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2.
Bioorg Med Chem Lett ; 76: 129020, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36216031

RESUMO

In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4-d]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC50 = 0.59 µM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers.


Assuntos
Antineoplásicos , Apoptose , Pirimidinas , Humanos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Poli(ADP-Ribose) Polimerases/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral
3.
Bioorg Med Chem Lett ; 76: 128972, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36265914

RESUMO

Herein, we present the synthesis of several fluorinated pomalidomide derivatives and their thionated counterparts with subsequent biological evaluation against classical markers of cellular inflammation. Treatment in LPS-challenged cells effected varying reductions in levels of secreted TNF-α and nitrite relative to basal amounts. While arene fluorination and thioamidation had marginal and sporadic effects on TNF-α production, specific 7-position fluorination combined with subsequent increases in carbonyl thionation produced compounds 11, 14, and 15 which demonstrated corresponding and escalating anti-nitrite activities concurrent with minimal cellular toxicity. In this regard, compound 15 displayed roughly 96 % cell viability combined with a 65 % drop in nitrite production when supplied to RAW cells challenged with 60 ng/mL LPS. When a focused family of fluorinated isomers were directly compared, the analogous 5-fluorinated isomer 17 displayed comparable minimal toxicity but markedly less anti-nitrite activity versus 15 in RAW cells challenged with 70 ng/mL LPS. Compound 15 was subsequently screened in human liver microsomes for preliminary Phase 1 analysis where it demonstrated heightened stability relative to its non-fluorinated counterpart 3,6'-dithiopomalidomide 4, a result in line with the expected metabolic fortitude provided by fluorination at the sensitive pomalidomide 7-position.


Assuntos
Inflamação , Talidomida , Fator de Necrose Tumoral alfa , Animais , Humanos , Camundongos , Biomarcadores/metabolismo , Inflamação/tratamento farmacológico , Lipopolissacarídeos , Nitritos/antagonistas & inibidores , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo , Talidomida/análogos & derivados , Talidomida/síntese química , Talidomida/farmacologia , Talidomida/uso terapêutico
4.
Langmuir ; 38(41): 12602-12609, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36194518

RESUMO

Droplet fusion technology is a key technology for many droplet-based biochemical medical applications. By integrating a symmetrical flow channel structure, we demonstrate an acoustics-controlled fusion method of microdroplets using surface acoustic waves. Different kinds of microdroplets can be staggered and ordered in the symmetrical flow channel, proving the good arrangement effect of the microfluidic chip. This method can realize not only the effective fusion of microbubbles but also the effective fusion of microdroplets of different sizes without any modification. Further, we investigate the influence of the input frequency and peak-to-peak value of the driving voltage on microdroplets fusion, giving the effective fusion parameter conditions of microdroplets. Finally, this method is successfully used in the preparation of hydrogel microspheres, offering a new platform for the synthesis of hydrogel microspheres.


Assuntos
Acústica , Hidrogéis , Microbolhas , Microesferas , Hidrogéis/síntese química , Hidrogéis/química , Microfluídica
5.
Bioorg Med Chem Lett ; 76: 129018, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36209967

RESUMO

With the target to develop small molecules based anti-diabetic agents, we, herein, report the design, synthesis and biological studies on Lys-Pro and Gly-Pro esters, and a Phe-Pro-Phe tripeptide inhibiting the activity of glycoprotein dipeptidyl peptidase-4 (DPP-4). Since DPP-4 cleaves the glucagon like peptide (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) hormones which are responsible for inducing insulin secretion, the results of present studies could be significant in making control over glycemia. The structural analysis of DPP-4 and its binding mode with the substrate as well as the reported inhibitors provided the background for the design of new molecules. Among the 17 compounds screened against DPP-4, 14 compounds displayed IC50 better than the known drug Sitagliptin. Collectively, a highly encouraging set of molecules was identified that may prove as the clinical candidates for the treatment of diabetes.


