39 results on '"Jorge Soto-Delgado"'
Search Results
2. Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles
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Marcos Lorca, Cesar Morales-Verdejo, David Vásquez-Velásquez, Juan Andrades-Lagos, Javier Campanini-Salinas, Jorge Soto-Delgado, Gonzalo Recabarren-Gajardo, and Jaime Mella
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β3-adrenergic receptor ,obesity ,diabetes ,overactive bladder ,aryloxypropanolamines ,mirabegron ,vibegron ,3D-QSAR ,CoMFA ,CoMSIA ,Organic chemistry ,QD241-441 - Abstract
The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2ncv = 0.993 and 0.984 and values of r2test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).
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- 2018
- Full Text
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3. 2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β3-Adrenergic Activity
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Gastón Apablaza, Luisa Montoya, Cesar Morales-Verdejo, Marco Mellado, Mauricio Cuellar, Carlos F. Lagos, Jorge Soto-Delgado, Hery Chung, Carlos David Pessoa-Mahana, and Jaime Mella
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QSAR ,CoMSIA ,beta-3 adrenergic receptor ,diabetes ,obesity ,mirabegron ,vibegron ,indole ,Organic chemistry ,QD241-441 - Abstract
The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.
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- 2017
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4. The catalytic effects of a thiazolium salt in the oxa-Diels–Alder reaction between benzaldehyde and Danishefsky's diene: a molecular electron density theory study
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Jorge Soto-Delgado, Patricia Pérez, Mar Ríos-Gutiérrez, and Luis R. Domingo
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Diene ,010405 organic chemistry ,Hydrogen bond ,Organic Chemistry ,Regioselectivity ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,0104 chemical sciences ,Catalysis ,Benzaldehyde ,chemistry.chemical_compound ,chemistry ,Electrophile ,Physical and Theoretical Chemistry ,Danishefsky's diene ,Diels–Alder reaction - Abstract
The oxa-Diels–Alder (ODA) reaction of benzaldehyde with Danishefsky's diene in the presence of a [thiazolium][Cl] salt, as a model of an ionic liquid, has been studied within Molecular Electron Density Theory (MEDT) at the M06-2X/6-311G(d,p) computational level. The formation of two hydrogen bonds (HBs) between the thiazolium cation and the carbonyl oxygen of benzaldehyde modifies neither the electrophilic character of benzaldehyde nor its electronic structure substantially but accelerates the reaction considerably. This ODA reaction presents an activation energy of 4.5 kcal mol−1; the formation of the only observed dihydropyranone is strongly exothermic by −28.8 kcal mol−1. The presence of the [thiazolium][Cl] salt decreases the Gibbs free energy of activation of the ODA reaction between benzaldehyde and Danishefsky's diene by 5.9 kcal mol−1. This ODA reaction presents total para regioselectivity and high endo stereoselectivity. This ODA reaction takes place through a highly asynchronous polar transition state structure (TS) associated with a non-concerted two-stage one-step mechanism. ELF analysis of para/endo TSs associated with the ODA reactions in the absence and presence of the [thiazolium][Cl] salt shows that the formation of the HBs at the TSs does not modify their electronic structure substantially. This MEDT study makes it possible to conclude that the acceleration found in the ODA reaction of benzaldehyde with Danishefsky's diene in ILs is a consequence of an increase of the global electron density transfer at TS3-pn, resulting from HB formation, and the greater strength of the HBs at the polar TS3-pn compared to that at the benzaldehyde : [thiazolium][Cl] complex, and that the strength in the HB formed is more relevant that than an increase of the electrophilic character of the interaction between reagent.
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- 2021
5. Synthesis multicomponent based on o‐tolyl‐isocyanide; cholinesterase inhibitors and computational studies
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Lorena Camargo-Ayala, Efraín Polo-Cuadrado, Edison Osorio, Jorge Soto-Delgado, Yorley Duarte, Luis Prent-Peñaloza, and Margarita Gutiérrez
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Inorganic Chemistry ,Organic Chemistry ,Spectroscopy ,Analytical Chemistry - Published
- 2022
6. Experimental and Theoretical Approaches in the Study of Phenanthroline‐Tetrahydroquinolines for Alzheimer's Disease
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Jans Alzate-Morales, Yorley Duarte, Rocío Álvarez, Jorge Soto-Delgado, and Margarita Gutiérrez
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tetrahydroquinolines ,Phenanthroline ,Substituent ,Activation energy ,010402 general chemistry ,01 natural sciences ,lcsh:Chemistry ,chemistry.chemical_compound ,Pyridine ,density functional theory ,Cholinesterase ,biology ,Full Paper ,010405 organic chemistry ,Biological activity ,General Chemistry ,acetylcholinesterase ,Full Papers ,Combinatorial chemistry ,Acetylcholinesterase ,Alzheimer's disease imino-Diels-Alder ,0104 chemical sciences ,chemistry ,lcsh:QD1-999 ,Yield (chemistry) ,biology.protein - Abstract
The imino‐Diels‐Alder reaction is one of the most common strategies in organic chemistry and is an important tool for providing a broad spectrum of biologically active heterocyclic systems. A combined theoretical and experimental study of the imino‐Diels‐Alder reaction is described. The new phenanthroline‐tetrahydroquinolines were evaluated as cholinesterase inhibitors. Their cytotoxicity in human neuroblastoma SH‐SY5Y cells was also evaluated. The theoretical results suggest that compounds formation in stages can be explained by endo cycloadducts under the established reaction conditions, thereby confirming experimental results obtained for percentage yield. These results allowed us to establish that pyridine substituent remarkably influences activation energy and reaction yield, as well as in acetylcholinesterase (AChE) activity. Among these derivatives, compounds with 4‐pyridyl and 4‐nitrophenyl showed favorable AChE activity and proved to be non‐cytotoxic.
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- 2019
7. State of the art of Smo antagonists for cancer therapy: advances in the target receptor and new ligand structures
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Christian Espinosa-Bustos, Jaime Mella, Cristian O. Salas, and Jorge Soto-Delgado
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Models, Molecular ,Protein Conformation ,Vismodegib ,Antineoplastic Agents ,Ligands ,01 natural sciences ,Sonidegib ,03 medical and health sciences ,chemistry.chemical_compound ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Basal cell carcinoma ,Molecular Targeted Therapy ,Hedgehog ,030304 developmental biology ,Pharmacology ,Medulloblastoma ,0303 health sciences ,business.industry ,Cancer ,medicine.disease ,Smoothened Receptor ,Hedgehog signaling pathway ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Drug Design ,Cancer research ,Molecular Medicine ,business ,Signal Transduction ,medicine.drug - Abstract
Since the Hedgehog signaling pathway has been associated with cancer, it has emerged as a therapeutic target for cancer therapy. The main target among the key Hedgehog proteins is the GPCR-like Smo receptor. Therefore, some Smo antagonists that have entered clinical trials, including the US FDA-approved drugs vismodegib and sonidegib, to treat basal cell carcinoma and medulloblastoma. However, early resistance of these drugs has spawned the need to understand the molecular bases of this phenomena. We therefore reviewed details about Smo receptor structures and the best Smo antagonist chemical structures. In addition, we discussed strategies that should be considered to develop new, safer generations of Smo antagonists that avoid current clinical limitations.
