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1.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206076

RESUMO

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Pirróis/síntese química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia
2.
Molecules ; 26(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200763

RESUMO

The development of new antimicrobial strategies that act more efficiently than traditional antibiotics is becoming a necessity to combat multidrug-resistant pathogens. Here we report the efficacy of laser-light-irradiated 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin (mTHPP) loaded onto an ethylcellulose (EC)/chitosan (Chs) nanocomposite in eradicating multi-drug resistant Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans. Surface loading of the ethylcelllose/chitosan composite with mTHPP was carried out and the resulting nanocomposite was fully characterized. The results indicate that the prepared nanocomposite incorporates mTHPP inside, and that the composite acquired an overall positive charge. The incorporation of mTHPP into the nanocomposite enhanced the photo- and thermal stability. Different laser wavelengths (458; 476; 488; 515; 635 nm), powers (5-70 mW), and exposure times (15-45 min) were investigated in the antimicrobial photodynamic therapy (aPDT) experiments, with the best inhibition observed using 635 nm with the mTHPP EC/Chs nanocomposite for C. albicans (59 ± 0.21%), P. aeruginosa (71.7 ± 1.72%), and S. aureus (74.2 ± 1.26%) with illumination of only 15 min. Utilization of higher doses (70 mW) for longer periods achieved more eradication of microbial growth.


Assuntos
Antibacterianos/química , Celulose/análogos & derivados , Quitosana/química , Nanocompostos/química , Porfirinas/química , Piridonas/química , Pirróis/química , Animais , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular , Celulose/química , Chlorocebus aethiops , Lasers , Luz , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Células Vero
3.
Aging (Albany NY) ; 13(12): 16425-16444, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34156352

RESUMO

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.


Assuntos
Biologia Computacional , Simulação de Acoplamento Molecular , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sítios de Ligação , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ligantes , Osteossarcoma/genética , Osteossarcoma/patologia , Mapas de Interação de Proteínas/genética , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida
4.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070488

RESUMO

The electronic nature of 4-hydroxy-1H-pyrrolo[3,4-c]pyridine-1,3,6(2H,5H)-trione (HPPT) was comprehensively investigated in liquid media at room temperature using steady-state and time-resolved femtosecond transient absorption spectroscopic techniques. The analysis of the linear photophysical and photochemical parameters of HPPT, including steady-state absorption, fluorescence and excitation anisotropy spectra, along with the lifetimes of fluorescence emission and photodecomposition quantum yields, revealed the nature of its large Stokes shift, specific changes in the permanent dipole moments under electronic excitation, weak dipole transitions with partially anisotropic character, and high photostability. Transient absorption spectra of HPPT were obtained with femtosecond resolution and no characteristic solvate relaxation processes in protic (methanol) solvent were revealed. Efficient light amplification (gain) was observed in the fluorescence spectral range of HPPT, but no super-luminescence and lasing phenomena were detected. The electronic structure of HPPT was also analyzed with quantum-chemical calculations using a DFT/B3LYP method and good agreement with experimental data was shown. The development and investigation of new pyrrolo[3,4-c]pyridine derivatives are important due to their promising fluorescent properties and potential for use in physiological applications.


Assuntos
Elétrons , Corantes Fluorescentes/química , Piridinas/química , Pirróis/química , Análise Espectral , Química Computacional , Fluorescência , Corantes Fluorescentes/síntese química , Estrutura Molecular , Teoria Quântica , Solventes/química
5.
Biosensors (Basel) ; 11(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072661

RESUMO

This work reports the design of a novel plastic antibody for cystatin C (Cys-C), an acute kidney injury biomarker, and its application in point-of-care (PoC) testing. The synthetic antibody was obtained by tailoring a molecularly imprinted polymer (MIP) on a carbon screen-printed electrode (SPE). The MIP was obtained by electropolymerizing pyrrole (Py) with carboxylated Py (Py-COOH) in the presence of Cys-C and multiwall carbon nanotubes (MWCNTs). Cys-C was removed from the molecularly imprinted poly(Py) matrix (MPPy) by urea treatment. As a control, a non-imprinted poly(Py) matrix (NPPy) was obtained by the same procedure, but without Cys-C. The assembly of the MIP material was evaluated in situ by Raman spectroscopy and the binding ability of Cys-C was evaluated by the cyclic voltammetry (CV) and differential pulse voltammetry (DPV) electrochemical techniques. The MIP sensor responses were measured by the DPV anodic peaks obtained in the presence of ferro/ferricyanide. The peak currents decreased linearly from 0.5 to 20.0 ng/mL of Cys-C at each 20 min successive incubation and a limit of detection below 0.5 ng/mL was obtained at pH 6.0. The MPPy/SPE was used to analyze Cys-C in spiked serum samples, showing recoveries <3%. This device showed promising features in terms of simplicity, cost and sensitivity for acute kidney injury diagnosis at the point of care.


