series of 4-phenyl-1,3-thiazole and 2-hydrazinyl-4-phenyl-1,3-thiazole derivatives were synthesized and tested in vitro for their anti-Candida potential. Two compounds (7a and 7e) showed promising inhibitory activity against the pathogenic C. albicans strain, exhibiting substantially lower MIC values (7.81 μg/mL and 3.9 μg/mL, respectively) as compared with the reference drug fluconazole (15.62 μg/mL). Their anti-Candida activity is also supported by molecular docking studies, usin…
Rational design of allosteric modulators of the aromatase enzyme: An unprecedented therapeutic strategy to fight breast cancer.
2019
Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we id…
Suitability ofMMGBSAfor the selection of correct ligand binding modes from docking results
2018
The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics-generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (a) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (b) improved the correlation coefficient of computational and experimental results of rescor…
Derribos, ventas y destinos de conventos suprimidos de la ciudad de Valencia y de los enajenados entre los años 1837 y 1839
2005
El artículo manifiesta los destinos de algunos conventos y monasterios de la ciudad de Valencia durante el siglo XIX, tras la supresión de muchas fundaciones religiosas en España, especialmente la suerte de los que fueron transferidos, de 1837 a 1839, a ciudadanos particulares, así como muchos otros testimonios referidos a estos edificios. (A)
Potential of the EPA/DHA 6/1 formulation to prevent endothelial dysfunction and cardiopulmonary remodeling in pulmonary arterial hypertension in rats
2016
Pulmonary arterial hypertension (PAH) is characterized by remodeling of the small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure. Pulmonary endothelial dysfunction, inflammation and oxidative stress promote the development of pulmonary hypertension. Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) have been shown to protect the cardiovascular system and reduce inflammation and oxidative stress. The present study evaluate the potential of EPA:DHA 6:1 to prevent monocrotaline-induced PAH in rats. EPA:DHA 6:1 treatment (500 mg/kg/d, p.o) prevented the MCT-induced mean pul…