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Using a set of conformationally restricted Proline-derived Modules (ProMs), our group has recently succeeded in developing inhibitors for the enabled/vasodilator-stimulated phosphoprotein homologyâ 1 (EVH1) domain, which is a key mediator of cell migration and plays an important role in tumor metastasis. While these (formally) pentapeptidic compounds show nanomolecular binding affinities towards EVH1, their drug-like properties and cell permeability need to be further optimized before they can be clinically tested as therapeutic agents against metastasis. In this study, we sought to improve these properties by removing the C-terminal carboxylic acid function of our peptoids, either by late-stage decarboxylation or by direct synthesis. For late-stage decarboxylation of ProM-like systems, a method for reductive halo decarboxylation was optimized and applied to several proline-derived substrates. In this way, a series of new decarboxy ProMs suitable as building blocks for decarboxy EVH1 inhibitors were obtained. In addition, we incorporated decarboxy-ProM-1 into the pentapeptide-like compound Ac[2ClF][ProM-2][Decarb-ProM-1], which showed similar affinity towards EVH1 as the methyl ester derivative (Ac[2Cl-F][ProM-2][ProM1]OMe). However, despite better calculated drug-like properties, this compound did not inhibit chemotaxis in a cellular assay.
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Péptidos , Prolina , Prolina/química , Descarboxilación , Péptidos/química , Péptidos/farmacología , Humanos , Unión ProteicaRESUMEN
BACKGROUND: Pancreatitis is a common exocrine inflammatory disease of the pancreas and lacks specific medication currently. Rhei Radix et Rhizoma (RR) and its anthraquinone derivatives (AQs) have been successively reported for their pharmacological effects and molecular mechanisms in experimental and clinical pancreatitis. However, an overview of the anti-pancreatitis potential of RR and its AQs is limited. PURPOSE: To summarize and analyze the pharmacological effects of RR and its AQs on pancreatitis and the underlying mechanisms, and discuss their drug-like properties and future perspectives. METHODS: The articles related to RR and its AQs were collected from the Chinese National Knowledge Infrastructure, Wanfang data, PubMed, and the Web of Science using relevant keywords from the study's inception until April first, 2024. Studies involving RR or its AQs in cell or animal pancreatitis models as well as structure-activity relationship, pharmacokinetics, toxicology, and clinical trials were included. RESULTS: Most experimental studies are based on severe acute pancreatitis rat models and a few on chronic pancreatitis. Several bioactive anthraquinone derivatives of Rhei Radix et Rhizoma (RRAQs) exert local protective effects on the pancreas by maintaining pancreatic acinar cell homeostasis, inhibiting inflammatory signaling, and anti-fibrosis, and they improve systemic organ function by alleviating intestinal and lung injury. Pharmacokinetic and toxicity studies have revealed the low bioavailability and wide distribution of RRAQs, as well as hepatotoxicity and nephrotoxicity. However, there is insufficient research on the clinical application of RRAQs in pancreatitis. Furthermore, we propose effective strategies for subsequent improvement in terms of balancing effectiveness and safety. CONCLUSION: RRAQs can be developed as either candidate drugs or novel lead structures for pancreatitis treatment. The comprehensive review of RR and its AQs provides references for optimizing drugs, developing therapies, and conducting future studies on pancreatitis.
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Antraquinonas , Pancreatitis , Rheum , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/uso terapéutico , Animales , Rheum/química , Humanos , Pancreatitis/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Rizoma/química , Páncreas/efectos de los fármacos , Relación Estructura-Actividad , Ratas , Modelos Animales de EnfermedadRESUMEN
Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.
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Quinasas Ciclina-Dependientes , Inhibidores de Proteínas Quinasas , Relación Estructura-Actividad , Quinasa 2 Dependiente de la Ciclina/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Diseño de Fármacos , Descubrimiento de DrogasRESUMEN
The potential of 2,6-bis(4-fluorophenyl)-3,3-dimethylpiperidin-4-one (BFDP) as an anti-Parkinson's, anti-lung cancer, and anti-human infectious agent was extensively assessed in the current study. To accomplish this, the compound BFDP was synthesised and analysed using several spectroscopic approaches, such as NMR, mass and FT-IR spectral studies. The computational calculations for the molecule were carried out using density functional theory (DFT) at the B3LYP/6-311G++ (d,p) level of theory. A X-ray diffraction (XRD) study allows us to analyse the crystalline structure of our BFDP molecule. Intermolecular interactions were assessed using 3D Hirshfeld surfaces (3D-HS) and 2D fingerprint plots. AIM and NCI-RDG were done using quantum calculations and the DFT technique, and topological ELF and LOL, as well as vibrational parameters, have been obtained. The thermodynamic and thermal properties of the BFDP compound were determined. To investigate the pharmacokinetic characteristics of BFDP, a molecular docking study and an in silico ADMET study were done.