Assuntos
Técnicas Biossensoriais , Cistatina C/análise , Nanotubos de Carbono/química , Polímeros/química , Pirróis/química , Espectroscopia Dielétrica , Técnicas Eletroquímicas , Eletrodos , Humanos , Limite de Detecção , Impressão Molecular , Plásticos
6.
J Ind Microbiol Biotechnol ; 48(3-4)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33982054

RESUMO

The ammosamides (AMMs) are a family of pyrroloquinoline alkaloids that exhibits a wide variety of bioactivities. A biosynthetic gene cluster (BGC) that is highly homologous in both gene content and genetic organization to the amm BGC was identified by mining the Streptomyces uncialis DCA2648 genome, leading to the discovery of a sub-family of new AMM congeners, named ammosesters (AMEs). The AMEs feature a C-4a methyl ester, differing from the C-4a amide functional group characteristic to AMMs, and exhibit modest cytotoxicity against a broad spectrum of human cancer cell lines, expanding the structure-activity relationship for the pyrroloquinoline family of natural products. Comparative analysis of the ame and amm BGCs supports the use of a scaffold peptide as an emerging paradigm for the biosynthesis of the pyrroloquinoline family of natural products. AME and AMM biosynthesis diverges from a common intermediate by evolving the pathway-specific Ame24 O-methyltransferase and Amm20 amide synthetase, respectively. These findings will surely inspire future efforts to mimic Nature's combinatorial biosynthetic strategies for natural product structural diversity.


Assuntos
Genoma Bacteriano , Pirróis/metabolismo , Quinolinas/metabolismo , Streptomyces/metabolismo , Amidas/química , Amidas/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Humanos , Família Multigênica , Pirróis/química , Quinolinas/química , Streptomyces/química , Streptomyces/genética
7.
J Med Chem ; 64(9): 6021-6036, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33949196

RESUMO

In recent years, PD-1 immune checkpoint inhibitors based on monoclonal antibodies have revolutionized cancer therapy, but there still exist unresolved issues, such as the high cost, the relatively low response rates, and so on, compared with small-molecule drugs. Herein a type of pyrrole-imidazole (Py-Im) polyamide as a small-molecule DNA binder was designed and synthesized, which could competitively bind to the same double-stranded DNA stretch in the PD-L1 promoter region as the STAT3 binding site and thus downregulate PD-L1 expression. It was demonstrated that the Py-Im polyamides directly caused apoptosis in tumor cells and retarded cell migration in the absence of T cells through inhibiting the Akt/caspase-3 pathway. Also, in a coculture system, they enhanced the T-cell-mediated killing of tumor cells by the reversal of immune escape. Because such polyamides induced antitumor effects via both immune and nonimmune pathways, they could be further developed as promising PD-L1 gene-targeting antitumor drugs.


Assuntos
Antígeno B7-H1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Desenho de Fármacos , Imidazóis/química , Nylons/química , Nylons/farmacologia , Pirróis/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/imunologia , Humanos , Imunidade/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
8.
J Med Chem ; 64(10): 6985-6995, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33942608

RESUMO

Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/química , Pirróis/química , Administração Oral , Animais , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Pirróis/metabolismo , Pirróis/uso terapêutico , Relação Estrutura-Atividade , Transplante Heterólogo
9.
J Chromatogr A ; 1648: 462192, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33984649

