RESUMEN
A smooth traceless ligation strategy using an air-stable phosphane probe (2-(diphenylphosphanyl)phenyl)methanol as a C-terminus activator has been demonstrated at simple and sterically hindered amino acid junctions (Gly, Ala, Trp, Glu). This Staudinger peptide ligation proceeds via formation of a seven-membered transition state to afford di-, tetra-, and pentapeptides in 78-95% yields. The experimental results of ligation at Gly junction and regioselective ligation at Glu junction were theoretically studied by computational calculations. These findings established the versatile behavior of our synthesized phosphane probe for Staudinger peptide ligation toward synthesizing peptides and proteins of choice.
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A one-pot ligation strategy at aspartic acid junctions has been developed by successfully incorporating aziridin-2,3-dicarboxylate to the N-side of a peptide fragment, affording N-aziridine appended peptides, which were ligated in solution phase with a variety of small peptide thio acids to afford native peptides, following a ring-opening/peptidyl migration/desulfurization strategy. The reaction proceeds in a highly regiospecific manner, and provides short native peptides in good isolable yields. A variety of aspartame based peptides were synthesized to showcase the generality of this aziridine based ligation. Computational studies have also been performed to obtain insight about the reaction pathway.
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GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (α1ß3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis,trans-isomers were isolated from commercially available 2,6-dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 µM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 µM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > > cis,trans-isomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the ß3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis > trans,trans > cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices.
Asunto(s)
Anestésicos Generales/química , Anestésicos Generales/farmacología , Ciclohexanoles/química , Ciclohexanoles/farmacología , Receptores de GABA-A/metabolismo , Línea Celular , Fenómenos Electrofisiológicos/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Conformación Proteica , Receptores de GABA-A/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
An efficient methodology for cysteine-free ligation at a tryptophan (Trp) site is described. A chemically active scaffold, ß-hydroxy-α-azidotryptophan, has been synthesized and explored towards the synthesis of a series of ß-hydroxytryptophan appended native peptides in good yields via one-pot reductive traceless ligation of ß-O-peptidyl-α-azidotryptophan involving an O â N peptidyl transfer strategy. Pre-organized conformational analysis and reaction energy pathway based theoretical studies further supported the experimental findings on the chemical structure stability of ligated products.
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5-Hidroxitriptófano/química , Péptidos/química , Modelos Moleculares , Conformación MolecularRESUMEN
Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.
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Antibacterianos/síntesis química , Antibacterianos/farmacología , Antifúngicos/síntesis química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Compuestos Macrocíclicos/farmacología , Peptidomiméticos/farmacología , Antibacterianos/química , Antifúngicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Relación Estructura-Actividad CuantitativaRESUMEN
QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software. The dispiro[3H-indole-3,2'-pyrrolidine-3',3"-piperidines] 24-48 were synthesized via [3 + 2]-cycloaddition reaction of azomethine ylides, (generated in situ via decarboxylative condensation of isatins 21-23 with sarcosine) and 3E,5E-1-alkyl-3,5-bis(arylmethylidene)-4-piperidones 10-20. Some of the synthesized analogues exhibited promising antitumor properties against HELA (cervical), HEPG2 (liver), T-47D, MCF7 (breast), and HCT116 (colon) human tumor cell lines, demonstrating activity close to or even better than the standard Doxorubicin, based on in vitro Sulfo-Rhodamine-B bio-assay.
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Alcaloides/farmacología , Antineoplásicos/farmacología , Relación Estructura-Actividad Cuantitativa , Compuestos de Espiro/farmacología , Alcaloides/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Programas Informáticos , Compuestos de Espiro/químicaRESUMEN
Chemical ligations to form native peptides from NâN acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. NâN acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.
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Péptidos/química , Péptidos/síntesis química , Triptófano/química , Acilación , Ligadura , Estructura Molecular , Estereoisomerismo , Triptófano/análogos & derivadosRESUMEN
Dimerization-macrocyclization has been a long-standing problem in the cyclization of peptides since, together with the desired cyclic product, many cyclic oligomers and linear polymers may also be formed during the reaction. Therefore, the development of a process that affords the cyclic dimer predominantly is difficult. A novel and versatile strategy for the synthesis of symmetric cyclo-tetrapeptides by palladium-promoted tandem deprotection/cyclo-dimerization from readily available Cbz-dipeptidoyl benzotriazolides is reported (Cbz=carboxybenzyl).
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Compuestos Macrocíclicos/síntesis química , Péptidos Cíclicos/síntesis química , Triazoles/química , Ciclización , Dimerización , Compuestos Macrocíclicos/química , Modelos Moleculares , Paladio/química , Péptidos Cíclicos/química , Triazoles/síntesis químicaRESUMEN
A diverse training set composed of 76 in-house synthesized and 61 collected from the literature was subjected to molecular field topology analysis. This resulted in a high-quality quantitative structure-activity relationships model (R² = 0.932, Q² = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay.
