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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 251: 119388, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33503560

RESUMO

Prospective antiviral molecule (2E)-N-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been probed using Fourier transform infrared (FTIR), FT-Raman and quantum chemical computations. The geometry equilibrium and natural bond orbital analysis have been carried out with density functional theory employing Becke, 3-parameter, Lee-Yang-Parr method with the 6-311G++(d,p) basis set. The vibrational assignments pertaining to different modes of vibrations have been augmented by normal coordinate analysis, force constant and potential energy distributions. Drug likeness and oral activity have been carried out based on Lipinski's rule of five. The inhibiting potency of 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide has been investigated by docking simulation against SARS-CoV-2 protein. The optimized geometry shows a planar structure between the chromone and the side chain. Differences in the geometries due to the substitution of the electronegative atom and intermolecular contacts due to the chromone and hydrazinecarbothioamide were analyzed. NBO analysis confirms the presence of two strong stable hydrogen bonded NH⋯O intermolecular interactions and two weak hydrogen bonded CH⋯O interactions. The red shift in NH stretching frequency exposed from IR substantiates the formation of NH⋯O intermolecular hydrogen bond and the blue shift in CH stretching frequency substantiates the formation of CH⋯O intermolecular hydrogen bond. Drug likeness, absorption, distribution, metabolism, excretion and toxicity property gives an idea about the pharmacokinetic properties of the title molecule. The binding energy of the nonbonding interaction with Histidine 41 and Cysteine 145, present a clear view that 2(2E)-methyl-2-[(4-oxo-4H-chromen-3-yl)methylidene]-hydrazinecarbothioamide can irreversibly interact with SARS-CoV-2 protease.


Assuntos
Antivirais , Cromonas , Drogas em Investigação , Tioureia , Antivirais/análise , Antivirais/síntese química , Antivirais/química , Antivirais/farmacocinética , Cromonas/análise , Cromonas/síntese química , Cromonas/química , Cromonas/farmacocinética , Química Computacional , Cristalografia por Raios X , Drogas em Investigação/análise , Drogas em Investigação/síntese química , Drogas em Investigação/química , Drogas em Investigação/farmacocinética , Humanos , Hidrazinas/química , Hidrogênio/química , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Tioamidas/análise , Tioamidas/síntese química , Tioamidas/química , Tioamidas/farmacocinética , Tioureia/análise , Tioureia/síntese química , Tioureia/química , Tioureia/farmacocinética , Vibração
2.
J Enzyme Inhib Med Chem ; 35(1): 759-772, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32183548

RESUMO

A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.


Assuntos
Antineoplásicos/farmacologia , Cromonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Óxido Nítrico/análise , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade
3.
Molecules ; 25(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041131

RESUMO

A new approach to synthesize cannabilactones using Suzuki cross-coupling reaction followed by one-step demethylation-cyclization is presented. The two key cannabilactone prototypes AM1710 and AM1714 were obtained selectively in high overall yields and in a lesser number of synthetic steps when compared to our earlier synthesis. The new approach expedited the synthesis of cannabilactone analogs with structural modifications at the four potential pharmacophoric regions.


Assuntos
Canabinoides/síntese química , Cromonas/síntese química
4.
Mol Divers ; 24(1): 191-200, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30905029

RESUMO

The DBU-mediated annulations of 2-aryl-3-nitro-2H-chromenes with 1,3-cyclohexanediones have been developed. This reaction involves a highly efficient domino sequence consisting of regioselective intermolecular Michael addition, intramolecular nucleophilic addition and aromatization as key unit steps. The reaction appears to be general for a variety of 2-aryl-3-nitro-2H-chromenes and tolerates the presence of aromatic moieties with electron-withdrawing and electron-donating substituents. This transformation provides a straightforward synthetic protocol for constructing benzofuro[2,3-c]chromenone derivatives.


Assuntos
Cromonas/síntese química , Cicloexanonas/química , Ureia/análogos & derivados , Catálise , Técnicas de Química Sintética , Cromonas/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/química
5.
Anticancer Res ; 39(12): 6479-6488, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810912