RESUMO

Determination of folic acid and riboflavin in biological samples is difficult due to their high polarity, low concentration, chemical instability, and complex matrix. In this study, the polypyrrole-coated magnetic nanocomposite (Fe3O4@PPy) was synthesized innovatively with the assistance of hexadecyltrimethylammonium bromide. To evaluate the adsorption mechanism and the feasibility of synthesized Fe3O4@PPy as an adsorbent, the adsorption capacities, kinetics and thermodynamics of folic acid and riboflavin were investigated systemically. Furthermore, in light of the chemical instability of folic acid and riboflavin a method for rapid extraction and detection of them from human urine within 10 min was developed successfully by combining magnetic solid phase extraction with ultra-performance liquid chromatography (MSPE/UPLC). The adsorption parameters including sorbent amount, pH value, extraction time, desorption solvent and desorption time were studied. Under optimum conditions, the performance of the established determination method was validated with the linearly dependent coefficients (>0.9995), the limits of detection (0.02-0.05 µg/mL), the limits of quantification (0.07-0.18 µg/mL), and the recoveries (92.2-105.1%, with relative standard deviation < 3.3%). The rapid extraction and detection of folic acid and riboflavin from real urine samples were achieved subsequently. The present study suggests that the developed method exhibits a promising application in the analysis of free folic acid and riboflavin in human urine samples, which can provide a reference for the clinical drug monitoring and treatment.


Assuntos
Cromatografia Líquida/métodos , Ácido Fólico/urina , Magnetismo/métodos , Polímeros/química , Pirróis/química , Riboflavina/urina , Extração em Fase Sólida/métodos , Adsorção , Humanos , Limite de Detecção , Nanocompostos/química , Solventes/química
10.
Molecules ; 26(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947062

RESUMO

1-Pyrrolines are important intermediates of active natural products, such as the 2,5-dialkyl-1-pyrroline derivatives found in fire ant venoms. Here, 5-hexyl-2-methyl-3,4-dihydro-2H-pyrrole was synthesized by the enzymatic transamination/cyclization of 2,5-undecadione, and enantiodifferenciation was successfully achieved by capillary electrophoresis with sulfobutyl ether-ß-cyclodextrin as the chiral selector. The rationale of the enantiomeric discrimination was based on the results of a docking simulation that revealed the higher affinity of (S)-5-hexyl-2-methyl-3,4-dihydro-2H-pyrrole for the sulfobutyl ether-ß-cyclodextrin.


Assuntos
Pirróis/química , beta-Ciclodextrinas/química , Técnicas de Química Sintética , Ciclodextrinas/química , Eletroforese Capilar , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirróis/análise , Pirróis/síntese química , beta-Ciclodextrinas/análise
11.
Int J Nanomedicine ; 16: 3105-3119, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967577

RESUMO

Background: Photothermal therapy (PTT) has attracted considerable attention for cancer treatment as it is highly controllable and minimally invasive. Various multifunctional nanosystems have been fabricated in an "all-in-one" form to guide and enhance PTT by integrating imaging and therapeutic functions. However, the complex fabrication of nanosystems and their high cost limit its clinical translation. Materials and Methods: Herein, a high efficient "one-for-all" nanodroplet with a simple composition but owning multiple capabilities was developed to achieve ultrasound (US) imaging-guided and cavitation-enhanced PTT. Perfluoropentane (PFP) nanodroplet with a polypyrrole (PPy) shell (PFP@PPy nanodroplet) was synthesized via ultrasonic emulsification and in situ oxidative polymerization. After characterization of the morphology, its photothermal effect, phase transition performance, as well as its capabilities of enhancing US imaging and acoustic cavitation were examined. Moreover, the antitumor efficacy of the combined therapy with PTT and acoustic cavitation via the PFP@PPy nanodroplets was studied both in vitro and in vivo. Results: The nanodroplets exhibited good stability, high biocompatibility, broad optical absorption over the visible and near-infrared (NIR) range, excellent photothermal conversion with an efficiency of 60.1% and activatable liquid-gas phase transition performance. Upon NIR laser and US irradiation, the phase transition of PFP cores into microbubbles significantly enhanced US imaging and acoustic cavitation both in vitro and in vivo. More importantly, the acoustic cavitation enhanced significantly the antitumor efficacy of PTT as compared to PTT alone thanks to the cavitation-mediated cell destruction, which demonstrated a substantial increase in cell detachment, 81.1% cell death in vitro and 99.5% tumor inhibition in vivo. Conclusion: The PFP@PPy nanodroplet as a "one-for-all" theranostic agent achieved highly efficient US imaging-guided and cavitation-enhanced cancer therapy, and has considerable potential to provide cancer theranostics in the future.