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- 2019
8. New benzimidazolequinones as trypanosomicidal agents
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Claudia López-Lira, A. Graham Lappin, Jorge Soto-Delgado, Juan Diego Maya, Allen G. Oliver, Michel Lapier, Ricardo A. Tapia, Eugenio Uriarte, and Alejandra Herrera
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Stereochemistry ,Trypanosoma cruzi ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,parasitic diseases ,Drug Discovery ,medicine ,Imidazole ,Moiety ,Nifurtimox ,Molecular Biology ,IC50 ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Quinones ,biology.organism_classification ,Trypanocidal Agents ,In vitro ,Naphthoquinone ,0104 chemical sciences ,Quinone ,010404 medicinal & biomolecular chemistry ,chemistry ,Drug Design ,Benzimidazoles ,medicine.drug - Abstract
Herein, the design and synthesis of new 2-phenyl(pyridinyl)benzimidazolequinones and their 5-phenoxy derivatives as potential anti-Trypanosoma cruzi agents are described. The compounds were evaluated in vitro against the epimastigotes and trypomastigote forms of Trypanosoma cruzi. The replacing of a benzene moiety in the naphthoquinone system by an imidazole enhanced the trypanosomicidal activity against Trypanosoma cruzi. Three of the tested compounds (11a-c) showed potent trypanosomicidal activity and compound 11a, with IC50 of 0.65 μM on the trypomastigote form of T. cruzi, proved to be 15 times more active than nifurtimox. Additionally, molecular docking studies indicate that the quinone derivatives 11a-c could have a multitarget profile interacting preferentially with trypanothione reductase and Old Yellow Enzyme.
- Published
- 2020
9. Identification of the naphthoquinone derivative inhibitors binding site in heat shock protein 90: an induced-fit docking, molecular dynamics and 3D-QSAR study
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Roberto León, Nicolas Bravo-Acuña, Fernando Faunes, Gloria Arriagada, Jorge Soto-Delgado, and Claudio Godoy-Castillo
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Quantitative structure–activity relationship ,Binding Sites ,Molecular model ,biology ,Chemistry ,Drug discovery ,Stereochemistry ,Quantitative Structure-Activity Relationship ,General Medicine ,Molecular Dynamics Simulation ,Hsp90 ,Naphthoquinone ,Molecular Docking Simulation ,chemistry.chemical_compound ,Structural Biology ,Docking (molecular) ,Heat shock protein ,biology.protein ,HSP90 Heat-Shock Proteins ,Binding site ,Molecular Biology ,Naphthoquinones ,Protein Binding - Abstract
The combination of molecular modeling methods to identify the putative binding site of inhibitors constitutes an important tool in drug discovery. In this work, we used these analyses to understand the potent inhibitory effect of naphthoquinone derivatives on heat shock protein 90 (Hsp90), one of the proteins involved in many types of cancer. Molecular docking results indicated that some favorable interactions of key amino acid residues at the binding site of Hsp90 with these quinones would be responsible for the inhibition of Hsp90 activity. Molecular docking and molecular dynamics simulation were carried out to further understand the binding modes and the interactions between the protein and these inhibitors. The main residues of the internal cavity were Val136, Phe138, Tyr139, Val150, Trp162 and Val186. The high concordance between the docking results and 3D-QSAR contour maps gives us helpful information about the environment of the binding site. Our results provide the bases for a rational modification of new molecules based in quinone scaffold, in order to design more potent Hsp90 inhibitors, which would exhibit highly potent antitumor activity.Communicated by Ramaswamy H. Sarma.
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- 2020
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10. Influence of structural changes on photophysical properties of terpyridine derivates: Experimental studies and theoretical calculations
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Yanko Moreno, Octavio Peña, Jorge Soto-Delgado, Dominique Toledo, Jean Yves Pivan, Francisco Brovelli, Departamento de Química Analítica e Inorgánica, Universidad de Concepción - University of Concepcion [Chile], Universidad Andrés Bello [Santiago] (UNAB), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CNRS, Centre National de la Recherche Scientifique, 1130433, FONDECYT, Fondo Nacional de Desarrollo Científico y Tecnológico, 21120148, CONICYT, Consejo Nacional de Innovación, Ciencia y Tecnología, DI-773-15R, UNAB, Universidad Autónoma de Bucaramanga, UDEC-VRID 216.412.049–1.0, UdeC, Universidad de Concepción, Université de Rennes 1, Universidad de Concepción [Chile], Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)
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Solvothermal synthesis ,Theoretical calculations ,Spectroscopic method ,Ligands ,Spectroscopic analysis ,010402 general chemistry ,Photochemistry ,Electrochemistry ,01 natural sciences ,Analytical Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,13C NMR spectroscopy ,Electrochemical behaviors ,Molecule ,Thermal stability ,Nuclear magnetic resonance spectroscopy ,Spectroscopy ,Chelation ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,010405 organic chemistry ,Chemistry ,Crystal structure ,Aryl ,Organic Chemistry ,X ray diffraction analysis ,Photophysical properties ,0104 chemical sciences ,[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry ,Crystallography ,Single crystal X-ray diffraction analysis ,Substitution reactions ,Density functional theory ,Single crystals ,One-pot procedures ,Terpyridine ,Single crystal - Abstract
International audience; Four terpyridine ligands containing different aryl substituents 4'-(4-quinolinyl)-3,2':6′,3″-terpyridine (3-qtpy), 4'-(4-quinolinyl)-2,2':6′,2″-terpyridine (2-qtpy), 4'-(3-methyl-2-thienyl)-4,2':6′,4″-terpyridine (4-stpy) and 4'-(3-methyl-2-thienyl)-2,2':6′,2″-terpyridine (2-stpy) were synthesized in a one-pot procedure and characterized by elemental analysis, FT-IR and 1H- and 13C NMR spectroscopy. Additionally, the 2-stpy structure was confirmed by single crystal X-ray diffraction analysis. The influence of the N-position in the tpy and aryl substituents on the photophysical properties was systematically investigated by spectroscopic methods and simulated by density functional theory (DFT and TD-DFT) calculations. Thermal stability was observed until about 280 °C, making these kind of ligands interesting candidates for their use as complex ligands, which are obtained by solvothermal synthesis under temperatures of about 180 °C. The electrochemical behavior was also investigated. All molecules show irreversible anodic and cathodic voltammetric peaks in organic medium.
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- 2018
11. Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives
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Jaime Mella-Raipán, Claudia López-Lira, Jorge Soto-Delgado, Jans Alzate-Morales, Margot Paulino, Cristian O. Salas, and Ricardo A. Tapia
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0301 basic medicine ,Quantitative structure–activity relationship ,Stereochemistry ,Static Electricity ,Quantitative Structure-Activity Relationship ,Quinone oxidoreductase ,01 natural sciences ,Biochemistry ,Cofactor ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,NAD(P)H Dehydrogenase (Quinone) ,Humans ,Least-Squares Analysis ,Binding site ,Pharmacology ,Flavin adenine dinucleotide ,Binding Sites ,biology ,010405 organic chemistry ,Hydrogen bond ,Organic Chemistry ,Quinones ,Protein Structure, Tertiary ,0104 chemical sciences ,Quinone ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Docking (molecular) ,Flavin-Adenine Dinucleotide ,biology.protein ,Computer-Aided Design ,Molecular Medicine - Abstract
A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2LOO ) of .75 and .73 as well as conventional correlation coefficients (R2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.