RESUMO

BACKGROUND/AIM: 4H-1-Benzopyran-4-one (chromone), present in various flavonoids as a backbone structure, has been used for the synthesis of anticancer drugs. The study aimed at investigating the cytotoxicity of eight 2-arylazolylchromones and twelve 2-triazolylchromones against four human oral squamous cell carcinoma (OSCC) cell lines and three human normal mesenchymal oral cells, and then performed a quantitative structure-activity relationship (QSAR) analysis. MATERIALS AND METHODS: Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The distribution of cells to various phases of cell cycle was determined by cell cycle analysis. A total of 3,218 physicochemical, structural and quantum chemical features were calculated for QSAR analysis from the most stabilized structure optimized using CORINA. RESULTS: 2-[4-(4-fluorophenyl)-1H-imidazol-1-yl]-4H-1-benzopyran-4-one [6] had the highest tumor-specificity (TS), comparable with that of 5-flurouracil (5-FU) and doxorubicin, inducing cytostatic growth inhibition, accumulation of G2+M phase cells with no cells in the G1 phase. All eight 2-triazolylchromones showed much lower tumor-specificity, confirming our previous finding. Tumor-specificity was also correlated with 3D shape, topological shape, size, ionization potential, and the presence of more than two aromatic rings in the molecule and imidazole ring in the nitrogen-containing heterocyclic ring. CONCLUSION: [6] can be a lead compound for designing anticancer drugs.


Assuntos
Antineoplásicos/síntese química , Carcinoma de Células Escamosas/tratamento farmacológico , Cromonas/síntese química , Neoplasias Bucais/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromonas/química , Cromonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Quantitativa Estrutura-Atividade , Teoria Quântica
6.
Anticancer Res ; 39(12): 6489-6498, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810913

RESUMO

BACKGROUND/AIM: Studies of biological activity of 2-styrylchromone derivatives focusing on antioxidant, anti-inflammatory, antiviral and antitumor activity are limited. In this study, eighteen synthetic 2-styrylchromone derivatives were investigated for their cytotoxicity against human malignant and non-malignant cells, and then subjected to quantitative structure-activity relationship (QSAR) analysis. MATERIALS AND METHODS: Tumor-specificity was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against four normal oral cells to that against oral squamous cell carcinoma cell lines. Induction of apoptosis and growth arrest were evaluated by cell-cycle analysis. For QSAR analysis, 3,117 types of physicochemical, structural, and quantum chemical features were calculated from the most stabilized structure of 2-styrylchromone derivatives. RESULTS: Two 2-styrylchromone derivatives in which a methoxy group was introduced at the 4-position of the benzene ring showed tumor-specificity equivalent to or higher than doxorubicin in TS value. These compounds accumulated the subG1 and G2/M phase cells, suggesting the induction of apoptosis. Their tumor-specificity can be explained mainly by molecular shape and electronic state. CONCLUSION: These findings suggest the applicability of 2-styrylchromone to develop safe and effective anticancer agents as seed compounds.


Assuntos
Antineoplásicos/síntese química , Carcinoma de Células Escamosas/tratamento farmacológico , Cromonas/síntese química , Neoplasias Bucais/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromonas/química , Cromonas/farmacologia , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Quantitativa Estrutura-Atividade
7.
Molecules ; 24(23)2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31757041

RESUMO

6-Bromochromone-2-carboxylic acid (3) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base/number of reagent equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds 4B-10B) were obtained with good yields (54-93%). Only in the case of the nitro substituent (compound 11B), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.


Assuntos
Cromonas , Cromonas/síntese química , Cromonas/química , Ligantes , Estrutura Molecular
8.
Curr Alzheimer Res ; 16(9): 815-820, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31660831

RESUMO

BACKGROUND: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets. OBJECTIVE: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals. METHODS: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed. RESULTS: Compounds 4f [IC50 (EeAChE) = 0.30 µM; IC50 (eqBuChE) = 0.09 µM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 µM; IC50 (eqBuChE) = 0.03 µM; ORAC = 0.50 TE] were identified as hits for further development. CONCLUSION: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Cromonas/farmacologia , Donepezila/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Cromonas/síntese química , Donepezila/síntese química , Avaliação Pré-Clínica de Medicamentos , Depuradores de Radicais Livres/síntese química , Depuradores de Radicais Livres/farmacologia , Humanos
9.
Eur J Med Chem ; 184: 111772, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31630055

RESUMO

The membrane transporter BCRP/ABCG2 has emerged as a privileged biological target for the development of small compounds capable of abolishing multidrug resistance. In this context, the chromone skeleton was found as an excellent scaffold for the design of ABCG2 inhibitors. With the aims of optimizing and developing more potent modulators of the transporter, we herewith propose a multidisciplinary medicinal chemistry approach performed on this promising scaffold. A quantitative structure-activity relationship (QSAR) study on a series of chromone derivatives was first carried out, giving a robust model that was next applied to the design of 13 novel compounds derived from this nucleus. Two of the most active according to the model's prediction, namely compounds 22 (5-((3,5-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide) and 31 (5-((2,4-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide), were synthesized and had their biological potency evaluated by experimental assays, confirming their high inhibitory activity against ABCG2 (experimental EC50 below 0.10 µM). A supplementary docking study was then conducted on the newly designed derivatives, proposing possible binding modes of these novel molecules in the putative ligand-binding site of the transporter and explaining why the two aforementioned compounds exerted the best activity according to biological data. Results from this study are recommended as references for further research in hopes of discovering new potent inhibitors of ABCG2.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Cromonas/farmacologia , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Células Cultivadas , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo
10.
J Enzyme Inhib Med Chem ; 34(1): 1678-1689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530032