Assuntos
Meios de Contraste/química , Nanoestruturas/química , Neoplasias Experimentais/diagnóstico por imagem , Terapia Fototérmica/métodos , Ultrassonografia/métodos , Animais , Meios de Contraste/farmacologia , Feminino , Fluorcarbonetos/química , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Microbolhas , Nanoestruturas/uso terapêutico , Neoplasias/terapia , Neoplasias Experimentais/terapia , Transição de Fase , Técnicas Fotoacústicas/métodos , Polímeros/química , Pirróis/química , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916806

RESUMO

Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.


Assuntos
Isoquinolinas/análise , Isoquinolinas/síntese química , Nitrilas/química , Pirróis/química , Benzofenonas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoquinolinas/farmacologia , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Prótons
13.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33803018

RESUMO

An efficient method for the synthesis of pharmaceutically prospective pyrrole-aminopyrimidine ensembles (in up to 91% yield) by the cyclocondensation of easily available acylethynylpyrroles with guanidine nitrate has been developed. The reaction proceeds under heating (110-115 °C, 4 h) in the KOH/DMSO system. In the case of 2-benzoylethynylpyrrole, the unexpected addition of the formed pyrrole-aminopyrimidine as N- (NH moiety of the pyrrole ring) and C- (CH of aminopyrimidine) nucleophiles to the triple bond is observed.


Assuntos
Reação de Cicloadição/métodos , Guanidinas/química , Pirimidinas/química , Pirróis/química , Dimetil Sulfóxido/química , Temperatura Alta , Hidróxidos/química , Compostos de Potássio/química
14.
Cancer Sci ; 112(6): 2504-2512, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33811417

RESUMO

Mitochondrial DNA (mtDNA) mutations occur frequently in cancer cells, and some of them are often homoplasmic. Targeting such mtDNA mutations could be a new method for killing cancer cells with minimal impact on normal cells. Pyrrole-imidazole polyamides (PIPs) are cell-permeable minor groove binders that show sequence-specific binding to double-stranded DNA and inhibit the transcription of target genes. PIP conjugated with the lipophilic triphenylphosphonium (TPP) cation can be delivered to mitochondria without uptake into the nucleus. Here, we investigated the feasibility of the use of PIP-TPP to target a mtDNA mutation in order to kill cancer cells that harbor the mutation. We synthesized hairpin-type PIP-TPP targeting the A3243G mutation and examined its effects on the survival of HeLa cybrid cells with or without the mutation (HeLamtA3243G cells or HeLamtHeLa cells, respectively). A surface plasmon resonance assay demonstrated that PIP-TPP showed approximately 60-fold higher binding affinity for the mutant G-containing synthetic double-stranded DNA than for the wild-type A-containing DNA. When added to cells, it localized in mitochondria and induced mitochondrial reactive oxygen species production, extensive mitophagy, and apoptosis in HeLamtA3243G cells, while only slightly exerting these effects in HeLamtHeLa cells. These results suggest that PIP-TPPs targeting mtDNA mutations could be potential chemotherapeutic drugs to treat cancers without severe adverse effects.


Assuntos
DNA Mitocondrial/efeitos dos fármacos , Imidazóis/farmacologia , Mitocôndrias/genética , Neoplasias/genética , Pirróis/química , Compostos de Sulfônio/química , Sobrevivência Celular/efeitos dos fármacos , DNA Mitocondrial/genética , Células HeLa , Humanos , Imidazóis/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Nylons/química , Espécies Reativas de Oxigênio/metabolismo , Ressonância de Plasmônio de Superfície
15.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918322