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- 2017
12. Structural, electrochemical and theoretical study of a new chalcone derivative containing 3-thiophene rings
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Ricardo Baggio, Marcela Pinto, Francisco Brovelli, Jorge Soto-Delgado, and Yanko Moreno
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Chalcone ,010405 organic chemistry ,Organic Chemistry ,Stacking ,Crystal structure ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Atomic orbital ,chemistry ,Computational chemistry ,Thiophene ,Molecule ,Cyclic voltammetry ,Single crystal ,Spectroscopy - Abstract
The title chalcone, 1,3-di(thiophene-3-yl)prop-2-en-1-one (C11H8OS2) is an essentially planar molecular with its terminal thiophene rings subtending an angle of 8.9°. The crystal structure consists in the π··π stacking of molecules defining columns along [010], further linked along c by non conventional C H⋯O bonds, thus determining broad planar arrays parallel to (100). In addition, there are weak S⋯S contacts connecting these weakly interacting 2D substructures. The experimental results obtained from single crystal X-ray diffraction data and the theoretical geometry calculated by molecular mechanics are in good agreement. Electrochemical records reveal an anodic profile with an unsymmetrical irreversible peak at 1.77 V and a shoulder at 1.62 V vs SCE, a behavior interpretable as due to the oxidation of reactive sites present in the molecule. On the other hand, the electrochemical reduction shows a narrow peak at −1.58 V vs SCE, a fact attributable to the carbonyl group. Finally, the values for the energy involved in the departure/arrival of electrons from border orbitals, as calculated using DFT, is compared with experimental data from cyclic voltammetry.
- Published
- 2016
13. Ion-ion repulsions and charge-shielding effects dominate the permeation mechanism through the OmpF porin channel
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Juan Torras, Carlos Alemán, Juan Carlos Ahumada, Jorge Soto-Delgado, Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, and Universitat Politècnica de Catalunya. IMEM-BRT- Innovation in Materials and Molecular Engineering - Biomaterials for Regenerative Therapies
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010304 chemical physics ,Chemistry ,education ,Cationic polymerization ,Ionic bonding ,Permeation ,010402 general chemistry ,Electrostatics ,01 natural sciences ,0104 chemical sciences ,Surfaces, Coatings and Films ,Ion ,Turn (biochemistry) ,Enginyeria química [Àrees temàtiques de la UPC] ,Chemical engineering ,Chemical physics ,0103 physical sciences ,Porin ,Electromagnetic shielding ,Materials Chemistry ,Physical and Theoretical Chemistry ,Enginyeria química - Abstract
OmpF is a wide channel bacterial porin frequently employed to study selective ionic translocation. The cationic preference of this porin is mainly determined by electrostatic forces between the translocated ion and the protein and the formation of ion pairs (e.g., K+···Cl-) being previously pointed as the main cause to favor the cationic transport through the constriction zone. Hybrid quantum mechanics/molecular mechanics-molecular dynamics simulations, which have provided polarization-containing potentials of mean force profiles for different permeation scenarios, reveal significant new insights related with the ion translocation mechanism. Results show that the permeation is dominated by electrostatic interactions, which in turn affect ion-protein interactions at the constriction zone. However, it is observed that ion flow is favored by ion-ion repulsions and, in a lesser extent, by charge-shielding effects, instead of the previously pointed ionic pair formation.
- Published
- 2019
14. Structural insight on the Hsp90-binding modes of Naphthoquinone derivatives. Molecular Modeling study for antitumoral drug design
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Claudio Godoy-Castillo, Jorge Soto-Delgado, and Jorge Gonzalez
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Molecular model ,biology ,Cell growth ,Chemistry ,Cell ,Context (language use) ,Hsp90 ,Cell biology ,Folding (chemistry) ,medicine.anatomical_structure ,Heat shock protein ,medicine ,biology.protein ,Protein folding - Abstract
Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. HSPs play important roles in carcinogenesis via the regulation of angiogenesis, cell proliferation, migration, invasion, and metastasis. One of the most attractive targets for novel antitumor agents during recent years is the Heat shock proteins 90 (Hsp90), which is an essential molecular chaperone and it is responsible for the folding and maturation of nascent proteins.1 In this context, inhibition of Hsp90 has potential to disrupt multiple oncogenic pathways by an indirect attack on critical proteins and has become an attractive target for cancer therapy.2 This work aims to develop of new molecules based on quinone scaffold due that quinones derivatives have demonstrated potent anti-proliferative activity against estrogen-dependent cancers cell, as well as, induce the degradation of oncogenic Hsp90 client proteins. The set of 35 molecules reported by Blagg et al.3 were studied based in a hybrid strategy including Molecular Docking, Molecular Dynamics and 3D-QSAR analysis to identify the most relevant ligand-receptor interactions.4 The Correlation between the free energy of binding and binding modes for nafthoquinones derivatives are discussed. These results provide a new insight into protein–ligand interactions into the Hsp90, in addition, the analysis of the contour maps derived for 3D-QSAR provide helpful way about the rational modification of molecules in order to design more potent Hsp90 inhibitors.
- Published
- 2018
15. Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles
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Jaime Mella, Javier Campanini-Salinas, Cesar Morales-Verdejo, Juan Andrades-Lagos, Gonzalo Recabarren-Gajardo, Jorge Soto-Delgado, Marcos Lorca, and David Vásquez-Velásquez
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0301 basic medicine ,Models, Molecular ,obesity ,Aryloxypropanolamines ,aryloxypropanolamines ,Pharmaceutical Science ,Quantitative Structure-Activity Relationship ,Pharmacology ,01 natural sciences ,Analytical Chemistry ,Propanolamines ,Drug Discovery ,Vibegron ,β3-adrenergic receptor ,diabetes ,overactive bladder ,mirabegron ,vibegron ,3D-QSAR ,CoMFA ,CoMSIA ,Molecular Structure ,Chemistry ,Diabetes ,Biological activity ,Multiple pathologies ,Chemistry (miscellaneous) ,Anti obesity ,Molecular Medicine ,Amine gas treating ,medicine.drug ,Quantitative structure–activity relationship ,Β3-adrenergic receptor ,Static Electricity ,Adrenergic beta-3 Receptor Agonists ,Article ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,medicine ,Humans ,Hypoglycemic Agents ,Obesity ,Physical and Theoretical Chemistry ,Mirabegron ,β3 adrenergic receptor ,Binding Sites ,010405 organic chemistry ,Overactive bladder ,Organic Chemistry ,External validation ,0104 chemical sciences ,030104 developmental biology ,Drug Design ,Anti-Obesity Agents - Abstract
Indexación: Scopus. Acknowledgments: This work was supported by FONDECYT No. 11130701. We would also like to thank fDoTr CthLeafbr efeora vthaeil afrbeilei tayvoafiltahbeilsitoyf towfa trheer seoqfutwireadret orecqaulciureladt etothcealAcuDla(thet ttph:e/ A/dDt c(lhatbt.pw:/e/dbstc.cloabm.w/seobfst.wcoamre/-stoofotlws aarned-tools and http://teqip.jdvu.ac.in/QSAR_Tools/). SDG. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2 ncv = 0.993 and 0.984 and values of r2 test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2 m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561). © 2018 by the authors. https://www.mdpi.com/1420-3049/23/5/1191
- Published
- 2018
16. Examining the compatibility of collagen and a polythiophene derivative for the preparation of bioactive platforms
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Carlos Alemán, Juan Torras, Francesc Estrany, Jorge Soto-Delgado, Luis J. del Valle, Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, Universitat Politècnica de Catalunya. IMEM - Innovació, Modelització i Enginyeria en (BIO) Materials, Universitat Politècnica de Catalunya. PSEP - Polimers Sintètics: Estructura i Propietats. Polimers Biodegradables, and Universitat Politècnica de Catalunya. PSEP - Polimers Sintètics: Estructura i Propietats. Polimers Biodegradables.