RESUMO

A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Cromonas/farmacologia , Interleucina-6/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Adjuvante de Freund , Interleucina-6/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese
11.
Bioorg Chem ; 92: 103285, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31561103

RESUMO

A series of eighteen 2-styrylchromone derivatives (see Chart 1) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R1 and chlorine at R4 showed both the best MAO-B inhibitory activity (IC50 = 17 ±â€¯2.4 nM) and the best MAO-B selectivity (IC50 for MAO-A/IC50 for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure-activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC50 values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P < 0.05). We then examined the 2-styrylchromone structures as useful scaffolds through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The model using pIC50 value indexes for MAO-B exhibited a determination coefficient (R2) of 0.873 as well as a Leave-One-Out cross-validated determination coefficient (Q2) of 0.675. These data suggested that the 2-styrylchromone structure might be a useful scaffold for the design and development of novel MAO-B inhibitors.


Assuntos
Cromonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Quantitativa Estrutura-Atividade , Proteínas Recombinantes/metabolismo
12.
Bioorg Med Chem ; 27(21): 115089, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31540827

RESUMO

Colorectal carcinoma (CRC) is one of the most common cancers with high metastatic potential, explaining why identifying new drug candidates that inhibit tumour metastasis is an urgent need. The aim of this study was to evaluate the biological activities of pectolinarigenin (PEC, a natural flavonoid present in Cirsium chanroenicum) in CRC in vitro and in vivo and to determine its underlying mechanism of action. Here, we observed that treatment with PEC could inhibit cell viability and induce apoptosis in cancer cells in a concentration- and time-dependent manner. The occurrence of apoptosis was associated with activation of caspase-3 and Bax and decreased expression of Bcl-2. In addition, PEC markedly impaired CRC cell migration and invasion by downregulating the expression of matrix metalloproteinase (MMP-9) and phosphorylated-Stat3Tyr705. Moreover, our studies showed that PEC inhibited abdominal metastasis models of murine colorectal cancer. In addition, histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, MMP9-positive cells and p-Stat3Tyr705 cells upon treatment with PEC compared to control samples. Furthermore, PEC reduced the number of myeloid-derived suppressor cells (MDSCs) in the blood and tumours, which was accompanied by the increased infiltration of CD8+T cells in the blood. Taken together, our findings suggested that PEC could be used as a natural drug to inhibit CRC metastasis.


Assuntos
Antineoplásicos/uso terapêutico , Cromonas/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/síntese química , Regulação para Baixo , Feminino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Células Supressoras Mieloides/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
13.
Comput Biol Chem ; 83: 107104, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546212

RESUMO

In this paper, we have established methylenebis (4-hydroxy-2H-chromen-2-one) as a promising anticancer scaffold with kinesin spindle protein (KSP) inhibitory activity under malignant condition. A series of biscoumarin derivatives (MN1 to MN30) with different substituent were synthesized, and their anticancer activity was explored. Six biscoumarin derivatives that were found active were further selected to formulate organic nanoparticles (ONPs). Anticancer activity of both the forms (viz conventional and ONPs) was compared. MN30 was found most potent whereby MN10 showed good anticancer activity in both, i.e., conventional and ONP form; the structural activity relationship (SAR) study has been established. Computational investigation revealed biscoumarin scaffold as a suitable pharmacophore to bind against KSP protein. Molecular dynamics simulation studies revealed protein-ligand stability and dynamic behavior of biscoumarin-KSP complex. Finally, accruing signal transduction model was formulated to explain the observed MTT trend of conventional and ONP form. The model seems useful towards solving population specific varied results of chemotherapeutic agents. According to the model, MN10 and MN30 derivatives have good pharmacodynamics inertia and therefore, both the molecules were able to provide dose-dependent cytotoxic results.


Assuntos
Antineoplásicos/farmacocinética , Cromonas/farmacologia , Simulação por Computador , Transdução de Sinais/efeitos dos fármacos , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Cinesina/antagonistas & inibidores , Cinesina/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Bioorg Chem ; 91: 103161, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31387060

RESUMO

In continuation of our investigation of pharmacologically-motivated natural products, we have isolated bergenin (1) as a major compound from Mallotus philippensis, which is deployed in different Indian traditional systems of medicine. Here, a series of bergenin-1,2,3-triazole hybrids were synthesized and evaluated for their potentials against a panel of cancer cell lines. Several of the hybrid derivatives were found more potent in comparison to parent compound bergenin (1). Among them, 4j demonstrated potent activity against A-549 and HeLa cell lines with IC50 values of 1.86 µM and 1.33 µM, respectively, and was equipotent to doxorubicin. Cell cycle analysis showed that 4j arrested HeLa cells at G2/M phase and lead to accumulation of Cyclin B1 protein. Cell based tubulin polymerization assays and docking studies demonstrated that 4j disrupts tubulin assembly by occupying colchicine binding pocket of tubulin.