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Bioensayo , Compuestos Heterocíclicos/farmacología , Vasodilatadores/farmacología , Compuestos Heterocíclicos/química , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Vasodilatadores/químicaRESUMEN
Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported to be rather unstable in solution (half-life 4.5 min). In this work, we report the synthesis of an aminoxy analog of Goralatide. Aminoxy moiety is expected to provide increased stability and bioavailability of the Goralatide analog.
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Oligopéptidos/síntesis química , Péptidos/síntesis química , Espectroscopía de Resonancia Magnética , Oligopéptidos/química , Péptidos/químicaRESUMEN
Open-chain N-Cbz-protected-peptidoyl benzotriazolides are converted by a novel lactamization strategy using proline as a turn introducer into both symmetrical (5a-c and 11a-c) and unsymmetrical (19a-e) bis-2,5-diketopiperazines (bis-2,5-DKPs), previously recognized as difficult targets.
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Dicetopiperazinas/síntesis química , Lactamas/química , Dicetopiperazinas/química , Modelos Moleculares , Conformación Molecular , Estructura MolecularRESUMEN
COPD is a multifactorial lung disease causing breathing difficulties in individuals and is becoming a major health concern worldwide. The unclear pathogenic mechanism and high mortality rate urge the development of drugs against this disease. In this study, around six COPD biomarkers identified from the preceding research through integrated gene expression analysis were taken as COPD target proteins. A total of 3307 phytocompounds were included in the COPD phytocompound library from 59 therapeutic plant sources. Furthermore, a crucial three-step virtual screening process (Absorption, Distribution, Metabolism, and Excretion, respiratory nontoxicity, less harmful and nontoxic compound category) was implemented to filter the potential drug-like phytocompounds. As a result, 160 phytocompounds were filtered with desired Absorption, Distribution, Metabolism, Excretion and Toxicity properties. The filtered 160 phytocompounds were docked against six COPD target proteins and the best-docked complexes were identified through visual inspection based on six unique parameters in SeeSAR. Furthermore, the best docked complexes were subjected to molecular dynamics simulation studies to assess the stability and conformational changes of the complexes. The presence of few amino acid residues within the crucial active, allosteric and catalytic sites of the six target proteins were revealed from the binding interaction types and major residual fluctuations from molecular docking and dynamic simulation studies respectively. This is indicative of the potential inhibitory activity of phytocompounds against the COPD biomarkers. Here we report the identified phytocompounds as a promising lead molecule for the six COPD biomarkers through in silico analysis opening new avenues in COPD pathogenesis and treatments.Communicated by Ramaswamy H. Sarma.
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Novel, efficient and mild preparation of 7- and 8-membered cyclic di- and 10-membered cyclic tripeptides containing α-, ß- or γ-amino acid residues is effected by a Staudinger-mediated ring closure. Medium-sized cyclic di- and tripeptides--recognized as difficult targets--were obtained in moderate to good yields according to a straightforward sequence. Empirical force-field calculations were undertaken to determine their conformational behaviors and showed high levels of similarity with X-ray results. A computational study at the B3LYP/6-31+G** level of theory afforded information regarding the impact of the sequence, ring-size and substitution on the activation barriers for the cyclization of azido peptide thioesters.
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Péptidos Cíclicos/síntesis química , Aminoácidos/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Estructura Molecular , Péptidos Cíclicos/química , Teoría CuánticaRESUMEN
A new model for predicting the UV-visible absorption spectra of secondary organic aerosols (SOA) has been developed. The model consists of two primary parts: a SOA formation model and a semiempirical quantum chemistry method. The mass of SOA is predicted using the PHRCSOA (Partitioning Heterogeneous Reaction Consortium Secondary Organic Aerosol) model developed by Cao and Jang [Environ. Sci. Technol., 2010, 44, 727]. The chemical composition is estimated using a combination of the kinetic model (MCM) and the PHRCSOA model. The absorption spectrum is obtained by taking the sum of the spectrum of each SOA product calculated using a semiempirical NDDO (Neglect of Diatomic Differential Overlap)-based method. SOA was generated from the photochemical reaction of toluene or α-pinene at different NO(x) levels (low NO(x): 24-26 ppm, middle NO(x): 49 ppb, high NO(x): 104-105 ppb) using a 2 m(3) indoor Teflon film chamber. The model simulation reasonably agrees with the measured absorption spectra of α-pinene SOA but underestimates toluene SOA under high and middle NO(x) conditions. The absorption spectrum of toluene SOA is moderately enhanced with increasing NO(x) concentrations, while that of α-pinene SOA is not affected. Both measured and calculated UV-visible spectra show that the light absorption of toluene SOA is much stronger than that of α-pinene SOA.