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Aqueous solution ,Hydrogen bond ,Chemistry ,General Chemical Engineering ,Enginyeria electrònica [Àrees temàtiques de la UPC] ,Solvation ,General Chemistry ,Electrochemistry ,Bioactive compounds ,Enginyeria química::Biotecnologia [Àrees temàtiques de la UPC] ,Enginyeria química [Àrees temàtiques de la UPC] ,PEDOT:PSS ,Chemical engineering ,Monolayer ,Polythiophenes ,Molecule ,Organic chemistry ,Collagen ,Polímers conductors ,Compostos bioactius ,Biocomposite ,Polyalkylthiophenes--Electric properties ,Col·lagen - Abstract
Fundamental characteristics of bioactive platforms based on biocomposites of poly(3,4-ethylenedioxythiophene) (PEDOT) and collagen, named P(EDOT:CLG), have been examined using an experimental–computational approach. The protein affects both the morphology and electrochemical activity of PEDOT. Specifically, P(EDOT:CLG) shows spherical-like nodules that have been attributed to the collagen rod aggregates organized in phases separated from that of PEDOT. This phase separation results in a reduction of the ability to exchange charge reversibly, even though collagen stabilizes the PEDOT matrix from electrochemical degradation. On the other hand, viability assays indicate that the bioactivity of P(EDOT:CLG) is significantly higher than that of PEDOT in terms of cellular adhesion and proliferation. Thus, the biocomposite promotes the formation of 3D biostructures formed by the superposition of cellular monolayers, mimicking the growth of biological tissues. In order to gain microscopic information about the formation of specific interactions between PEDOT and collagen molecules in the biocomposite, quantum mechanical calculations on complexes formed by their building blocks have been performed in different environments (i.e. vacuum, chloroform and aqueous solution). Results evidence the important role played by non-conventional C–HO hydrogen bonds, which is consistent with previous findings on complexes involving DNA and dopamine. The environment affects considerably the binding energy, which decreases with increasing polarity of the environment. However, in all environments the repeating units of PEDOT form stronger interactions with L-hydroxyproline than with L-proline. On the other hand, intermolecular interaction patterns predicted using implicit and explicit solvation models present a remarkable agreement and have been identified by visualizing the reduced electron density gradient.
- Published
- 2015
17. New aryloxy-quinone derivatives as potential anti-Chagasic agents: synthesis, trypanosomicidal activity, electrochemical properties, pharmacophore elucidation and 3D-QSAR analysis
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Jorge Soto-Delgado, Karina Vázquez, Jaime Pizarro, Mercedes González, Javier Varela, Hugo Cerecetto, Rodrigo Segura, Christian Espinosa-Bustos, Margot Paulino, Ricardo A. Tapia, Estefanía Birriel, and Cristian O. Salas
- Subjects
Quantitative structure–activity relationship ,biology ,Stereochemistry ,Chemistry ,General Chemical Engineering ,In silico ,General Chemistry ,biology.organism_classification ,Combinatorial chemistry ,In vitro ,Quinone ,medicine ,Pharmacophore ,Trypanosoma cruzi ,Cytotoxicity ,Nifurtimox ,medicine.drug - Abstract
A set of new aryloxy-quinones were synthesized and evaluated in vitro against the epimastigote form of Trypanosoma cruzi and their unspecific cytotoxicity was tested on murine macrophages J-774 cells. Most of these novel compounds were found to be much more potent and selective than the standard drug nifurtimox. Interestingly, 2-phenoxy-naphthoquinone 3b displayed a remarkable nanomolar inhibitory activity, IC50 = 20 nM, and a high selectivity index, SI = 625. The Epc1 was determined for the most interesting compounds and no correlation with the trypanosomicidal effect was found. Therefore, an in silico study was carried out to obtain a pharmacophoric model and quantitative structure–trypanosomicidal activity relationship. The designed pharmacophore recognized the more potent and selective molecules, exhibiting five pharmacophoric features. A correlation coefficient R2 of 0.99 of pIC50 plotted against the predicted values indicated that the 3D-QSAR equation could be applied to further predictions of newly designed trypanosomicidal compounds.
- Published
- 2015
18. 2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β3-Adrenergic Activity
- Author
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Jaime Mella, Mauricio Cuellar, Marco Mellado, Luisa Montoya, C. D. Pessoa-Mahana, Cesar Morales-Verdejo, Carlos F. Lagos, Gastón Apablaza, Jorge Soto-Delgado, and Hery Chung
- Subjects
0301 basic medicine ,Drug ,Quantitative structure–activity relationship ,obesity ,Stereochemistry ,media_common.quotation_subject ,Pharmaceutical Science ,Adrenergic ,Pharmacology ,01 natural sciences ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,Vibegron ,Drug Discovery ,medicine ,Obesity ,Physical and Theoretical Chemistry ,Receptor ,beta-3 adrenergic receptor ,media_common ,Mirabegron ,diabetes ,010405 organic chemistry ,Chemistry ,QSAR ,Diabetes ,Organic Chemistry ,Rational design ,Beta-3 adrenergic receptor ,vibegron ,mirabegron ,0104 chemical sciences ,030104 developmental biology ,indole ,Indole ,Chemistry (miscellaneous) ,Molar refractivity ,Lipophilicity ,Molecular Medicine ,CoMSIA ,medicine.drug - Abstract
Indexación: Web of Science; Scopus. The beta(3) adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new beta(3) adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent (3) adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving beta(3) adrenergic activity is given. http://www.mdpi.com/1420-3049/22/3/404
- Published
- 2017
19. Synthesis and biological characterization of new aryloxyindole-4,9-diones as potent trypanosomicidal agents
- Author
-
Estefanía Birriel, Javier Varela, Jorge Soto-Delgado, Ricardo A. Tapia, Karina Vázquez, Hugo Cerecetto, Cristian O. Salas, Margot Paulino, Mercedes González, and Christian Espinosa-Bustos
- Subjects
Indoles ,Stereochemistry ,Trypanosoma cruzi ,In silico ,Clinical Biochemistry ,High selectivity ,Pharmaceutical Science ,Biochemistry ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,Drug Discovery ,medicine ,Nifurtimox ,Cytotoxicity ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Organic Chemistry ,biology.organism_classification ,Trypanocidal Agents ,Combinatorial chemistry ,In vitro ,Molecular Medicine ,Pharmacophore ,medicine.drug - Abstract
A new indole-4,9-dione and their phenoxy derivatives were synthesized and evaluated in vitro against the epimastigote form of Trypanosoma cruzi , Y strain. All of these novel compounds were found to be extremely potent and selective that the standard drug nifurtimox. Interestingly, phenoxyindole-4,9-dione 9d displayed excellent nanomolar inhibitory activity, IC 50 = 20 nM, and high selectivity index, SI = 625. In silico studies using MOE program were performed to generate a preliminary pharmacophore model.
- Published
- 2014
20. On the Catalytic Effect of Water in the Intramolecular Diels–Alder Reaction of Quinone Systems: A Theoretical Study
- Author
-
Jorge Soto-Delgado, Arie Aizman, Renato Contreras, and Luis R. Domingo
- Subjects
lcsh:QD241-441 ,lcsh:Organic chemistry ,Alder reactions ,polar Diels– ,DFT reactivity indices ,local reactivity difference index ,intramolecular Diels– ,water catalysis - Abstract
The mechanism of the intramolecular Diels–Alder (IMDA) reaction of benzoquinone 1, in the absence and in the presence of three water molecules, 1w, has been studied by means of density functional theory (DFT) methods, using the M05-2X and B3LYP functionals for exploration of the potential energy surface (PES). The energy and geometrical results obtained are complemented with a population analysis using the NBO method, and an analysis based on the global, local and group electrophilicity and nucleophilicity indices. Both implicit and explicit solvation emphasize the increase of the polarity of the reaction and the reduction of activation free energies associated with the transition states (TSs) of this IMDA process. These results are reinforced by the analysis of the reactivity indices derived from the conceptual DFT, which show that the increase of the electrophilicity of the quinone framework by the hydrogen-bond formation correctly explains the high polar character of this intramolecular process. Large polarization at the TSs promoted by hydrogen-bonds and implicit solvation by water together with a high electrophilicity-nucleophilicity difference consistently explains the catalytic effects of water molecules.
