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1.
Int J Mol Sci ; 23(7)2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35409144

RESUMO

α-Aminoamidines are promising reagents for the synthesis of a diverse family of pyrimidine ring derivatives. Here, we demonstrate the use of α-aminoamidines for the synthesis of a new series of 5,6,7,8-tetrahydroquinazolines by their reaction with bis-benzylidene cyclohexanones. The reaction occurs in mild conditions and is characterized by excellent yields. It has easy workup, as compared to the existing methods of tetrahydroquinazoline preparation. Newly synthesized derivatives of 5,6,7,8-tetrahydroquinazoline bear protecting groups at the C2-tert-butyl moiety of a quinazoline ring, which can be easily cleaved, opening up further opportunities for their functionalization. Moreover, molecular docking studies indicate that the synthesized compounds reveal high binding affinity toward some essential enzymes of Mycobacterial tuberculosis, such as dihydrofolate reductase (DHFR), pantothenate kinase (MtPanK), and FAD-containing oxidoreductase DprE1 (MtDprE1), so that they may be promising candidates for the molecular design and the development of new antitubercular agents against multidrug-resistant strains of the Tubercle bacillus. Finally, the high inhibition activity of the synthesized compounds was also predicted against ß-glucosidase, suggesting a novel tetrahydroquinazoline scaffold for the treatment of diabetes.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Antituberculosos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo
2.
Molecules ; 27(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35408693

RESUMO

Cancer is the most devastating disease and second leading cause of death around the world. Despite scientific advancements in the diagnosis and treatment of cancer which can include targeted therapy, chemotherapy, endocrine therapy, immunotherapy, radiotherapy and surgery in some cases, cancer cells appear to outsmart and evade almost any method of treatment by developing drug resistance. Quinazolines are the most versatile, ubiquitous and privileged nitrogen bearing heterocyclic compounds with a wide array of biological and pharmacological applications. Most of the anti-cancer agents featuring quinazoline pharmacophore have shown promising therapeutic activity. Therefore, extensive research is underway to explore the potential of these privileged scaffolds. In this context, a molecular hybridization approach to develop hybrid drugs has become a popular tool in the field of drug discovery, especially after witnessing the successful results during the past decade. Histone deacetylases (HDACs) have emerged as an important anti-cancer target in the recent years given its role in cellular growth, gene regulation, and metabolism. Dual inhibitors, especially based on HDAC in particular, have become the center stage of current cancer drug development. Given the growing significance of dual HDAC inhibitors, in this review, we intend to compile the development of quinazoline based HDAC dual inhibitors as anti-cancer agents.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico
3.
Bioorg Med Chem Lett ; 67: 128703, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35364239

RESUMO

It is generally believed that EGFR/HER2 dual-target inhibitors may overcome the resistance of EGFR TKIs caused by HER2 overexpression. The structure-based synthesis and biological evaluation of quinazoline derivatives as EGFR/HER2 dual-target inhibitors has been studied in this paper. II-1, II-2, III-3, III-4 displayed comparable inhibitory potency against EGFR and HER2 and II-1 showed remarkable antiproliferative activities against NCI-H358/PC-9/Calu-3/NCI-H1781 (EGFR IC50 = 0.30 nM, HER2 IC50 = 6.07 nM, NCI-H358 GI50 = 23.30 nM, PC-9 GI50 = 1.95 nM, Calu-3 GI50 = 23.13 nM NCI-H1781 GI50 = 41.61 nM).


Assuntos
Antineoplásicos , Quinazolinas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 67: 128714, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367591

RESUMO

The systemic use of GABAB orthosteric agonist baclofen might be limited due to its detrimental properties: sedation and motor impairment. In contrast, GABAB positive allosteric modulators produce less adverse effects. Using BHF-177 as a starting point, we found a new active scaffold: the 6-aryl-quinazoline scaffold. Further elaborating the scaffold, we identified several in vitro and in vivo active compounds.