Assuntos
Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Benzopiranos/química , Cromonas/síntese química , Cromonas/farmacologia , Mitose , Triazóis/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Antimitóticos/síntese química , Antineoplásicos/síntese química , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química
15.
Eur J Med Chem ; 182: 111630, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31446244

RESUMO

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC50 ranging from 0.03 to 0.09 µM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC50 = 0.009 µM) over PI3Kß, γ and δ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3Kα inhibitor.


Assuntos
Antineoplásicos/farmacologia , Cromonas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Piperazina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ácidos Sulfínicos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Ácidos Sulfínicos/química , Células Tumorais Cultivadas
16.
Molecules ; 24(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311096

RESUMO

In this manuscript, a novel, decarboxylative Michael reaction between α-substituted azlactones and chromone-3-carboxylic acids is described. The reaction proceeds in a sequence Michael addition followed by decarboxylative deprotonation, and it results in the formation of chromanones bearing an azlactone structural unit. The possibility of transforming an azlactone moiety into a protected α,α-disubstituted α-amino acid derivative is also demonstrated.


Assuntos
Cromonas/síntese química , Cromonas/química , Reação de Cicloadição , Descarboxilação , Estrutura Molecular , Estereoisomerismo
17.
Org Biomol Chem ; 17(5): 1062-1066, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30638240

RESUMO

We report an efficient and highly diastereoselective protocol for the rapid construction of 3-nitro substituted 4-chromanones by an intramolecular Michael-type cyclization of α-nitro aryl ketones bearing unsaturated ester units. A catalytic amount of KOtBu was found to be crucial for the high diastereoselective control of this transformation. With this protocol, a series of 3,3-disubstituted 3-nitro-4-chromanones were synthesized in good to excellent yields with high diastereoselectivities and showed moderate to good in vitro antitumor activities, representing promising antitumor hits for further drug discovery.


Assuntos
Antineoplásicos/química , Cromonas/síntese química , Catálise , Cromonas/química , Ciclização , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Estereoisomerismo
18.
Mol Divers ; 23(4): 897-913, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30666491

RESUMO

Based on reports that chromone compounds are good potency inhibitors of monoamine oxidase (MAO), the present study evaluates the effect of substitution with flexible side chains on the 3 position on MAO inhibition potency. Fifteen chromone derivatives were synthesised by reacting aromatic and aliphatic amines and alcohols with chromone 3-carboxylic acid in the presence of carbonyldiimidazole (CDI). This yielded chromane-2,4-dione and ester chromone derivatives. Generally, the esters exhibited weak MAO inhibition, while the chromane-2,4-dione derivatives showed promise as selective MAO-B inhibitors with IC50 values in the micromolar range. Compound 14b, 3-[(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC50 value of 638 µM. This compound was shown to be a reversible and competitive MAO-B inhibitor with a Ki of 94 µM. In conclusion, the effect of chain elongation and introduction of flexible substituents on position 3 of chromone were explored and the results showed that aminomethylidene substitution is preferable over ester substitution. Good potency MAO-B inhibitors may act as leads for the design and development of therapy for Parkinson's disease where these agents reduce the central metabolism of dopamine.


Assuntos
Cromonas/síntese química , Inibidores da Monoaminoxidase/síntese química , Cromonas/química , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Proteínas Recombinantes/química
19.
Bioorg Chem ; 83: 432-437, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30428433

RESUMO

A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors.


Assuntos
Inibidores da Colinesterase/química , Cromonas/química , Inibidores da Monoaminoxidase/química , Acetilcolinesterase/química , Animais , Sítios de Ligação , Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Cromonas/síntese química , Cavalos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Relação Estrutura-Atividade
20.
Org Biomol Chem ; 17(1): 151-155, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30525178

RESUMO

A highly enantio- and diastereoselective method for the synthesis of functionalized chroman-2-ones and chromanes was achieved by using an organocatalytic domino Michael/hemiacetalization reaction of aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols followed by a PCC oxidation and dehydroxylation, respectively. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good to high yields (up to 97%) and excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 99% ee).


Assuntos
Cromanos/síntese química , Cromonas/síntese química , Aldeídos/química , Aminoácidos/química , Catálise , Alcaloides de Cinchona/química , Oxirredução , Fenóis/química , Estereoisomerismo
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