- Published
- 2012
21. On the Catalytic Effect of Water in the Intramolecular Diels–Alder Reaction of Quinone Systems: A Theoretical Study
- Author
-
Luis R. Domingo, Renato Contreras, Jorge Soto-Delgado, and Arie Aizman
- Subjects
Models, Molecular ,Implicit solvation ,Population ,polar Diels–Alder reactions ,Molecular Conformation ,Pharmaceutical Science ,Photochemistry ,Article ,Catalysis ,Analytical Chemistry ,lcsh:QD241-441 ,lcsh:Organic chemistry ,Computational chemistry ,Drug Discovery ,DFT reactivity indices ,Computer Simulation ,Physical and Theoretical Chemistry ,education ,Diels–Alder reaction ,education.field_of_study ,Cycloaddition Reaction ,Chemistry ,Organic Chemistry ,intramolecular Diels–Alder reactions ,Solvation ,Quinones ,Water ,Hydrogen Bonding ,water catalysis ,Benzoquinone ,Transition state ,Models, Chemical ,Chemistry (miscellaneous) ,Intramolecular force ,Molecular Medicine ,Quantum Theory ,Thermodynamics ,Density functional theory ,local reactivity difference index ,Diterpenes ,Algorithms - Abstract
The mechanism of the intramolecular Diels#8211;Alder (IMDA) reaction of benzoquinone 1, in the absence and in the presence of three water molecules, 1w, has been studied by means of density functional theory (DFT) methods, using the M05-2X and B3LYP functionals for exploration of the potential energy surface (PES). The energy and geometrical results obtained are complemented with a population analysis using the NBO method, and an analysis based on the global, local and group electrophilicity and nucleophilicity indices. Both implicit and explicit solvation emphasize the increase of the polarity of the reaction and the reduction of activation free energies associated with the transition states (TSs) of this IMDA process. These results are reinforced by the analysis of the reactivity indices derived from the conceptual DFT, which show that the increase of the electrophilicity of the quinone framework by the hydrogen-bond formation correctly explains the high polar character of this intramolecular process. Large polarization at the TSs promoted by hydrogen-bonds and implicit solvation by water together with a high electrophilicity-nucleophilicity difference consistently explains the catalytic effects of water molecules.
- Published
- 2012
22. Structural analysis and molecular docking of trypanocidal aryloxy-quinones in trypanothione and glutathione reductases: a comparison with biochemical data
- Author
-
Brenda Vera, Victoria Espinosa, Carolina Mascayano, Cristian O. Salas, Ricardo A. Tapia, Karina Vázquez, Jorge Soto-Delgado, and Margot Paulino
- Subjects
0301 basic medicine ,Protein Conformation, alpha-Helical ,030103 biophysics ,Stereochemistry ,Trypanosoma cruzi ,Glutathione reductase ,Amino Acid Motifs ,Trypanothione ,Protozoan Proteins ,Biology ,Nicotinamide adenine dinucleotide ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,Structural Biology ,Humans ,NADH, NADPH Oxidoreductases ,Protein Interaction Domains and Motifs ,Enzyme kinetics ,Binding site ,Enzyme Inhibitors ,Molecular Biology ,Trypanocidal agent ,Binding Sites ,General Medicine ,Glutathione ,Trypanocidal Agents ,Molecular Docking Simulation ,Kinetics ,030104 developmental biology ,Glutathione Reductase ,Biochemistry ,chemistry ,Enzyme inhibitor ,biology.protein ,Thermodynamics ,Protein Conformation, beta-Strand ,Protein Multimerization ,NADP ,Naphthoquinones ,Protein Binding - Abstract
A set of aryloxy-quinones, previously synthesized and evaluated against Trypanosoma cruzi epimastigotes cultures, were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic, and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones. Biochemical assays indicated that three naphthoquinones (Nq-h, Nq-g, and Nq-d) selectively inhibit TR and the TR kinetic analyses indicated that Nq-h inhibit TR in a noncompetitive mechanism. Molecular dockings were performed in TR and GR in the following three putative binding sites: the catalytic site, the dimer interface, and the nicotinamide adenine dinucleotide phosphate-binding site. In TR and GR, the aryloxy-quinones were found to exhibit high affinity for a site near it cognate-binding site in a place in which the noncompetitive kinetics could be justified. Taking as examples the three compounds with TR specificity (TRS) (Nq-h, Nq-g, and Nq-d), the presence of a network of contacts with the quinonic ring sustained by the triad of Lys62, Met400', Ser464' residues, seems to contribute hardly to the TRS. Compound Nq-b, a naphthoquinone with nitrophenoxy substituent, proved to be the best scaffold for the design of trypanocidal compounds with low toxicity. However, the compound displayed only a poor and non-selective effect toward TR indicating that TR inhibition is not the main reason for the antiparasitic activity of the aryloxy-quinones.
- Published
- 2016
23. LOCATION, ORIENTATION AND DYNAMICS OF TWO MOLECULES WITH MITOCHONDRIAL ACTIVITY DISSOLVED IN ANIONIC LYOMESOPHASE: A ²H-NMR AND MD STUDY
- Author
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Boris E. Weiss-López, Maximiliano Martínez-Cifuentes, Víctor E Bahamonde-Padilla, Álvaro Ruiz, Jorge Soto-Delgado, Ramiro Araya-Maturana, Hernán Ahumada, and Daniel Muñoz-Masson
- Subjects
Chemistry ,Lyomesophase ,Bilayer ,Relaxation (NMR) ,Quinones ,General Chemistry ,Hydroquinones ,Crystallography ,Molecular dynamics ,Deuterium ,Lyotropic liquid crystal ,Liquid crystal ,Quadrupole ,Molecule ,Deuterium Quadrupole Splitting ,Longitudinal Relaxation Time - Abstract
4,4-Dimethyl-5,8-dihydroanthracene-1,9,10(4 H )-trione (Q1) and 9,10-Dihydroxy-4,4-dimethyl-5,8-dihydro-1(4 H )-anthracenone (Q2), two molecules that inhibit cancer cell respiration, were selectively deuterated and dissolved in an anionic discotic nematic lyotropic liquid crystal (dnllc) solution. The solution provides a magnetic field oriented anisotropic medium, where the location, average orientation and dynamics of Q1 and Q2 were examined by measuring 2 H-NMR quadrupole splittings (Dn Q ) and 2 H longitudinal relaxation times (T 1 ). The NMR data shows that both molecules are strongly attached to the aggregate and, when dissolved, increase the alignment of the interface components with the magnetic field. However they present different average orientations. To assist with the interpretation of the experimental results, 300ns Molecular Dynamics (MD) trajectories of a bilayer model of the aggregate were calculated. The results show that both molecules spontaneously diffuse inside the bilayer, to locate in the limit between the hydrophobic core and the interface. The orientations of both molecules in the aggregate are determined by the formation of H-bonds with water.
- Published
- 2012
24. STRUCTURAL REASSIGNMENT OF EPIERYTHRATIDINE, AN ALKALOID FROM Erythrinafusca, BASED ON NMR STUDIES AND COMPUTATIONAL METHODS
- Author
-
Patricio Iturriaga-Vásquez, Bruce K. Cassels, Jorge Soto-Delgado, Carlos Areche, and Olimpo García-Beltrán
- Subjects
Diene ,biology ,Stereochemistry ,Alkaloid ,General Chemistry ,Carbon-13 NMR ,biology.organism_classification ,chemistry.chemical_compound ,chemistry ,Proton NMR ,Two-dimensional nuclear magnetic resonance spectroscopy ,Derivative (chemistry) ,Erythrina ,Erythrina fusca - Abstract
The diene Erythrina alkaloids erysotrine (1), erysodine (2), erythraline (3), erytharbine (4), and erysotrine N-oxide (5), plus the hydroxylated dihydro derivative of 1, epierythratidine (6) were isolated from seeds of Erythrina fusca Lour., and their 1H and 13C NMR spectra were completely assigned using 2D experiments (H-H COSY, HMQC, HMBC and H-H NOESY). Our assignments for 1-5 agree well with the literature, but the present work shows that the published interpretation of the spectra of 6 must be revised. A combined study based on NMR data and quantum-mechanical calculations using DFT/GIAO indicate that 6 is the correct structure of epierythratidine.