Assuntos
Agonistas dos Receptores de GABA-B , Receptores de GABA-B , Regulação Alostérica , Baclofeno , Agonistas dos Receptores de GABA-B/farmacologia , Quinazolinas/farmacologia
5.
Bioorg Chem ; 122: 105710, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35278776

RESUMO

The antitumor activity of newly synthesized 4-anilino-2-vinylquinazolines 8a-r was measured comparable to sorafenib as a standard drug. The 2-vinylquinazolines 8a-r were evaluated for their in vitro antitumor activity. The most active antitumor agents were subjected to in vitro VEGFR-2 inhibition and apoptotic inducing assay. Compounds 8 h, 8 l, and 8r showed potential antitumor activities with IC50 values of 4.92-14.37 µM relative to the reference drug, sorafenib (IC50 values of 5.47-9.18 µM). Compound 8 h possessed potential VEGFR-2 inhibitory activity (IC50 = 60.27 nM) compared to standard drug sorafenib (IC50 = 55.43 nM), whereas compound 8 l showed moderate inhibitory activity (IC50 = 93.50 nM). The most active compound, 8 h, exhibited total apoptosis with 36.24% on MCF-7 cells, more than the apoptotic effect provoked by sorafenib (32.46%) and the cell cycle arrested at a G1/S phase. Compound 8 h, a potent VEGFR-2 inhibitor, was docked into the VEGFR-2 binding pocket, where this compound showed binding interaction similar to co-crystallized inhibitor sorafenib.


Assuntos
Antineoplásicos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Antineoplásicos/química , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases , Quinazolinas/farmacologia , Relação Estrutura-Atividade
6.
Sci Rep ; 12(1): 4742, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304513

RESUMO

Tuberculosis is a disease that remains a significant threat to public health worldwide, and this is mainly due to the selection of strains increasingly resistant to Mycobacterium tuberculosis, its causative agent. One of the validated targets for the development of new antibiotics is DNA gyrase. This enzyme is a type II topoisomerase responsible for regulating DNA topology and, as it is essential in bacteria. Thus, to contribute to the search for new molecules with potential to act as competitive inhibitors at the active site of M. tuberculosis DNA gyrase B, the present work explored a dataset of 20,098 natural products that were filtered using the FAF-Drugs4 server to obtain a total of 5462 structures that were subsequently used in virtual screenings. The consensus score analysis between LeDock and Auto-Dock Vina software showed that ZINC000040309506 (pyrrolo[1,2-a]quinazoline derivative) exhibit the best binding energy with the enzyme. In addition, its subsequent optimization generated the derivative described as PQPNN, which show better binding energy in docking analysis, more stability in molecular dynamics simulations and improved pharmacokinetic and toxicological profiles, compared to the parent compound. Taken together, the pyrrolo[1,2-a]quinazoline derivative described for the first time in the present work shows promising potential to inhibit DNA gyrase B of M. tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Antituberculosos/química , DNA Girase/metabolismo , Humanos , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/metabolismo , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Inibidores da Topoisomerase II/metabolismo
7.
Int J Mol Sci ; 23(5)2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35269887

RESUMO

Mesenchymal stem cells (MSCs) are considered to be a powerful tool in the treatment of various diseases. Scientists are particularly interested in the possibility of using MSCs in cancer therapy. The research carried out so far has shown that MSCs possess both potential pro-oncogenic and anti-oncogenic properties. It has been confirmed that MSCs can regulate tumor cell growth through a paracrine mechanism, and molecules secreted by MSCs can promote or block a variety of signaling pathways. These findings may be crucial in the development of new MSC-based cell therapeutic strategies. The abilities of MSCs such as tumor tropism, deep migration and immune evasion have evoked considerable interest in their use as tumor-specific vectors for small-molecule anticancer agents. Studies have shown that MSCs can be successfully loaded with chemotherapeutic drugs such as gemcitabine and paclitaxel, and can release them at the site of primary and metastatic neoplasms. The inhibitory effect of MSCs loaded with anti-cancer agents on the proliferation of cancer cells has also been observed. However, not all known chemotherapeutic agents can be used in this approach, mainly due to their cytotoxicity towards MSCs and insufficient loading and release capacity. Quinazoline derivatives appear to be an attractive choice for this therapeutic solution due to their biological and pharmacological properties. There are several quinazolines that have been approved for clinical use as anticancer drugs by the US Food and Drug Administration (FDA). It gives hope that the synthesis of new quinazoline derivatives and the development of methods of their application may contribute to the establishment of highly effective therapies for oncological patients. However, a deeper understanding of interactions between MSCs and tumor cells, and the exploration of the possibilities of using quinazoline derivatives in MSC-based therapy is necessary to achieve this goal. The aim of this review is to discuss the prospects for using MSC-based cell therapy in cancer treatment and the potential use of quinazolines in this procedure.


