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1.
ACS Omega ; 8(15): 14097-14112, 2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-37091407

RESUMO

We herein disclose the microwave-assisted synthesis of previously unreported 6-methoxy-5,6-dihydro-5-azapurines, whose purine-like scaffold is promising for drug discovery. The method is simple, fast, and relies on easily accessible reagents such as trimethyl orthoformate, acetic acid, and aminotriazole-derived N,N'-disubstituted formamidines. The preliminary biological evaluation revealed that selected representatives of synthesized 6-methoxy-5,6-dihydro-5-azapurines dose-dependently reduce the viability of HepG2 and A549 cancer cells having little to no influence on five tested purinergic receptors.

2.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674884

RESUMO

The homotrimeric P2X7 receptor (P2X7R) is expressed by virtually all cells of the innate and adaptive immune system and plays a crucial role in various pathophysiological processes such as autoimmune and neurodegenerative diseases, inflammation, neuropathic pain and cancer. Consequently, the P2X7R is considered a promising target for therapy and diagnosis. As the development of tracers comes hand-in-hand with the development of potent and selective receptor ligands, there is a rising number of PET tracers available in preclinical and clinical studies. This review analyzes the development of P2X7R positron emission tomography (PET) tracers and their potential in various PET imaging applications.


Assuntos
Neoplasias , Doenças Neurodegenerativas , Humanos , Receptores Purinérgicos P2X7 , Tomografia por Emissão de Pósitrons/métodos , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
3.
J Med Chem ; 65(18): 12292-12318, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36084304

RESUMO

Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer's disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σ1R, σ2R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities. Nine fulfilled in silico drug-likeness criteria and did not display toxicity in three cell lines. Seven displayed cytoprotective activity in two stress-induced cellular models. Compared to donepezil, six showed equal/better synaptic protection in a zebrafish model of acute amyloidosis-induced synaptic degeneration. Two P2X7R antagonists alleviated the activation state of microglia in vivo. Permeability studies were performed, and four did not inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead MTDLs are promising drug candidates for synaptic integrity protection and could serve as disease-modifying AD treatment. Our study also proposes zebrafish as a useful preclinical tool for drug discovery and development.


Assuntos
Doença de Alzheimer , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Colinesterases , Donepezila/uso terapêutico , Chumbo/uso terapêutico , Ligantes , Peixe-Zebra/metabolismo
4.
J Med Chem ; 65(16): 11291-11308, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35930402

RESUMO

The orthosteric ATP-binding site of the P2X receptors is poorly understood. Only a few compounds were well characterized for their P2X receptor functional activity and subtype selectivity. This study represents the first fully functional characterization of various ATP derivatives combined with in silico studies to advance the understanding of SARs at the orthosteric binding sites of P2X receptors leading to the identification of 2-chloro-3-trifluoromethylbenzoyl ATP ester as a novel pan-P2X receptor agonist and several subtype-selective P2X receptor agonists. Furthermore, esterification of both hydroxyl functions of ATP using 1-naphthoic acid has led to compound 26 acting as an antagonist at P2X1-4 and P2X2/3 receptors and an agonist at P2X7 receptors. This particular ATP derivative will allow interrogating the P2X7 receptor function while antagonizing all other P2X receptor subtypes and therefore serve as a valuable pharmacological tool in the future.


Assuntos
Trifosfato de Adenosina , Canais Iônicos , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Canais Iônicos/metabolismo , Domínios Proteicos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-Atividade
5.
Molecules ; 27(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35408685

RESUMO

The adenosine A3 receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at 1-, 2-, and 6-positions of the purine ring and variations of the 5'-position at the bicyclo[3.1.0]hexane moiety, closing existing gaps in the structure-affinity relationships. The most potent derivative 30 displayed moderate A3AR affinity (Ki of 0.38 µM) and high A3R selectivity. A subset of compounds varied at 5'-position was further evaluated in functional P2Y1R assays, displaying no off-target activity.


Assuntos
Hexanos , Receptor A3 de Adenosina , Animais , Células CHO , Cricetinae , Ligantes , Nucleosídeos/química , Ensaio Radioligante , Receptor A3 de Adenosina/química , Relação Estrutura-Atividade
6.
J Med Chem ; 65(3): 2409-2433, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35080883