- Published
- 2012
25. Understanding the stereo- and regioselectivities of the polar Diels-Alder reactions between 2-acetyl-1,4-benzoquinone and methyl substituted 1,3-butadienes: a DFT study
- Author
-
Renato Contreras, Ramiro Araya-Maturana, Jorge Soto-Delgado, and Luis R. Domingo
- Subjects
education.field_of_study ,Stereochemistry ,Chemistry ,Organic Chemistry ,Population ,Regioselectivity ,Medicinal chemistry ,Transition state ,1,4-Benzoquinone ,chemistry.chemical_compound ,Nucleophile ,Electrophile ,Physical and Theoretical Chemistry ,Selectivity ,education ,Natural bond orbital - Abstract
The polar Diels–Alder (DA) reactions of 2-acetyl-1,4-benzoquinone (acBQ) with methyl substituted 1,3-butadienes have been studied using DFT methods at the B3LYP/6-31G(d) level of theory. These reactions are characterized by a nucleophilic attack of the unsubstituted ends of the 1,3-dienes to the β conjugated position of the acBQ followed by ring-closure. The reactions present a total regioselectivity and large endo selectivity. The analysis based on the global electrophilicity of the reagents at the ground state, and the natural bond orbital (NBO) population analysis at the transition states correctly explain the polar nature of these cycloadditions. The large electrophilic character of acBQ is responsible for the acceleration observed in these polar DA reactions. Copyright © 2008 John Wiley & Sons, Ltd.
- Published
- 2009
26. Antioxidant properties and free radical-scavenging reactivity of a family of hydroxynaphthalenones and dihydroxyanthracenones
- Author
-
Claudio Olea-Azar, Ester Norambuena, Cristina Cavieres, Jorge Rodríguez, Ramiro Araya-Maturana, Tomás Delgado-Castro, and Jorge Soto-Delgado
- Subjects
Antioxidant ,DPPH ,Radical ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Naphthalenes ,Photochemistry ,Sensitivity and Specificity ,Biochemistry ,Antioxidants ,law.invention ,Mice ,chemistry.chemical_compound ,Galvinoxyl ,law ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Organic chemistry ,Reactivity (chemistry) ,Electron paramagnetic resonance ,Molecular Biology ,Anthracenes ,Molecular Structure ,Hydroquinone ,Spin trapping ,Organic Chemistry ,Electron Spin Resonance Spectroscopy ,Reproducibility of Results ,Hydrogen Bonding ,Free Radical Scavengers ,Oxygen ,Kinetics ,chemistry ,Molecular Medicine ,Reactive Oxygen Species - Abstract
This study was undertaken to investigate the free radical-scavenging and antioxidant activities of various structurally related hydroquinones including hydroxynaphthalenones and dihydroxyanthracenones. Electron spin resonance spectroscopy and spin trapping techniques were used to evaluate the ability of hydroquinones to scavenge hydroxyl, diphenylpicrylhydrazyl, and galvinoxyl radicals. In addition, the oxygen radical absorbing capacity assay using fluorescein (ORAC-FL) was used to obtain the relative antioxidant capacity of these radicals. The rate constants of the first H atom abstraction by 2,2-diphenyl-2-picrylhydrazyl ( k 2 ), were obtained under pseudo-first-order conditions. The free radical-scavenging activities and k 2 values discriminate well between hydroxynaphthalenones and dihydroxyanthracenones, showing that the latter have better antioxidant properties. The aforementioned experimental data agree with quantum-chemical results demonstrating the relevance of intramolecular H bonding to radical-scavenging activities.
- Published
- 2007
27. Effects of 9,10-dihydroxy-4,4-dimethyl-5,8-dihydro-1(4H)-anthracenone derivatives on tumor cell respiration
- Author
-
Hernán Pessoa-Mahana, Jorge Soto-Delgado, Boris E. Weiss-López, Jorge Ferreira, Bruce K. Cassels, Ramiro Araya-Maturana, Mario Pavani, Tomás Delgado-Castro, Dante Miranda, and Wilson Cardona
- Subjects
Stereochemistry ,Cellular respiration ,Cell Respiration ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Tumor cells ,Naphthalenes ,Biochemistry ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,Oxygen Consumption ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Respiration ,Animals ,Humans ,Molecular Biology ,Anthracenes ,Histiocytic lymphoma ,Chemistry ,Organic Chemistry ,Quinone ,Molecular Medicine ,Anthraquinone Derivatives ,P388 leukemia ,Drug Screening Assays, Antitumor - Abstract
A series of tricyclic hydroquinones, incorporating a carbonyl group in the ortho position relative to the phenol function, were tested as inhibitors of oxygen uptake against the TA3 mouse carcinoma cell line and its multidrug-resistant variant TA3-MTX-R. The title compound, which proved to be the most active one, also exhibited low micromolar dose-dependent growth inhibition of the human tumor U937 cell line (human monocytic leukemia). A tentative structure-activity relationship is proposed for these substances. A comparison between the cytotoxicities of the title compound and 4,4-dimethyl-5,8-dihydroxynaphthalene-1-one, with their activities as inhibitors of oxygen uptake by the TA3-MTX-R cell line, is presented. Also, the inhibition of oxygen uptake by 6-(4-methylpent-3-enyl)-1,4-naphthoquinone was determined and compared with its reported cytotoxicity toward P-388 (murine lymphocytic leukemia), A-549 (human lung carcinoma), HT-29 (human colon carcinoma), and MEL-28 (human melanoma) cells. The inhibition of oxygen uptake by TA3-MTX-R cells is useful as a quick test for preliminary screening of possible anticancer activity.
- Published
- 2006
28. On the mechanism of biological activity of hydroquinone derivatives that inhibit tumor cell respiration. A theoretical study
- Author
-
Boris E. Weiss-López, Víctor E Bahamonde-Padilla, Jorge Soto-Delgado, and Ramiro Araya-Maturana
- Subjects
Hydroquinone ,Chemistry ,Solvation ,Biological activity ,Condensed Matter Physics ,Biochemistry ,Gibbs free energy ,symbols.namesake ,chemistry.chemical_compound ,Membrane ,Computational chemistry ,Mechanism (philosophy) ,symbols ,Molecule ,Density functional theory ,Physical and Theoretical Chemistry - Abstract
A simple mechanism to understand the biological activity of a series of hydroquinone derivatives is proposed. To validate this proposition Gibbs free energies of formation of the different species involved were calculated. The calculations were performed using density functional theory (DFT) at B3LYP/6-31++G(2df,p) level of theory, including solvation effect. The results show that two important variables to examine are the equilibrium phenol-phenoxide and the solvation energy of neutral species, since the balance between both variables affects the capability of the molecules to cross membranes. Once the molecule crossed the membrane, the formation of radical species shows a qualitative correlation with the magnitude of IC 50 values. This provides a reasonable criterion to search for more efficient anticancer drug.