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Aberrant activation of N-methyl-d-aspartate receptors (NMDAR) and the resulting neuronal nitric oxide synthase (nNOS) excessive activation play crucial pathogenic roles in neuronal damage caused by stroke. Disrupting postsynaptic density protein 95 (PSD95)-nNOS protein-protein interaction (PPI) has been proposed as a potential therapeutic strategy for ischemic stroke without incurring the unwanted side effects of direct NMDAR antagonism. Based on a specific PSD95-nNOS PPI inhibitor (SCR4026), we conducted a detailed study on structure-activity relationship (SAR) to discover a series of novel benzyloxy benzamide derivatives. Here, our efforts resulted in the best 29 (LY836) with improved neuroprotective activities in primary cortical neurons from glutamate-induced damage and drug-like properties. Whereafter, co-immunoprecipitation experiment demonstrated that 29 significantly blocked PSD95-nNOS association in cultured cortical neurons. Furthermore, 29 displayed good pharmacokinetic properties (T1/2 = 4.26 and 4.08 h after oral and intravenous administration, respectively) and exhibited powerful therapeutic effects in rats subjected to middle cerebral artery occlusion (MCAO) by reducing infarct size and neurological deficit score. These findings suggested that compound 29 may be a promising neuroprotection agent for the treatment of ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Accidente Cerebrovascular , Ratas , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana/metabolismo , Ratas Sprague-Dawley , Homólogo 4 de la Proteína Discs Large , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Benzamidas/farmacología , Benzamidas/uso terapéutico , Óxido Nítrico Sintasa de Tipo I/metabolismo , Isquemia Encefálica/tratamiento farmacológicoRESUMEN
Zika virus is responsible for causing Zika infections and was declared as a public health emergency of international concern in February 2016. The Zika virus NS3-helicase is a viable drug target for the design of inhibitors due to its essential role in the replication of viral genome. The viral RNA is unwound by the NS3-helicase in order to enable the reproduction of viral genome by the NS5 protein. Zika virus infections in humans are being reported for the last 15 years. We have therefore carried out amino acid mutational analyses of NS3-helicase. NS3-helicase has two crucial binding sites: the ATP and RNA binding sites. The cofactor-ATP based pharmacophore was generated for virtual screening of ZINC database using Pharmit server, that is followed by molecular docking and molecular dynamics simulations of potential hits as probable Zika virus NS3-helicase inhibitors at the cofactor binding site. The drug-like properties of the molecules were analysed and, DFT calculations were performed on the five best molecules to reveal their stability in solvent phase compared to gas phase, the HOMO and LUMO and electrostatic potential maps to analyze the electronic and geometric characteristics. These are significant findings towards the discovery of new inhibitors of Zika virus NS3-helicase, a promising drug target to treat the Zika virus infection.Communicated by Ramaswamy H. Sarma.