Assuntos
Inibidores da Dipeptidil Peptidase IV , Desenho de Fármacos , Hipoglicemiantes , Oligopeptídeos , Glicemia/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Prolina/química , Fosfato de Sitagliptina/química , Fosfato de Sitagliptina/farmacologia , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologia
6.
Bioorg Chem ; 129: 106192, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36265355

RESUMO

Capsid assembly modulators (CAMs) represent a novel class of antiviral agents targeting hepatitis B virus (HBV) capsid to disrupt the assembly process. NVR 3-778 is the first CAM to demonstrate antiviral activity in patients infected with HBV. However, the relatively low aqueous solubility and moderate activity in the human body halted further development of NVR 3-778. To improve the anti-HBV activity and the drug-like properties of NVR 3-778, we designed and synthesized a series of NVR 3-778 derivatives. Notably, phenylboronic acid-bearing compound 7b (EC50 = 0.83 ± 0.33 µM, CC50 = 19.4 ± 5.0 µM) displayed comparable anti-HBV activity to NVR 3-778 (EC50 = 0.73 ± 0.20 µM, CC50 = 23.4 ± 7.0 µM). Besides, 7b showed improved water solubility (328.8 µg/mL, pH 7) compared to NVR 3-778 (35.8 µg/mL, pH 7). Size exclusion chromatography (SEC) and quantification of encapsidated viral RNA were used to demonstrate that 7b behaves as a class II CAM similar to NVR 3-778. Moreover, molecular dynamics (MD) simulations were conducted to rationalize the structure-activity relationships (SARs) of these novel derivatives and to understand their key interactions with the binding pocket, which provide useful indications for guiding the further rational design of more effective anti-HBV drugs.


Assuntos
Antivirais , Benzamidas , Capsídeo , Desenho de Fármacos , Vírus da Hepatite B , Montagem de Vírus , Humanos , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacologia , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Montagem de Vírus/efeitos dos fármacos
7.
Bioorg Chem ; 129: 106151, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36220004

RESUMO

A multi-FRET three-fluorophore probe containing coumarin, fluorescein and rhodamine B with two enzymatically cleavable linkers has been synthesized and optimized for the simultaneous activity detection and relative quantification of two proteases - caspase-8 and caspase-9. The probe designed as a ratiometric single-excitation triple-emission system shows specific change in fluorescence intensities upon enzymatic cleavage of individual linkers in model mixtures as well as in a cell lysate. The activation of caspase-8 and caspase-9 is responsible for initiation of extrinsic or intrinsic apoptotic pathway, respectively, and the probe was proposed as a single chemical tool which could help to decipher a mechanism of cell death induced by various stimuli. The main advantage of this probe is the simplicity of its preparation using conventional organic synthesis, easy application for measurement and evaluation of the results.


Assuntos
Caspase 8 , Caspase 9 , Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes , Apoptose , Caspase 8/análise , Caspase 8/metabolismo , Caspase 9/análise , Caspase 9/metabolismo , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Ativação Enzimática
8.
Bioorg Chem ; 129: 106179, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36244322

RESUMO

A series of novel pyranocarbazole alkaloids were designed and synthesized as derivatives of Claulansine F and CZ-7. Some of the compounds showed strong neuroprotective effects and anti-lipid peroxidation capacity. Among these compounds, 10b, introduced leucine at the C-3 position of pyranocarbazole, was the most active in inhibiting the programmed death of SH-SY5Y cells. This compound exhibited stronger free radical scavenging activity than Edaravone. Furthermore, 10b could penetrate the blood-brain barrier (BBB). More importantly, 10b showed a tendency of improvement in learning and memory in the dose range of 10-40 mg/kg. The research on mechanisms indicated that 10b could reduce oxidative stress in the brain of Aß25-35-intoxicated mice, and then improve the cognitive function of Aß25-35-intoxicated mice. Our findings suggest that 10b may be promising for further evaluation as an intervention for Alzheimer's Disease.