- Published
- 2013
29. Bond Fukui functions as descriptor of the electron density reorganization in π conjugated systems
- Author
-
M Gonzalez-Suarez, Renato Contreras, Arie Aizman, and Jorge Soto-Delgado
- Subjects
chemistry.chemical_classification ,Double bond ,Chemistry ,Computational chemistry ,Electrophilic addition ,Yield (chemistry) ,Organic Chemistry ,Michael reaction ,Reactivity (chemistry) ,Conjugated system ,Photochemistry ,Cycloaddition ,Fukui function - Abstract
The bond Fukui function is introduced and tested as a new reactivity index capable of predicting the evolution of bond breaking and formation processes during an organic reaction involving π conjugated systems. As an illustration, we examine many cases where substituted ethylenes and dienes may respond to different reagents to yield cycloaddition, Michael addition, and other reactions at double bonds.
- Published
- 2011
30. Microbial transformation of marine halogenated sesquiterpenes
- Author
-
Álvaro Carrasco, Aurelio San Martin, M. Cristina Chamy, Renato Contreras, Jorge Soto-Delgado, Juana Rovirosa, and Silvia Orejarena
- Subjects
Pharmacology ,Mucor plumbeus ,Magnetic Resonance Spectroscopy ,biology ,Aspergillus niger ,Laurencia ,Microbial transformation ,Plant Science ,General Medicine ,biology.organism_classification ,Sesquiterpene ,chemistry.chemical_compound ,Complementary and alternative medicine ,chemistry ,Mucor ,Drug Discovery ,Organic chemistry ,Gibberella fujikuroi ,Sesquiterpenes ,Biotransformation - Abstract
The sesquiterpene pacifenol is one of the main constituents of the red alga Laurencia claviformis. Earlier work on the semisynthetic derivatives of pacifenol afforded a series of halogenated sesquiterpenes. The aim of the present work was to obtain new hydroxylated derivatives of halogenated sesquiterpenes by means of microbial transformation using Aspergillus níger, Gibberella fujikuroi and Mucor plumbeus. The best results were obtained with M. plumbeus. The microbiological transformation by M. plumbeus of pacifenol, and two semisynthetic derivatives, is described. The structures of the new compounds obtained were determined by spectroscopic means.
- Published
- 2011
31. A dft study of the regioselectivity in intramolecular diels-alder reactions with formation of a tricyclodecane skeleton
- Author
-
Renato Contreras, Jorge Soto-Delgado, Arie Aizman, and Luis R. Domingo
- Subjects
chemistry.chemical_compound ,Diene ,Chemistry ,Stereochemistry ,Reagent ,Intramolecular force ,Organic Chemistry ,Diels alder ,Regioselectivity ,Density functional theory ,Activation energy ,Methylene ,Biochemistry - Abstract
Three different intramolecular Diels-Alder (IMDA) reactions associated with the formation of fused and bridged tricyclodecane skeletons have been studied at the B3LYP/6-31G(d) computational level. While substitution on the diene and dienophile fragments modulates the polar character of the reaction, the strain effect produced by the methylene tether affects the activation energy, and its torsion controls the different regioisomeric channels of the IMDA process. Analysis of the reactivity indices recently proposed (J. Soto-Delgado et al., Org. Biomol. Chem., 2010, 8, 3678) within the conceptual density functional theory allows for the characterization of the mechanism including the charge transfer within the reagents involved in these IMDA reactions as well as for the direction of the electronic flux in the intramolecular processes.
- Published
- 2011
32. Invariance of electrophilicity of independent fragments. Application to intramolecular diels-alder reactions
- Author
-
Jorge Soto-Delgado, Luis R. Domingo, Renato Contreras, and Arie Aizman
- Subjects
Computational chemistry ,Stereochemistry ,Chemistry ,Group (periodic table) ,Intramolecular force ,Electrophile ,Diels alder ,General Physics and Astronomy ,Molecule ,Physical and Theoretical Chemistry - Abstract
We herein demonstrate that the global electrophilicity may be distributed into fragments within a single molecule by using an empirical partitioning scheme of the electronic chemical potential framed on the chemical potential inequality principle. Group electrophilicity for several fragments may thereby be defined. Their values show a remarkable stability, independent of the chemical environment they are attached to. The model is applied to asses the chemical reactivity of a series of fragments involved in intramolecular Diels–Alder reactions.
- Published
- 2010
33. Understanding the influence of lewis acids in the regioselectivity of the diels-alder reactions of 2-methoxy-5-methyl-1,4-benzoquinone: a dft study
- Author
-
Jorge Soto-Delgado, Renato Contreras, and Luis R. Domingo
- Subjects
Regioselectivity ,Condensed Matter Physics ,Photochemistry ,Biochemistry ,Benzoquinone ,Cycloaddition ,Transition state ,Catalysis ,1,4-Benzoquinone ,chemistry.chemical_compound ,chemistry ,Computational chemistry ,Electrophile ,Lewis acids and bases ,Physical and Theoretical Chemistry - Abstract
The mechanisms of the Diels–Alder (DA) reactions of 2-methoxy-5-methyl-1,4-benzoquinone 1 with 2-methyl-1,3-butadiene 2, in the absence and in the presence of LA catalysts, have been studied using the DFT method at the B3LYP/6-31G(d) level of theory. The uncatalyzed DA reactions between 1 and 2 take place via synchronous concerted TSs. The large activation barrier as well as the low stereo and regioselectivity associated with the uncatalyzed process are in clear agreement with the non-polar character of the cycloaddition. Coordination of the LA catalysts, BF3 or SnCl4, to the oxygen atoms of the benzoquinone 1 produces a large acceleration of the reaction, which can be associated with the large polar character of the cycloaddition. The different coordination modes of BF3 and SnCl4 LA catalysts to the oxygen atoms of benzoquinone 1 allow explaining the reverse para/meta regioselectivity observed in these LA-catalyzed DA reactions. The analysis based on the global and local electrophilicity indices of the reagents correctly explains the polar nature of the title reactions, as well as the change of regioselectivity experimentally observed.
- Published
- 2009
34. An unusual halogenated meroditerpenoid from Stypopodium flabelliforme: studies by NMR spectroscopic and computational methods
- Author
-
Renato Contreras, Aurelio San-Martín, Juana Rovirosa, Carlos Areche, and Jorge Soto-Delgado
- Subjects
Magnetic Resonance Spectroscopy ,biology ,Molecular Structure ,Stereochemistry ,Terpenes ,Chemical structure ,Stypopodium ,Computational Biology ,Stypotriol ,Plant Science ,General Medicine ,Horticulture ,biology.organism_classification ,Phaeophyta ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Halogen ,Dictyotaceae ,Molecule ,Stypopodium flabelliforme ,Diterpenes ,Molecular Biology ,Dichloromethane - Abstract
Meroditerpenoids, 2-[2'(E)-3',7',11',15'-tetramethylhexadec-2-en-1'-yl]-6-methyl-1,4-benzohydroquinone diacetate and 4'-chlorostypotriol triacetate, along with eight known compounds isolated from the dichloromethane extract of the brown alga Stypopodium flabelliforme after peracetylation are reported. One of them, 2-(1-oxo-hexadecyl)-1,3,5-trihydroxybenzene, is described for the first time within this genus. Structural elucidation was carried out on the basis of spectroscopic data and theoretical studies using GIAO/DFT analysis at B3LYP/6-31G(d) and mPW1PW91/6-31G(d) levels of theory for 4'-chlorostypotriol. This isomer is the first metabolite from the Stypopodium genus possessing one halogen atom.