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The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium.
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Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named CMC1-6. These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with CMC1 and CMC2 significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs.
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Age-associated memory loss is highly prevalent in the elder population. The inception of neurodegenerative diseases acts as a causative factor for the onset of memory loss in aged individuals. The pathophysiological mechanisms of memory loss associated with the onset of neurodegenerative diseases and normal aging processes share certain similarities as well as differences. The normal age-associated memory loss is attributed to the impairment of calcium metabolism, dysregulated cholesterol metabolism, the prevalence of oxidative stress, inappropriate functioning of hormones as well as genetic factors. Vital information regarding the key biological processes and the druggable targets involved in the onset of memory loss in the elder population has been provided in this article. The genomic and proteomic profiles of key druggable targets retrieved from the experimental evidence, co-expression studies and databases are also presented in this article. The genomic and proteomic information of druggable targets will aid in the identification of therapeutic agents which could effectively regulate the key biological processes involved in the age-associated memory loss.
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Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Envejecimiento/metabolismo , Fenómenos Biológicos/efectos de los fármacos , Calcio/metabolismo , Colesterol/metabolismo , Genoma , Genómica , Hormonas , Humanos , Enfermedades Neurodegenerativas/metabolismo , Estrés Oxidativo/fisiología , ProteómicaRESUMEN
Value-added phytochemicals from food by-products and waste materials have gained much interest and among them, dietary polyphenolic compounds with potential biological properties extend a promising sustainable approach. Oxyresveratrol (Oxy), a stilbenoid polyphenol, possesses great therapeutic potential, though its pharmacokinetic issues need attention. A good source of oxyresveratrol was found in underutilized coconut shells and the synbiotic applications of the compound in combination with a potential probiotic isolate Limosilactobacillus fermentum ASBT-2 was investigated. The compound showed lower inhibitory effects on the strain with minimum inhibitory concentration (MIC) of 1000 µg/mL. Oxyresveratrol at sub-MIC concentrations (500 µg/mL and 250 µg/mL) enhanced the probiotic properties without exerting any inhibitory effects on the strain. The combination at sub- MIC concentration of the compound inhibited Salmonella enterica and in silico approaches were employed to elucidate the possible mode of action of oxy on the pathogen. Thus, the combination could target pathogens in the gut without exerting negative impacts on growth of beneficial strains. This approach could be a novel perspective to address the poor pharmacokinetic properties of the compound.
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DNA gyrase and Topoisomerase IV are promising antibacterial drug targets as they regulate bacterial DNA replication and topology. In a quest for novel DNA topoisomerase inhibitors, a multidisciplinary approach was adopted that involves computational prediction of binding sites and molecular modelling followed by green synthesis and biological evaluation of antibacterial activity of spirobenzimidazo quinazolines derivatives. Using basic quantum chemistry principles, we evaluated spirobenzimidazo quinazolines derivatives with their pharmacokinetic profiles. Based on the results of the aforesaid in-silico studies, we synthesized a series of titled compounds using green synthetic methodology that were validated as potential antimicrobial agents. Quantum chemoinformatics based predicted activity for the synthesized compounds 9b, 9c, and 9j was concomitant with biological evaluation of broadspectrum antibacterial activity. Biological evaluation revealed that inhibition of biofilm formation was due to their potential antibacterial activity. We believe that the novel spirobenzimidazo quinazolines have the potential to be alternatives to aminocoumarins and classical quinazolines upon detailed target specific biological studies.
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Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bencimidazoles/farmacología , Diseño Asistido por Computadora , Girasa de ADN/metabolismo , Diseño de Fármacos , Quinazolinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Antibacterianos/síntesis química , Bacterias/crecimiento & desarrollo , Bencimidazoles/síntesis química , Sitios de Unión , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Girasa de ADN/química , Tecnología Química Verde , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Quinazolinas/síntesis química , Inhibidores de Topoisomerasa II/síntesis químicaRESUMEN
Aging is a biological process which accounts for the deterioration of effective physiological functions. The malfunctioning of vital organ systems leads to the onset of neurodegenerative, cardiovascular, and immunomodulatory diseases in the elder population. Age-dependent mitochondrial dysfunctions trigger the production of reactive oxygen species, which serve as a major contributing factor for the onset of age-associated diseases. The increasing burden of age-related pathologies explicates the relevance of identifying novel therapeutic agents with enhanced potency and bioavailability. Key information on the biological mechanisms of significant age-related diseases aids in understanding relevant druggable targets essential for the initiation and progression of the disease. This review provides detailed insights into the druggable targets of key anti-aging properties of therapeutic agents such as anti-oxidant, immunomodulation, cardioprotection, anti-melanogenic, and anti-elastase properties. This information aids in the development of novel therapeutic agents/ supplements with enhanced efficacy.