Assuntos
Doença de Alzheimer , Antioxidantes , Cognição , Desenho de Fármacos , Fármacos Neuroprotetores , Animais , Humanos , Camundongos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Cognição/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Linhagem Celular Tumoral , Estresse Oxidativo/efeitos dos fármacos
9.
Steroids ; 188: 109119, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36202314

RESUMO

Here, we report a synthetic approach to hetero-steroids and also studied their biological activities as anticancer agents. A novel class of oxacycles containing estrone moiety were synthesized in this report. Allyl ether derived from estrone underwent Claisen rearrangement (CR) and again O-allylation and subsequent ring-closure gave A-ring-furan and oxepine fused derivatives in high yields. We used double bond isomerization and ring-closing metathesis (RCM) as key steps to assemble hetero steroids containing a mixture of regio isomers like benzofurans and benzoxepine moieties. The novel benzofuran and benzoxepine-based hybrid steroid derivatives were subjected to in vitro cytotoxicity analysis and were found to exert cancer cell-specific activity.


Assuntos
Antineoplásicos , Estrona , Estrona/química , Estrona/farmacologia , Oxepinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia
10.
Science ; 378(6618): 405-412, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36302022

RESUMO

To synthesize a chirally inverted ribosome with the goal of building mirror-image biology systems requires the preparation of kilobase-long mirror-image ribosomal RNAs that make up the structural and catalytic core and about two-thirds of the molecular mass of the mirror-image ribosome. Here, we chemically synthesized a 100-kilodalton mirror-image T7 RNA polymerase, which enabled efficient and faithful transcription of the full-length mirror-image 5S, 16S, and 23S ribosomal RNAs from enzymatically assembled long mirror-image genes. We further exploited the versatile mirror-image T7 transcription system for practical applications such as biostable mirror-image riboswitch sensor, long-term storage of unprotected kilobase-long l-RNA in water, and l-ribozyme-catalyzed l-RNA polymerization to serve as a model system for basic RNA research.


Assuntos
DNA Polimerase Dirigida por DNA , RNA Catalítico , RNA Ribossômico 23S , RNA Ribossômico 5S , Ribossomos , Transcrição Genética , Proteínas Virais , Conformação de Ácido Nucleico , RNA Catalítico/genética , RNA Ribossômico 23S/biossíntese , RNA Ribossômico 23S/química , RNA Ribossômico 23S/genética , RNA Ribossômico 5S/biossíntese , RNA Ribossômico 5S/genética , DNA Polimerase Dirigida por DNA/síntese química , DNA Polimerase Dirigida por DNA/química , Proteínas Virais/síntese química , Proteínas Virais/química , RNA Ribossômico 16S/biossíntese , RNA Ribossômico 16S/genética
11.
Science ; 378(6618): 345-346, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36302030
12.
Org Lett ; 24(41): 7600-7604, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36223230

RESUMO

Exploration of an ambitious new strategy for the total synthesis of the cytotoxic marine natural product amphidinolide F is described, which features fabrication of the core structure from four readily accessible fragments and macrocycle construction through C9-C10 bond formation by intramolecular Stille coupling between an alkenyl iodide and alkenyl stannane. Efficient stereoselective synthesis of each of the four building-blocks and subsequent coupling of them to produce the requisite cyclization precursor has been accomplished, but suitable conditions for high-yielding palladium-mediated closure of the macrocycle to produce the fully protected amphidinolide F ring system have yet to be identified.


Assuntos
Produtos Biológicos , Macrolídeos , Paládio , Produtos Biológicos/síntese química , Iodetos , Macrolídeos/síntese química , Estrutura Molecular , Estereoisomerismo
13.
Eur J Med Chem ; 244: 114823, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36274278

RESUMO

In order to search for innovative nootropic agents, new 1-benzyl-4- (4- (R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrrolidine-2-ones was synthesized by reacting benzylamine with itaconic acid to 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, which was then subjected to hydrazinolysis followed by the addition of substituted isothiacyanate followed by cyclization of intermediate thiosemicarbazides. The structure and purity of the obtained substances were confirmed by elemental analysis, 1H NMR spectroscopy, 13C NMR spectroscopy and LC/MS. Docking studies were performed for the substances synthesized using Autodock 4.2 software. Approximate values of LD50 (in silico determination) are around 870-1000 mg/kg. All synthesized substances were tested for nootropic activity by the passive avoidance test on the scopolamine amnesia model in doses that are about 1/10 of the estimated LD50. Based on the results of docking and pharmacological experiment, the most promising substances 7a, as well as 7e, 7f were identified. The results of molecular docking (hit compound 7a) indicate a positive correlation between the obtained values of docking studies and experimental data.