- Published
- 2008
35. Synthesis of 9- and 10-Membered Macrolactones by Selective Ozonolysis of 1,4-Diazaphenanthrene Derivatives
- Author
-
Elisa Pérez-Sacau, Angel G. Ravelo, Jorge Soto-Delgado, and Ana Estévez-Braun
- Subjects
chemistry.chemical_classification ,Diazine ,chemistry.chemical_compound ,Ozonolysis ,Double bond ,chemistry ,Pyran ,Organic Chemistry ,Drug Discovery ,Organic chemistry ,General Medicine ,Biochemistry ,Enol - Abstract
9- and 10-membered macrolactones bearing benzo and diazine rings were obtained by chemoselective ozonolysis of dihydrofuran and pyran 1,4-diazaphenathrene derivatives. This is the first example of preparation of macrolactones by chemoselective ozonolysis of an enol double bond shared by aromatic and heterocyclic rings.
- Published
- 2005
36. Theoretical study on the molecular mechanism of the [5 + 2] vs. [4 + 2] cyclization mediated by Lewis acid in the quinone system
- Author
-
Luis R. Domingo, José Antonio López Sáez, Jorge Soto-Delgado, and Ricardo A. Tapia
- Subjects
Electron localization function ,Chemistry ,Stereochemistry ,Organic Chemistry ,Cycloaddition reaction ,Biochemistry ,Catalysis ,Quinone ,Nucleophile ,Diels-alder reaction ,Intramolecular force ,Elf analysis ,(-) Elisapterosin-B ,Electrophile ,Polarizable continuum model ,Single bond ,Lewis acids and bases ,(-) Colombiasin-A ,Physical and Theoretical Chemistry ,Topological analysis ,Bond formation ,Diels–Alder reaction - Abstract
[EN] The thermal and Lewis acid (LA) catalyzed cyclizations of quinone 1 involved in the synthesis of Colombiasin A and Elipsaterosin B have been theoretically studied using DFT methods at the B3LYP/6-311G(d,p) computational level. B3LYP calculations suggest that the formal endo [4 + 2] cycloadduct allowing the synthesis of Colombiasin A is preferentially formed under thermal conditions, while in the presence of the BF3 LA catalyst the formal [5 + 2] cycloadduct is seen, allowing the synthesis of Elipsaterosin B. The BF3 LA catalyst not only accelerates the nucleophilic attack on the C2 carbon of the quinone framework through a more polar C-C bond formation, but also provokes a different electron density rearrangement along the nucleophilic attack favoring the subsequent C-C bond formation at the C4 carbon with the formation of the formal [5 + 2] cycloadduct. ELF bonding analysis along these cyclizations indicates that the C-C single bond formation takes place in the range of 1.91-2.1 angstrom by C-to-C coupling of two pseudoradical centers. Along the formation of the first C2-C9 single bond, these pseudoradical centers appear at one of the most electrophilic and at one of the most nucleophilic centers of quinone 1, C2 and C9 carbons, respectively. Analysis of the Parr functions suggests that although the most favorable electrophilic/nucleophilic interaction is that involving the C2 carbon of quinone and the C12 carbon of the butadiene framework, the intramolecular nature of the cyclization prevents the corresponding reactive channel., This work was supported by the Post-Doctoral fellow FONDECYT Grant 3130359 and Project ICM-P10-003-F CILIS granted by Fondo de Innovacion para la Competitividad del Ministerio de Economia, Fomento y Turismo, Chile.
- Published
- 2013
37. Quantitative characterization of group electrophilicity and nucleophilicity for intramolecular Diels–Alder reactions
- Author
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Jorge Soto-Delgado, Renato Contreras, and Luis R. Domingo
- Subjects
Reaction mechanism ,Diene ,Stereochemistry ,Organic Chemistry ,Intermolecular force ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Intramolecular force ,Electrophile ,Molecule ,Reactivity (chemistry) ,Physical and Theoretical Chemistry - Abstract
In a previous work (L. R. Domingo, M. J. Aurell, P. Perez and R. Contreras, Tetrahedron 2002, 58, 4417) we proposed that the difference in global electrophilicity index be taken as a measure of the polarity at the transition state in intermolecular Diels-Alder reactions. We herein extend this model to deal with intramolecular Diels-Alder (IMDA) processes. The transferability of the empirical reactivity rules established for the intermolecular DA reactions to the IMDA reactions is discussed. The analysis based on group electrophilicity and nucleophilicity in general fails because having two different reactivity patterns within the same molecule hampers a clean classification of electrophilicity and nucleophilicity of the interacting fragments. We introduce dual philicity indexes E1 and E2 that solve this problem by separating a series of 30 IMDA reactions into two families, namely the diene to dienophile electron flow (DDpF) and the dienophile to diene electron flow (DpDF) processes. The new indexes correctly describe the charge transfer at the transition state and the reaction mechanism expected for the title reactions.
- Published
- 2010
38. Multiscale treatment for the molecular mechanism of a diels-alder reaction in solution: A QM/MM-MD study
- Author
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Ricardo A. Tapia, Jorge Soto-Delgado, Juan Torras, Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, and Universitat Politècnica de Catalunya. IMEM - Innovació, Modelització i Enginyeria en (BIO) Materials
- Subjects
Work (thermodynamics) ,Cyclopentadiene ,010304 chemical physics ,Chemistry ,Ab initio ,Molecular dynamics ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Computer Science Applications ,Reaction coordinate ,QM/MM ,chemistry.chemical_compound ,Enginyeria química [Àrees temàtiques de la UPC] ,Computational chemistry ,0103 physical sciences ,Methyl vinyl ketone ,Dinàmica molecular ,Physical and Theoretical Chemistry ,Diels–Alder reaction - Abstract
Thermodynamics and the solvent role in the acceleration of the Diels–Alder reaction between cyclopentadiene (CPD) and methyl vinyl ketone (MVK) have been revisited. In this work we use an ab initio hybrid QM/MM-MD scheme combined with multiple steered molecular dynamics to extract the free energy pofile in water and methanol using the bidirectional Minh–Adib estimator. We obtain 18.7 kcal mol–1 and 20.8 kcal mol–1 free energy barrier for the reaction in water and methanol, respectively. This methodology reproduces experimental values with an absolute error of about 0.8 kcal mol–1. The experimental difference between the activation free-energy barriers of water and methanol is also reproduced with an absolute error of about 0.1 kcal mol–1. We explore the charge transfer evolution along reaction coordinates to characterize the electronic behavior for this reaction. It is shown that the solvent molecules around the reaction system produce a global polarization along the reaction coordinate which is consistent with the solvent polarity. The results highlight the role of hydrogen bonding formed in the transition state to stabilize the system charge reorganization in the reaction process.
39. Experimental and Theoretical Approaches in the Study of Phenanthroline‐Tetrahydroquinolines for Alzheimer's Disease
- Author
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Dr. Yorley Duarte, Dr. Margarita Gutierrez, Dr. Rocío Álvarez, Dr. Jans H. Alzate‐Morales, and Dr. Jorge Soto‐Delgado
- Subjects
Alzheimer's disease imino-Diels-Alder ,acetylcholinesterase ,tetrahydroquinolines ,density functional theory ,Chemistry ,QD1-999 - Abstract
Abstract The imino‐Diels‐Alder reaction is one of the most common strategies in organic chemistry and is an important tool for providing a broad spectrum of biologically active heterocyclic systems. A combined theoretical and experimental study of the imino‐Diels‐Alder reaction is described. The new phenanthroline‐tetrahydroquinolines were evaluated as cholinesterase inhibitors. Their cytotoxicity in human neuroblastoma SH‐SY5Y cells was also evaluated. The theoretical results suggest that compounds formation in stages can be explained by endo cycloadducts under the established reaction conditions, thereby confirming experimental results obtained for percentage yield. These results allowed us to establish that pyridine substituent remarkably influences activation energy and reaction yield, as well as in acetylcholinesterase (AChE) activity. Among these derivatives, compounds with 4‐pyridyl and 4‐nitrophenyl showed favorable AChE activity and proved to be non‐cytotoxic.
- Published
- 2019
- Full Text
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