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Acute lung injury (ALI) is a clinically severe lung illness with high incidence rate and mortality. Especially, coronavirus disease 2019 (COVID-19) poses a serious threat to world wide governmental fitness. It has distributed to almost from corner to corner of the universe, and the situation in the prevention and control of COVID-19 remains grave. Traditional Chinese medicine plays a vital role in the precaution and therapy of sicknesses. At present, there is a lack of drugs for treating these diseases, so it is necessary to develop drugs for treating COVID-19 related ALI. Fagopyrum dibotrys (D. Don) Hara is an annual plant of the Polygonaceae family and one of the long-history used traditional medicine in China. In recent years, its rhizomes (medicinal parts) have attracted the attention of scholars at home and abroad due to their significant anti-inflammatory, antibacterial and anticancer activities. It can work on SARS-COV-2 with numerous components, targets, and pathways, and has a certain effect on coronavirus disease 2019 (COVID-19) related acute lung injury (ALI). However, there are few systematic studies on its aerial parts (including stems and leaves) and its potential therapeutic mechanism has not been studied. The phytochemical constituents of rhizome of F. dibotrys were collected using TCMSP database. And metabolites of F. dibotrys' s aerial parts were detected by metabonomics. The phytochemical targets of F. dibotrys were predicted by the PharmMapper website tool. COVID-19 and ALI-related genes were retrieved from GeneCards. Cross targets and active phytochemicals of COVID-19 and ALI related genes in F. dibotrys were enriched by gene ontology (GO) and KEGG by metscape bioinformatics tools. The interplay network entre active phytochemicals and anti COVID-19 and ALI targets was established and broke down using Cytoscape software. Discovery Studio (version 2019) was used to perform molecular docking of crux active plant chemicals with anti COVID-19 and ALI targets. We identified 1136 chemicals from the aerial parts of F. dibotrys, among which 47 were active flavonoids and phenolic chemicals. A total of 61 chemicals were searched from the rhizome of F. dibotrys, and 15 of them were active chemicals. So there are 6 commonly key active chemicals at the aerial parts and the rhizome of F. dibotrys, 89 these phytochemicals's potential targets, and 211 COVID-19 and ALI related genes. GO enrichment bespoken that F. dibotrys might be involved in influencing gene targets contained numerous biological processes, for instance, negative regulation of megakaryocyte differentiation, regulation of DNA metabolic process, which could be put down to its anti COVID-19 associated ALI effects. KEGG pathway indicated that viral carcinogenesis, spliceosome, salmonella infection, coronavirus disease - COVID-19, legionellosis and human immunodeficiency virus 1 infection pathway are the primary pathways obsessed in the anti COVID-19 associated ALI effects of F. dibotrys. Molecular docking confirmed that the 6 critical active phytochemicals of F. dibotrys, such as luteolin, (+) -epicatechin, quercetin, isorhamnetin, (+) -catechin, and (-) -catechin gallate, can combine with kernel therapeutic targets NEDD8, SRPK1, DCUN1D1, and PARP1. In vitro activity experiments showed that the total antioxidant capacity of the aerial parts and rhizomes of F. dibotrys increased with the increase of concentration in a certain range. In addition, as a whole, the antioxidant capacity of the aerial part of F. dibotrys was stronger than that of the rhizome. Our research afford cues for farther exploration of the anti COVID-19 associated ALI chemical compositions and mechanisms of F. dibotrys and afford scientific foundation for progressing modern anti COVID-19 associated ALI drugs based on phytochemicals in F. dibotrys. We also fully developed the medicinal value of F. dibotrys' s aerial parts, which can effectively avoid the waste of resources. Meanwhile, our work provides a new strategy for integrating metabonomics, network pharmacology, and molecular docking techniques which was an efficient way for recognizing effective constituents and mechanisms valid to the pharmacologic actions of traditional Chinese medicine.
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Antibody drugs should exhibit not only high-binding affinity for their target antigens but also favorable physicochemical drug-like properties. Such drug-like biophysical properties are essential for the successful development of antibody drug products. The traditional approaches used in antibody drug development require significant experimentation to produce, optimize, and characterize many candidates. Therefore, it is attractive to integrate new methods that can optimize the process of selecting antibodies with both desired target-binding and drug-like biophysical properties. Here, we summarize a selection of techniques that can complement the conventional toolbox used to de-risk antibody drug development. These techniques can be integrated at different stages of the antibody development process to reduce the frequency of physicochemical liabilities in antibody libraries during initial discovery and to co-optimize multiple antibody features during early-stage antibody engineering and affinity maturation. Moreover, we highlight biophysical and computational approaches that can be used to predict physical degradation pathways relevant for long-term storage and in-use stability to reduce the need for extensive experimentation.
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Anticuerpos Monoclonales , Descubrimiento de Drogas , Anticuerpos Monoclonales/química , Descubrimiento de Drogas/métodos , Desarrollo de MedicamentosRESUMEN
Tibetan medicine is traditionally prescribed as crude extracts or mixtures owing to the theoretical basis with cross fertilization from other medical systems like Ayurveda and traditional Chinese medicine. This is challenged to elucidate the action mechanism and material foundation of Tibetan medicine due to lacking a method to confirm the bioactive compounds determining the therapy. This work created a new strategy for screening and evaluating the bioactive compounds against cardiovascular ailments from Choerospondias axillaris. It involved the immobilization of endothelin receptor A (ETAR) by a one-step covalent assay, the screening and identification of the bioactive compounds by ETAR column combined with tandem mass spectrometry, and the evaluation of their drug-like properties by calculating the efficiency indexes using the data collected by frontal analysis and adsorption energy distribution. The immobilized ETAR remained good stability in three weeks in terms of specificity and repeatability. Catechin, pinocembrin, and hyperoside were identified as potential ETAR ligands from Choerospondias axillaris with two types of binding sites on the immobilized receptor. Their association constants on the high and low affinity binding sites were (2.53 ± 0.11) × 105 and (9.94 ± 0.02) × 103 M-1 for catechin, (1.01 ± 0.12) × 106 and (7.40 ± 0.03) × 104 for hyperoside, and (2.05 ± 0.04) × 105 and (2.47 ± 0.09)× 104 M-1 for pinocembrin, respectively. Owing to the highest association constant, hyperoside presented a surface efficiency index of 7.95, and binding efficiency index of 20.7, and the ligand-lipophilicity efficiency of 1.38. These indicated that the three compounds were the main ingredients for the therapy of Choerospondias axillaris, and had potential to become lead compounds for anti-cardiovascular drugs based on drug-ETAR interaction. The immobilized receptor-based strategy is possible to become an alternative for screening and assessing bioactive compounds from Tibetan medicine.