RESUMO

In this article, we showed the synthesis of new polycyclic aromatic compounds, such as thienotriazolopyrimidinones, N-(thienotriazolopyrimidine) acetamide, 2-mercapto-thienotriazolo-pyrimidinones, 2-(((thieno-triazolopyrimidine) methyl) thio) thieno-triazolopyrimidines, thieno-pyrimidotriazolo-thiazines, pyrrolo-triazolo-thienopyrimidines, thienopyrimido-triazolopyrrolo-quinoxalines, thienopyrimido-triazolo-pyrrolo-oxathiino-quinoxalinones, 1,4-oxathiino-pyrrolo- triazolothienopyrimidinones, imidazopyrrolotriazolothienopyrimidines and 1,2,4-triazoloimidazo- pyrrolotriazolothienopyrimidindiones, based on the starting material 2,3-diamino-6-benzoyl-5- methylthieno[2,3-d]pyrimidin-4(3H)-one (3). The chemical structures were confirmed using many spectroscopic ways (IR, 1H, 13C, -NMR and MS) and elemental analyses. A series of thiazine, imidazole, pyrrole, thienotriazolopyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines, i.e., CNE2 (nasopharyngeal), KB (oral), MCF-7 (breast) and MGC-803 (gastric) carcinoma cells. The compounds 20, 19, 17, 16 and 11 showed significant cytotoxicity against types of human cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Pirimidinas/síntese química , Pirróis/química , Quinoxalinas/síntese química , Tiazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia
16.
J Med Chem ; 64(9): 6085-6136, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33876936

RESUMO

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.


Assuntos
Antimaláricos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/farmacologia , Animais , Antimaláricos/química , Inibidores Enzimáticos/química , Camundongos , Plasmodium falciparum/efeitos dos fármacos , Pirróis/química , Relação Estrutura-Atividade
17.
Org Biomol Chem ; 19(12): 2603-2621, 2021 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-33683231

RESUMO

In this review various strategies for the incorporation of the signature pyrrole carboxamide moiety in the total syntheses of pyrrole-imidazole alkaloids (PIA) are discussed. These so-called oroidin alkaloids have a broad range of biological activities and display interesting skeletal diversity and complexity. These alkaloids are sponge-derived secondary metabolites and thus far more than 200 members of the PIA family have been isolated over the past few decades. Methods range from classical amide bond forming processes to non-traditional bond formation including the de novo synthesis of the pyrrole itself.


Assuntos
Alcaloides/síntese química , Imidazóis/química , Pirróis/química , Alcaloides/química , Alcaloides/metabolismo , Imidazóis/metabolismo , Estrutura Molecular , Pirróis/metabolismo
18.
Eur J Med Chem ; 217: 113339, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744686

RESUMO

Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80 ± 0.04 µM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50 = 0.55 ± 0.01 µM). Furthermore, in vitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 cancer cell lines exhibited compound 1c (IC50 = 4.70 ± 0.67 µM), and 1h (IC50 = 1.58 ± 0.20 µM) as the most cytotoxic compounds against MCF-7 and HT-29 cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Diester Fosfórico Hidrolases/metabolismo , Piridinas/síntese química , Piridinas/química , Pirofosfatases/metabolismo , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
19.
Molecules ; 26(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673017

RESUMO

Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.


Assuntos
Farmacorresistência Viral/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Subunidades Proteicas/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Virais/antagonistas & inibidores , Cristalografia por Raios X , Vírus da Influenza A/efeitos dos fármacos , Modelos Moleculares , Proteínas Mutantes/metabolismo , Mutação/genética , Domínios Proteicos , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Teoria Quântica , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/química , Termodinâmica , Proteínas Virais/química , Proteínas Virais/metabolismo
20.
Chem Commun (Camb) ; 57(21): 2641-2644, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33587062

RESUMO

An amphiphilic taurocholic acid (TCA) doped polypyrrole (PPy) film (PPy/TCA) was used as a dynamic mimic membrane model to explore how switchable surface wettability influences amyloid aggregation. Our results indicate that the hydrophobic surface, not the hydrophilic surface, plays important roles in Aß40 adsorption and aggregation.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Materiais Biomiméticos/química , Membranas Artificiais , Fragmentos de Peptídeos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Tensoativos/química , Molhabilidade , Adsorção/efeitos dos fármacos , Peptídeos beta-Amiloides/química , Técnicas Eletroquímicas , Interações Hidrofóbicas e Hidrofílicas , Fragmentos de Peptídeos/química , Polímeros/química , Pirróis/química , Ácido Taurocólico/química
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