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1.
Org Biomol Chem ; 17(38): 8749-8755, 2019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31549131

RESUMO

A direct coupling of 2H-indazoles' C3 position and acyl groups has been achieved to produce 3-acyl-2H-indazoles. The Ni(ii)-catalyzed acylation might proceed through a radical pathway for the reaction of 2H-indazoles with either aryl or alkyl aldehydes in the presence of the free radical initiator TBHP and additive PivOH. This method provided a superior approach to fulfil the direct C3-acylation of 2H-indazoles with yields up to 91%. And various substituted 2H-indazoles were well tolerated with this method, enriching the diversity of 2H-indazole derivatives. In comparison with previously reported approaches for the C3-acylation of 2H-indazoles, the developed reaction represents a more convenient and economical method directly using aldehydes as the acylation agents.

2.
Org Lett ; 21(6): 1740-1743, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30802072

RESUMO

Here we reported a method for Cu2+-catalyzed ortho-acyloxylation of either the C(sp2)-H or C(sp2)-X (X = Cl, Br) bond of aromatic amides with carboxylic acid, especially olefine acids, to obtain corresponding products in good yields up to 91%. The catalyst CuBr2 is cheap and stable to conserve in comparison with other metals, like Rh, Pd, Ru, and Cu+. This simple procedure is applicable for wide substrate scope and various functional groups to produce carboxylic esters without any additives or ligands.

3.
ChemMedChem ; 13(22): 2455-2463, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30246417

RESUMO

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB2 R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2 R in calcium mobilization assays, and four displayed CB2 R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2 R (EC50 =7.53±3.15 nm) had a selectivity over CB1 R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2 R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2 R.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Pirimidinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Triazinas/farmacologia , Animais , Sítios de Ligação , Células CHO , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Cricetulus , Desenho de Drogas , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
4.
Molecules ; 23(4)2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29584670

RESUMO

Fibroblast growth factor receptor 1 (FGFR1) has become a potential target for the treatment of cancer. Designing FGFR1-selective inhibitors remains fundamental to the development of anti-cancer drugs because of highly sequential homology among FGFR subtypes. In present work, four inhibitors were examined with intermolecular interaction patterns with FGFR1 and FGFR4, respectively, for the exploration of binding mechanisms by applying a combined approach of computational techniques, including flexible docking, binding site analyses, electronic structure computations, molecular dynamic simulations, and binding free energy predictions. Molecular simulation-predicted binding conformations and pharmacophoric features of these molecules in the active pocket of either FGFR1 or FGFR4. MMPB(GB)SA-calculated binding free energies were accordant with the ordering of their tested potency values. Furthermore, in silico mutations of two residues (FGFR1: Tyr563 and Ser565) were also performed to check their impact on ligand binding by applying MD simulations and binding free energy calculations. The present studies may provide a structural understanding of the FGFR1-selective mechanism. The viewpoints from computational simulations would be valuable guidelines for the development of novel FGFR1-selective inhibitors.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Sítios de Ligação , Domínio Catalítico/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/química , Pirazóis/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética
5.
Eur J Med Chem ; 137: 598-611, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28651225

RESUMO

Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC50 values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC50 = 3.665 ± 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series.


Assuntos
Piridazinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade
6.
ACS Med Chem Lett ; 8(6): 678-681, 2017 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-28626532

RESUMO

Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.

7.
Mol Biosyst ; 12(4): 1250-68, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26883408

RESUMO

CDK2 is a promising target for the development of anti-cancer agents. It is not an easy task to design CDK2-selective inhibitors which do not exhibit activity for other CDK family members, particularly CDK4, due to a high degree of structural homology among CDK family members. In this study, 4-substituted N-phenylpyrimidin-2-amine derivatives as CDK2 inhibitors were examined to understand the selectivity mechanism against CDK4 using a combined approach of 3D-QSAR, molecular docking, MESP, MD simulations, and binding free energy calculations. 3D-QSAR models were developed to propose structural determinants for CDK2 and CDK4 inhibition. High q(2) and r(2) values for CoMFA and CoMSIA models based on both internal and external validations suggested that the generated 3D-QSAR models may exhibit good capability to predict bioactivities of inhibitors against CDK2 or CDK4. Electrostatic potentials on the molecular surface have been discussed in detail for determining the binding affinity of studied inhibitors by combining molecular docking with MESP and Mulliken charge analyses. Binding free energy calculations suggested that the residues Gln85, Asp86, and Lys89 of CDK2 would play a critical role in selective CDK2 inhibition. The electrostatic interactions of an inhibitor with Glu144 and Asn145 of CDK4 may predominately drive CDK4 inhibition. These findings may provide a better structural understanding of the mechanism of CDK2 selective inhibition. The results obtained in the current study may provide valuable guidelines for developing novel potent and selective CDK2 inhibitors.


Assuntos
Aminas/química , Quinase 2 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/química , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Aminas/farmacologia , Aminoácidos/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Eletricidade Estática
8.
Mol Biosyst ; 12(1): 145-61, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26565382

RESUMO

Cyclin dependent kinase 2 (CDK2) was regarded as a potentially therapeutic target for cancer therapy. Since the CDK family includes couples of high homology members, designing CDK2-selective inhibitors would provide valuable opportunities for the development of anticancer drugs with optimal efficacy. In this study, three thiazo-5-yl-pyrimidines as CDK2 inhibitors with different selectivity over cyclin dependent kinase 7 (CDK7) were examined to study the selectivity mechanism using a combined approach of computational techniques of flexible docking, EasyMIFs, molecular electrostatic potential (MESP), natural bond orbital (NBO), molecular dynamics (MD) simulations, and binding free energy calculations. Molecular simulations elicited new chemical insights into steric and electronic complementarities of these molecules to the binding sites of CDK2 and CDK7. The computed binding free energies were consistent with the ranking of their experimental binding affinities on CDK2 and CDK7. We also conducted in silico mutations of three key amino acids (CDK2: Gln85, Lys89, Asp145) to examine their impact on ligand binding with MD simulations and binding free energy calculations. The results indicated that these residues exhibited a strong tendency to mediate ligand-protein interactions through the H-bond and vdW interaction with CDK2-selective inhibitor. The present work may provide a better structural understanding of the molecular mechanism of CDK2 selective inhibition. The new computational insights presented in this study are expected to be valuable for the guidelines and development of new potent CDK2 inhibitors.


Assuntos
Quinase 2 Dependente de Ciclina/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pironas/química , Pironas/metabolismo , Pironas/farmacologia , Relação Quantitativa Estrutura-Atividade
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