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Catequina , Catequina/química , Receptores de Endotelina , Ligandos , Extractos Vegetales/química , Medicina Tradicional ChinaRESUMEN
In the present work, we synthesized seven complexes. All complexes were identified by ESI-HRMS, 1H-NMR, 19F-NMR and 13C-NMR spectroscopies. The synthesized complexes were tested for their anticancer activities in vitro against three different human cell lines, including breast MDAMB231, cervical Hela, liver HepG2. IC50 values of complexes 1-7 were 34.98-667.35 µM. Complex 5 revealed higher sensitivity towards MDAMB231 cells with IC50 values 34.98 µM in comparison to 5-FU as positive control. Moreover, complex 5 caused a decrease of mitochondrial membrane potential and effectively induced ROS production against MDAMB231 cells. Western blot analysis showed that complex 5 could up-regulate the expression of Bax protein and down-regulate the expression of Bcl-2, activate Caspase-3, slightly down-regulate the expression of HO-1. The docking studies showed that complex 5 could be interacted with Bcl-2 protein through hydrophobic interactions, hydrogen bonds and salt bridges to enhance the binding affinity. All the analyzed coumarins obeyed the Lipinski's rule of five for orally administered drugs. Based on the aforementioned results, it suggests that the complex induced apoptosis cell via mitochondria pathways. Collectively, complex 5 could be considered as a promising hit for new anti-breast cancer agents. Carbonyl cobalt CORMs, as potential anticancer therapeutic agents, provided a new idea for the development of metal anticancer drugs.
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While high lipophilicity tends to improve potency, its effects on pharmacokinetics (PK) are complex and often unfavorable. To predict clinical PK in early drug discovery, we built human physiologically based PK (PBPK) models integrating either (i) machine learning (ML)-predicted properties or (ii) discovery stage in vitro data. Our test set was composed of 12 challenging development compounds with high lipophilicity (mean calculated log P 4.2), low plasma-free fraction (50% of compounds with fu,p < 1%), and low aqueous solubility. Predictions focused on key human PK parameters, including plasma clearance (CL), volume of distribution at steady state (Vss), and oral bioavailability (%F). For predictions of CL, the ML inputs showed acceptable accuracy and slight underprediction bias [an average absolute fold error (AAFE) of 3.55; an average fold error (AFE) of 0.95]. Surprisingly, use of measured data only slightly improved accuracy but introduced an overprediction bias (AAFE = 3.35; AFE = 2.63). Predictions of Vss were more successful, with both ML (AAFE = 2.21; AFE = 0.90) and in vitro (AAFE = 2.24; AFE = 1.72) inputs showing good accuracy and moderate bias. The %F was poorly predicted using ML inputs [average absolute prediction error (AAPE) of 45%], and use of measured data for solubility and permeability improved this to 34%. Sensitivity analysis showed that predictions of CL limited the overall accuracy of human PK predictions, partly due to high nonspecific binding of lipophilic compounds, leading to uncertainty of unbound clearance. For accurate predictions of %F, solubility was the key factor. Despite current limitations, this work encourages further development of ML models and integration of their results within PBPK models to enable human PK prediction at the drug design stage, even before compounds are synthesized. Further evaluation of this approach with more diverse chemical types is warranted.