Assuntos
Nootrópicos , Pirrolidinonas , Cromatografia Líquida , Espectroscopia de Ressonância Magnética , Espectrometria de Massas/métodos , Simulação de Acoplamento Molecular , Nootrópicos/síntese química , Nootrópicos/química , Nootrópicos/farmacologia , Relação Estrutura-Atividade , Pirrolidinonas/síntese química , Pirrolidinonas/química , Pirrolidinonas/farmacologia
14.
Bioorg Chem ; 129: 106207, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36270170

RESUMO

A new series of pyrazolo[3,4-d]pyrimidine analogues bearing different amino acid conjugates 10a-m were synthesized with the aim to evaluate their antitumor effect through simultaneous inhibition of human dihydrofolate reductase (hDHFR). All novel compounds were tested to screen their enzyme inhibition activity against (hDHFR) beside their in vitro cytotoxicity against six human MTX resistant cancer cell lines namely, human prostate cancer (PC-3), pancreatic human cancer cell lines (BxPC-3), colorectal carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), cervical carcinoma (HeLa), and mammary gland breast cancer (MCF-7), besides normal immortalized pancreatic cell line (HPDE). Compounds 10e, 10f, 10g inhibited DHFR at considerable low (IC50 < 1 µM) in comparison to MTX (IC50 = 5.61 µM) beside their characteristic cytotoxic effects on different resistant cancer cell lines. Flow cytometry was done for the most active candidate compound 10e against MCF-7 breast cancer cell line. The results illustrated that compound 10e induced apoptosis and arrested MCF-7 cell cycle in the G1/S phase. Western blot for visualization and quantification was used to confirm the capability of compound 10e to induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to reduce the expression of antiapoptotic Bcl-2 protein. Molecular modeling studies demonstrated that compound 10e elucidated binding energy of (S= - 8.4390 Kcal/mol) that exceed that of the normal ligand MTX (S= - 8.3951Kcal/mol) in addition to several favorable binding interactions with the active site residues.


Assuntos
Antineoplásicos , Antagonistas do Ácido Fólico , Pirazóis , Pirimidinas , Tetra-Hidrofolato Desidrogenase , Feminino , Humanos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacologia , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia
15.
Bioorg Chem ; 129: 106202, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36272252

RESUMO

Efforts have been devoted for the discovery and development of positive allosteric modulators (PAMs) of 5-HT2CR because of their potential advantages over the orthosteric agonist like Lorcaserin that was withdrawn from the market. On the other hand, pursuing a positive ago-allosteric modulator (PAAM) is considered as beneficial particularly when an agonist is not capable of affecting the potency of the endogenous agonist sufficiently. In search of a suitable PAAM of 5-HT2CR we adopted an in silico based approach that indicated the potential of the 3-(1-hydroxycycloalkyl) substituted isoquinolin-1-one derivatives against the 5-HT2CR as majority of these molecules interacted with the site other than that of Lorcaserin with superior docking scores. These compounds along with the regioisomeric 3-methyleneisoindolin-1-one derivatives were prepared via the Cu(OAc)2 catalyzed coupling of 2-iodobenzamide with 1-ethynylcycloalkanol under ultrasound irradiation. According to the in vitro studies, most of these compounds were not only found to be potent and selective agonists but also emerged as PAAM of 5-HT2CR whereas Lorcaserin did not show PAAM activities. According to the SAR study the isoquinolin-1(2H)-ones appeared as better PAAM than isoindolin-1-ones whereas the presence of hydroxyl group appeared to be crucial for the activity. With the potent PAAM activity for 5-HT2CR (EC50 = 1 nM) and 107 and 86-fold selectivity towards 5-HT2C over 5-HT2A and 5-HT2B the compound 4i was identified as a hit molecule. The compound showed good stability in male BALB/c mice brain homogenate (∼85 % remaining after 2 h), moderate stability in the presence of rat liver microsomes (42 % remaining after 1 h) and acceptable PK properties with fast reaching in the brain maintaining âˆ¼ 1:1 brain/plasma concentration ratio. The compound at a dose of 50 mg/kg exhibited decreased trend in the food intake starting from day 3 in S.D. rats, which reached significant by 5th day, and the effect was comparable to Lorcaserin (10 mg/kg) on day 5. Thus, being the first example of PAAM of 5-HT2CR the compound 4i is of further medicinal interest.