Assuntos
Antineoplásicos , Células-Tronco Mesenquimais , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Células-Tronco Mesenquimais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico
8.
Future Med Chem ; 14(8): 557-570, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35332778

RESUMO

Background: Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.


Assuntos
Histona-Lisina N-Metiltransferase , Leucemia , Adenina/farmacologia , Antídotos , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia/metabolismo , Simulação de Acoplamento Molecular , Quinazolinas/farmacologia
9.
Artigo em Chinês | MEDLINE | ID: mdl-35266363

RESUMO

OBJECTIVE: To investigate the effects of nitroquine on the development of different stages of Plasmodium yoelii in Anopheles stephensi. METHODS: An. stephensi mosquitoes were fed with conventional sucrose water or sucrose water containing 100 µmol/L nitroquine one day prior to P. yoelii infection. Following starvation for 24 hours, mosquitoes were fed with the blood of Kunming mice infected with P. yoelii, and the number of oocysts was observed in the stomach of An. stephensi. After 6 days and 14 days of infection, the mosquitoes were starved for 24 hours, and then fed with conventional sucrose water or nitroquine treated sucrose water. The An. stephensi mosquitoes were starved for 24 hours 6 and 14 days post-infection with P. yoelii, and then fed with conventional sucrose water or nitroquine-containing sucrose water, the numbers of P. yoelii sporozoites were examined in the hemolymph and salivary glands of An. stephensi. RESULTS: Following exposure to nitroquine-containing sucrose water one day prior to P. yoelii infections, the number of P. yoelii oocysts was significantly lower in the An. stephensi stomach on day 7 (119.2 ± 16.1 vs. 207.3 ± 21.8; t = 3.207, P < 0.05). After conventional sucrose water was ceased for 24 hours on day 6, and An. stephensi was fed with nitroquine-containing sucrose water, the number of P. yoelii sporozoites peaked in the hemolymph on day 14 in the nitroquine treatment group (952.3 ± 22.7) and on day 12 in the sucrose water treatment group (1 287.0 ± 39.0), and there was a significant difference in the number of sporozoites in the salivary glands between the nitroquine treatment group and the sucrose water treatment group (9 467.0 ± 1 304.0 vs. 10 533.0 ± 758.7; t = 0.707, P = 0.506) on day 17. After conventional sucrose water was ceased for 24 hours on day 14, and An. stephensi was fed with nitroquine-containing sucrose water, the number of sporozoites in the salivary glands was significantly greater in the nitroquine treatment group than in the sucrose water treatment group (21 900.0 ± 2 613.0 vs. 10 533.0 ± 732.3; t = 4.188, P < 0.05). CONCLUSIONS: Nitroquine treatment exhibits diverse effects the development of different stages of P. yoelii, and nitroquine treatment may reduce the transmission of P. yoelii in uninfected An. stephensi.


Assuntos
Anopheles , Plasmodium yoelii , Animais , Camundongos , Mosquitos Vetores , Quinazolinas/farmacologia
10.
J Headache Pain ; 23(1): 35, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35260079

RESUMO

BACKGROUND: Vestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN). METHODS: A CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining. RESULTS: The expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM. CONCLUSIONS: The present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca , Transmissão Sináptica , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Piperazinas/farmacologia , Quinazolinas/farmacologia , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina , Transmissão Sináptica/efeitos dos fármacos
11.
Eur J Med Chem ; 233: 114249, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35259690

RESUMO

Pan-HER inhibitors exhibit extensive biological activity and offer unique advantages and usually bind to targets in an irreversible manner. Owing to the off-target toxicity of irreversible inhibitors, reversible pan-HER inhibitors are desirable. Herein, we describe the process of N-(ring structure fused phenyl)quinazoline-4-amine-based design, synthesis, and biological evaluation of pan-HER inhibitors in vitro and in vivo. Compound C5, with the molecular skeleton of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine, displayed irreversible binding just like other effective pan-HER inhibitors. To our surprise, compound C6, which possessed the same skeleton, was found to be a high-strength reversible pan-HER inhibitor. This compound was capable of inhibiting HER1s (such as EGFR T790M/L858R and WT), HER2, and HER4 and can be considered as a breakthrough in the development of pan-HER inhibitors. Altogether, N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine can serve as an effective molecular skeleton for developing both reversible and irreversible pan-HER inhibitors in the following discovery of antitumor drugs.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Humanos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
12.
Alkaloids Chem Biol ; 88: 1-47, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35305754

RESUMO

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.