RESUMO

We recently reported N4-substituted 3-methylcytidine-5'-α,ß-methylenediphosphates as CD73 inhibitors, potentially useful in cancer immunotherapy. We now expand the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 16; Ki = 0.673 nM) and 4-iodo (MRS4620 18; Ki = 0.436 nM) substitution of the N4-benzyloxy group decreased Ki by ∼20-fold. Primary alkylamine derivatives coupled through a p-amido group with a varying methylene chain length (24 and 25) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformational adaptation, and the benzyloxyimino group (E configuration) binds to the same region (between the C-terminal and N-terminal domains) as N4-benzyl groups in adenine inhibitors. Molecular dynamics identified stabilizing interactions and predicted conformational diversity. Thus, by N4-benzyloxy substitution, we have greatly enhanced the inhibitory potency and added functionality enabling molecular probes. Their potential as anticancer drugs was confirmed by blocking CD73 activity in tumor tissues in situ.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Nucleotídeos de Citosina/farmacologia , Difosfonatos/farmacologia , Inibidores Enzimáticos/farmacologia , 5'-Nucleotidase/metabolismo , Adulto , Nucleotídeos de Citosina/síntese química , Nucleotídeos de Citosina/metabolismo , Difosfonatos/síntese química , Difosfonatos/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Neoplasias/enzimologia , Tonsila Palatina/enzimologia , Ligação Proteica , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 226: 113838, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34571173

RESUMO

The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists' potency from pIC50 values of 5.7-7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.


Assuntos
Ciclobutanos/farmacologia , Diamida/farmacologia , Piperazina/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X/metabolismo , Ciclobutanos/síntese química , Ciclobutanos/química , Diamida/síntese química , Diamida/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Piperazina/síntese química , Piperazina/química , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Cells ; 8(9)2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480740

RESUMO

High-content and high-throughput digital microscopes have generated large image sets in biological experiments and clinical practice. Automatic image analysis techniques, such as cell counting, are in high demand. Here, cell counting was treated as a regression problem using image features (phenotypes) extracted by deep learning models. Three deep convolutional neural network models were developed to regress image features to their cell counts in an end-to-end way. Theoretically, ensembling imaging phenotypes should have better representative ability than a single type of imaging phenotype. We implemented this idea by integrating two types of imaging phenotypes (dot density map and foreground mask) extracted by two autoencoders and regressing the ensembled imaging phenotypes to cell counts afterwards. Two publicly available datasets with synthetic microscopic images were used to train and test the proposed models. Root mean square error, mean absolute error, mean absolute percent error, and Pearson correlation were applied to evaluate the models' performance. The well-trained models were also applied to predict the cancer cell counts of real microscopic images acquired in a biological experiment to evaluate the roles of two colorectal-cancer-related genes. The proposed model by ensembling deep imaging features showed better performance in terms of smaller errors and larger correlations than those based on a single type of imaging feature. Overall, all models' predictions showed a high correlation with the true cell counts. The ensembling-based model integrated high-level imaging phenotypes to improve the estimation of cell counts from high-content and high-throughput microscopic images.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Neoplasias/patologia , Contagem de Células/métodos , Contagem de Células/normas , Humanos , Processamento de Imagem Assistida por Computador/normas , Células Tumorais Cultivadas
9.
J Med Chem ; 62(7): 3677-3695, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30895781

RESUMO

Cluster of differentiation 73 (CD73) converts adenosine 5'-monophosphate to immunosuppressive adenosine, and its inhibition was proposed as a new strategy for cancer treatment. We synthesized 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of purine and pyrimidine nucleosides, which represent nucleoside diphosphate analogues, and compared their CD73 inhibitory potencies. In the adenine series, most ribose modifications and 1-deaza and 3-deaza were detrimental, but 7-deaza was tolerated. Uracil substitution with N3-methyl, but not larger groups, or 2-thio, was tolerated. 1,2-Diphosphono-ethyl modifications were not tolerated. N4-(Aryl)alkyloxy-cytosine derivatives, especially with bulky benzyloxy substituents, showed increased potency. Among the most potent inhibitors were the 5'- O-[(phosphonomethyl)phosphonic acid] derivatives of 5-fluorouridine (4l), N4-benzoyl-cytidine (7f), N4-[ O-(4-benzyloxy)]-cytidine (9h), and N4-[ O-(4-naphth-2-ylmethyloxy)]-cytidine (9e) ( Ki values 5-10 nM at human CD73). Selected compounds tested at the two uridine diphosphate-activated P2Y receptor subtypes showed high CD73 selectivity, especially those with large nucleobase substituents. These nucleotide analogues are among the most potent CD73 inhibitors reported and may be considered for development as parenteral drugs.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nucleotídeos de Purina/química , Nucleotídeos de Purina/farmacologia , Nucleotídeos de Pirimidina/química , Nucleotídeos de Pirimidina/farmacologia , Animais , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Ratos , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 135: 401-413, 2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28463783

RESUMO

Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [3H]TAK-779 binding at the CCR5. Furthermore, introduction of a p-tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b. The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors.


Assuntos
Benzazepinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Receptores CCR5/metabolismo , Benzazepinas/síntese química , Benzazepinas/química , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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