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Aprendizaje Automático , Modelos Biológicos , Humanos , Estudios de Factibilidad , Disponibilidad Biológica , Solubilidad , Farmacocinética , Preparaciones Farmacéuticas , Simulación por ComputadorRESUMEN
Drug discovery strategies have advanced significantly towards prioritizing target selectivity to achieve the longstanding goal of identifying "magic bullets" amongst thousands of chemical molecules screened for therapeutic efficacy. A myriad of emerging and existing health threats, including the SARS-CoV-2 pandemic, alarming increase in bacterial resistance, and potentially fatal chronic ailments, such as cancer, cardiovascular disease, and neurodegeneration, have incentivized the discovery of novel therapeutics in treatment regimens. The design, development, and optimization of lead compounds represent an arduous and time-consuming process that necessitates the assessment of specific criteria and metrics derived via multidisciplinary approaches incorporating functional, structural, and energetic properties. The present review focuses on specific methodologies and technologies aimed at advancing drug development with particular emphasis on the role of thermodynamics in elucidating the underlying forces governing ligand-target interaction selectivity and specificity. In the pursuit of novel therapeutics, isothermal titration calorimetry (ITC) has been utilized extensively over the past two decades to bolster drug discovery efforts, yielding information-rich thermodynamic binding signatures. A wealth of studies recognizes the need for mining thermodynamic databases to critically examine and evaluate prospective drug candidates on the basis of available metrics. The ultimate power and utility of thermodynamics within drug discovery strategies reside in the characterization and comparison of intrinsic binding signatures that facilitate the elucidation of structural-energetic correlations which assist in lead compound identification and optimization to improve overall therapeutic efficacy.
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Drug discovery based on natural products like medicinal herbs remains challenging due to the technique limitations for rapidly screening and validating leads. To address the challenges, we employ the immobilized ß2- adrenergic recepotor (ß2-AR), an identified target of asthma, as the stationary phase in chromatographic column to screen compounds extracted from Stemonae Radix, Playtycodonis Radix, and Glycyrrhizae Radix et Rhizoma. To analyze binding properties of the extracted compounds to the immobilized receptors, we measured their retention behavior in the receptor chromatography and compared with six clinical asthma drugs. We identified tuberostemonine, platycodin D, and glycyrrhizic acid as the potential leads against asthma by our ß2-AR chromatography coupled with mass spectrum (MS). The association constants of the three compounds to ß2-AR were 2.85 × 10-5, 2.55 × 10-4, and 4.07 × 10-6 M with the dissociation rate constants of 6.91 ± 0.35, 11.88 ± 0.60, and 9.49 ± 0.64 min-1, respectively. Tuberostemonine, a pentacyclic Stemona alkaloids, presented the most optimum values of binding efficiency index (BEI) and surface efficiency index (SEI) as close to the diagonal of SEI-BEI optimization plane when it is compared with platycodin D, glycyrrhizic and the six clinical drugs. Our results suggest that tuberostemonine is a promising natural product to be developed for treating asthma because it exhibits better drug-like binding properties to ß2-AR than the clinical drugs. As such, we demonstrate a chromatographic strategy to identify bioactive natural products based on the ß2-AR immobilization, which can be widely adopted to screen natural products from mixture of herbal extracts.
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Productos Biológicos , Medicamentos Herbarios Chinos , Cromatografía , Descubrimiento de Drogas , Glycyrrhiza , Receptores Adrenérgicos beta 2RESUMEN
A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson's disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.
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CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.
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Antineoplásicos/farmacología , Quinasa 8 Dependiente de Ciclina/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quinasa 8 Dependiente de Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
In order to discover and develop drug-like anti-inflammatory agents against arthritis, based on "Hit" we found earlier and to overcome drawbacks of toxicity, twelve series of total 89 novel pyrimidine, pyrazolo[4,3-d]pyrimidine and thieno[3,2-d]pyrimidine derivatives were designed, synthesized and screened for their anti-inflammatory activity against NO and toxicity for normal liver cells (LO2). Relationships of balance toxicity and activity have been summarized through multi-steps, and title compounds 22o, 22l were found to show lower toxicity (against LO2: IC50 = 2934, 2301 µM, respectively) and potent effect against NO release (IR = 98.3, 97.67%, at 10 µM, respectively). Furthermore, compound 22o showed potent iNOS inhibitory activity with value of IC50 is 0.96 µM and could interfere stability and formation of the active dimeric iNOS. It's anti-inflammatory activity in vivo was assessed by AIA rat model. Furthermore, the results of metabolic stability, CYP, PK study in vivo, acute toxicity study and subacute toxicity assessment indicated this compound had good drug-like properties for treatment.