Assuntos
Indóis , Isoquinolinas , Agonistas do Receptor 5-HT2 de Serotonina , Animais , Masculino , Camundongos , Ratos , Encéfalo , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Camundongos Endogâmicos BALB C , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacologia , Indóis/síntese química , Indóis/química , Indóis/farmacologia
16.
Bioorg Chem ; 129: 106195, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36274386

RESUMO

The importance of the quinoxaline framework is exemplified by its presence in the well-known drugs such as varenicline, brimonidine, quinacillin, etc. In the past few years, preparation of a variety of organic compounds containing the quinoxaline framework has been reported by several research groups. The chloroquinoxalines were successfully used as substrates in many of these synthetic approaches due to their easy availability along with the reactivity especially towards a diverse range of metal and transition metal-catalyzed transformations including Sonogashira, Suzuki, Heck type of cross-coupling reactions. The transition metals e.g., Pd, Cu, Fe and Nb catalysts played a key role in these transformations for the construction of various CX (e.g., CC, CN, CO, CS, CP, CSe, etc) bonds. These approaches can be classified based on the catalyst employed, type of the reaction performed and nature of CX bond formation during the reaction. Several of these resultant quinoxaline derivatives have shown diverse biological activities which include apoptosis inducing activities, SIRT1 inhibition, inhibition of luciferace enzyme, antibacterial and antifungal activities, cytotoxicity towards cancer cells, inhibition of PDE4 (phosphodiesterase 4), potential uses against COVID-19, etc. Notably, a review article covering the literature based on transition metal-catalyzed reactions of chloroquinoxalines at the same time summarizing the relevant biological activities of resultant products is rather uncommon. Therefore, an attempt is made in the current review article to summarize (i) the recent advances noted in the transition metal-catalyzed reactions of chloroquinoxalines (ii) with the relevant mechanistic discussions (iii) along with the in vitro, and in silico biological studies (wherever reported) (iv) including Structure-Activity Relationship (SAR) within the particular series of the products reported between 2010 and 2022.


Assuntos
Preparações Farmacêuticas , Quinoxalinas , Elementos de Transição , Humanos , Catálise , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/farmacologia , Elementos de Transição/síntese química , Elementos de Transição/farmacologia , Relação Estrutura-Atividade , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
17.
Assay Drug Dev Technol ; 20(7): 317-337, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36269231

RESUMO

One of the most sought-after therapeutic targets for treating human cancers is the phosphoinositide 3-kinase; PI3k is an integral part of the PI3K/protein kinase B signaling arcade. This pathway is frequently activated in malignancies. Drug resistance and dose-limiting adverse effects are currently associated challenges with the existing anticancer chemotherapy. Therefore, in this research, a series of pyrimidine derivatives were designed and evaluated against human PI3K by using molecular docking analysis. The docking results were further verified by molecular dynamic simulation, which analyzed the strength of the macromolecular complex with respect to time. Compounds IV and XIV were found to be the most potent inhibitors of the human PI3K receptor with a high degree of stability within the active site of the target receptor for a timeframe of 50 ns. Thus, both of these compounds could be important drug candidates for the development of PI3K inhibitors as a prospective anticancer agent.


Assuntos
Antineoplásicos , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt , Pirimidinas/química , Pirimidinas/farmacologia
18.
Food Chem Toxicol ; 169: 113443, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36167259

RESUMO

Application of essential oils to mitigate aflatoxin B1 (AFB1) contamination in food is a current research hotspot; however, their direct incorporation may cause toxic effects, and changes in food organoleptic properties. This work aimed to synthesize novel synergistic formulation of Pinus roxburghii, Juniperus communis, and Cupressus sempervirens essential oils by mixture design assay (PJC) and encapsulation of PJC formulation into chitosan nanocomposite (Nm-PJC) with an aim to protect stored rice (Oryza sativa L., prime staple food) against fungi and AFB1 mediated loss of valuable minerals, macronutrients, and fatty acids. Nm-PJC was characterized through DLS, SEM, FTIR, and XRD analyses, along with controlled delivery from chitosan nanobiopolymer. Encapsulation of synergistic formulation into chitosan-nanomatrix improved antifungal (4.0 µL/mL), antiaflatoxigenic (3.5 µL/mL), and antioxidant activities (P < 0.05). Impairment in ergosterol and methylglyoxal biosynthesis along with in-silico-homology-modeling of major components with Ver-1 and Omt-A proteins advocated chemico-molecular interaction responsible for fungal growth inhibition and AFB1 secretion. In addition, in-situ efficacy against lipid-peroxidation, fatty acid biodeterioration, and preservation of minerals, macronutrients without affecting organoleptic attributes in rice and high mammalian safety profile (9874.23 µL/kg) suggested practical application of synergistic nanoformulation as innovative smart, and green candidate to mitigate AFB1 contamination, and shelf-life extension of stored food products.


Assuntos
Aflatoxina B1 , Quitosana , Contaminação de Alimentos , Armazenamento de Alimentos , Fungos , Óleos Voláteis , Oryza , Animais , Aflatoxina B1/química , Aflatoxina B1/toxicidade , Antifúngicos/farmacologia , Antioxidantes/farmacologia , Quitosana/farmacologia , Ergosterol/farmacologia , Ácidos Graxos/metabolismo , Óleos Voláteis/síntese química , Óleos Voláteis/química , Oryza/microbiologia , Oryza/toxicidade , Aldeído Pirúvico/farmacologia , Contaminação de Alimentos/prevenção & controle , Armazenamento de Alimentos/métodos
19.
Nature ; 610(7933): 680-686, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36049504

RESUMO

Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products1-3. A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized4-8. We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized9. Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset10,11. Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set.


Assuntos
Produtos Biológicos , Técnicas de Química Sintética , Preparações Farmacêuticas , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química , Estereoisomerismo , Especificidade por Substrato , Cromatografia com Fluido Supercrítico , Espectrometria de Massas , Técnicas de Química Sintética/métodos
20.
Science ; 377(6614): 1561-1566, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36173865

RESUMO

The conversion of polyolefins to monomers would create a valuable carbon feedstock from the largest fraction of waste plastic. However, breakdown of the main chains in these polymers requires the cleavage of carbon-carbon bonds that tend to resist selective chemical transformations. Here, we report the production of propylene by partial dehydrogenation of polyethylene and tandem isomerizing ethenolysis of the desaturated chain. Dehydrogenation of high-density polyethylene with either an iridium-pincer complex or platinum/zinc supported on silica as catalysts yielded dehydrogenated material containing up to 3.2% internal olefins; the combination of a second-generation Hoveyda-Grubbs metathesis catalyst and [PdP(tBu)3(µ-Br)]2 as an isomerization catalyst selectively degraded this unsaturated polymer to propylene in yields exceeding 80%. These results show promise for the application of mild catalysis to deconstruct otherwise stable polyolefins.


Assuntos
Alcenos , Etilenos , Polietileno , Gerenciamento de Resíduos , Alcenos/síntese química , Carbono/química , Catálise , Etilenos/química , Irídio , Platina , Polienos , Polietileno/química , Dióxido de Silício , Gerenciamento de Resíduos/métodos
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