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Artritis/tratamiento farmacológico , Desarrollo de Medicamentos , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Artritis/metabolismo , Células Cultivadas , Dimerización , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Adyuvante de Freund , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Masculino , Ratones , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/metabolismo , Pirazoles/administración & dosificación , Pirazoles/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
In this study, two series of novel carbon monoxide-releasing molecules (CO-RMs) containing Co were designed and synthesized. The synthesized complexes were characterized by IR, ESI-MS, 1H NMR and 13C NMR spectroscopies. The antitumor activity of all complexes on HepG2 cells, Hela cells and MDA-MB-231 cells were assayed by MTT. IC50 values of complexes 1-13 were 4.7-548.6 µM. Among these complexes, complex 1 was presented with a high selectivity to HepG2 cells (IC50 = 4.7 ± 0.76 µM). Compared with iCORM (inactive CORM), CORM (complex 1) showed a remarkable activity against tumor cells owing to co-effect of CO and the ligand of COX-2 inhibitor. In addition, complex 1 increased ROS in mitochondria and caused a decrease of dose-dependent mitochondrial membrane potential against HepG2 cells. Complex 1 down-regulated the expression of COX-2 protein in western blot analysis. The molecular docking study suggested that the complex 1 formed a hydrogen bond with amino acid R120 in the active site of the Human cyclooxygenase-2 (COX-2). Therefore, the complex 1 could induce apoptosis of HepG2 cells through targeting COX-2 and mitochondria pathways, and it maybe a potential therapeutic agent for cancer.
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Antineoplásicos/síntesis química , Monóxido de Carbono/metabolismo , Complejos de Coordinación/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Especies Reactivas de Oxígeno/metabolismoRESUMEN
This paper describes a comparative analysis of the physicochemical and structural properties of prodrugs and their corresponding drugs with regard to drug-likeness rules. The dataset used in this work was obtained from the DrugBank. Sixty-five pairs of prodrugs/drugs were retrieved and divided into the following categories: carrier-linked to increase hydrophilic character, carrier-linked to increase absorption, and bioprecursors. We compared the physicochemical properties related to drug-likeness between prodrugs and drugs. Our results show that prodrugs do not always follow Lipinski's Rule of 5, especially as we observed 15 prodrugs with more than 10 hydrogen bond acceptors and 18 with a molecular weight greater than 500â Da. This fact highlights the importance of extending Lipinski's rules to encompass other parameters as both strategies (filtering of drug-like chemical libraries and prodrug design) aim to improve the bioavailability of compounds. Therefore, critical reasoning is fundamental to determine whether a structure has drug-like properties or could be considered a potential orally active compound in the drug-design pipeline.
Asunto(s)
Profármacos/química , Administración Oral , Disponibilidad Biológica , Bases de Datos de Compuestos Químicos , Diseño de Fármacos , Enlace de Hidrógeno , Peso Molecular , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Profármacos/metabolismo , Profármacos/farmacocinéticaRESUMEN
To yield potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50 = 0.0021 µM), 1.7-fold (K103N, EC50 = 0.0019 µM), and slightly more potent (E138K, EC50 = 0.0075 µM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50 = 18.52 µM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3 (Fraction of sp3 carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.
Asunto(s)
Fármacos Anti-VIH/síntesis química , VIH-1/efectos de los fármacos , Pirimidinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Fármacos Anti-VIH/farmacología , Sitios de Unión , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Pirimidinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells. Compounds targeting this pathway are under active development as anticancer therapeutics and some of them have reached advanced clinical trials or been approved by the FDA. Dual PI3K/mTOR inhibitors combine multiple therapeutic efficacies in a single molecule by inhibiting the pathway both upstream and downstream of AKT. Herein, we report our efforts on the exploration of novel small molecule macrocycles (MCXs) as dual PI3K/mTOR inhibitors. Macrocyclization is an attractive approach used in drug discovery, as the semi-rigid character of these structures could provide improved potency, selectivity and favorable pharmacokinetic properties. Importantly, this strategy allows access to new chemical space thus obtaining a better intellectual property position. A series of MCXs based on GSK-2126458, a known clinical PI3K/mTOR inhibitor is described. These molecules showed potent biochemical and cellular dual PI3K/mTOR inhibition, demonstrated strong antitumoral effects in human cancer cell lines, and displayed good drug-like properties. Among them, MCX 83 presented remarkable selectivity against a panel of 468 kinases, high in vitro metabolic stability, and favorable pharmacokinetic parameters without significant CYP450 and h-ERG binding inhibition. This profile qualified this compound as a suitable candidate for future in vivo PK-PD and efficacy studies in mouse cancer models.