Assuntos
Alcaloides , Quinolinas , Alcaloides/farmacologia , Anti-Inflamatórios , Biologia , Quinazolinas/farmacologia , Quinolinas/farmacologia
13.
Arch Pharm Res ; 45(3): 123-141, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35314953

RESUMO

The gene amplification of human epidermal growth factor receptor 2 (HER2) plays an essential role in the proliferation and progression of several cancers. However, HER2 inhibitors such as lapatinib strongly suppress wild-type EGFR, resulting in severe adverse effects. Therefore, there is an unmet need for highly selective HER2 inhibitors. In this study, we describe the design and synthesis of novel quinazoline derivatives that exhibit enhanced selectivity for HER2 over wild-type EGFR. Structure-activity relationship analysis indicated that the selectivity for HER2 over EGFR depends on the aniline moiety at C-4 and the substituents at C-6 in the quinazoline derivatives. Compound 7c with an IC50 of 8 nM for HER2 exhibited significantly higher selectivity for HER2 over EGFR, with a 240-fold improvement over lapatinib. In addition, the synthesized compounds exhibited anti-proliferative activity in the nanomolar range against SKBR3, a human breast cancer cell line that overexpresses HER2.


Assuntos
Antineoplásicos , Quinazolinas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade
14.
Molecules ; 27(3)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35164248

RESUMO

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a-n. The structure of the newly prepared compounds was proved by microanalysis, IR, 1H-NMR, 13C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC50 value of 2.5 and 5 µM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2's active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinazolinas/farmacologia , Sulfonamidas/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Quinazolinas/química
15.
Bioorg Chem ; 121: 105673, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35217375

RESUMO

Fibroblast growth factor receptor 4 (FGFR4) together with co-receptors modulate the activation of downstream proteins that regulate fundamental processes, and elevated FGFR4 activity is associated with Hepatocellular Carcinoma (HCC). Hence, FGFR4 is a promising therapeutic target for HCC. Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy. Among them, a novel compound (C3) showed FGFR4 and cell proliferation inhibitory activity. Cellular mechanism studies demonstrated that compound C3 induced apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo
16.
J Med Chem ; 65(4): 3359-3370, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35148092

RESUMO

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kγ inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kγ in intact cells and that compounds from this series do not inhibit PI5P4Kα or PI5P4Kß. Furthermore, the first X-ray structure of PI5P4Kγ bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 Å from the ATP pocket.


Assuntos
Trifosfato de Adenosina/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Ligação Competitiva , Cristalografia por Raios X , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/química , Especificidade por Substrato
17.
Bioorg Chem ; 121: 105652, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35158284

RESUMO

KRas is the most frequently mutated protein of the three Ras isoforms in various cancer types. KRas mutations (i.e. G12C) are present in approximately 30% of human cancers. Based on our previously reported KRas G12C inhibitor LLK-10, we designed a series of quinazoline analogues with a trifluoromethacrylic acid warhead as covalent inhibitor of KRas G12C. The pharmacological activities of these compounds were assessed against a panel of KRas G12C mutated cancer cells (i.e. H358 and H23). Among them, K20 showed that highest antiproliferative potency with an average IC50 of 1.16 µM, clearly better than that of the lead LLK-10 (average IC50 = 2.32 µM), and comparable to that of ARS-1620 (average IC50 = 1.32 µM, a known KRas G12C inhibitor). K20 also exhibited better selectivity index (SI = 5 âˆ¼ 23) than LLK-10 (SI = 1.5-3) for inhibiting the growth of KRas G12C mutated cancer cells (i.e. H358 and H23) over other KRas (e.g. G13D, G12S, G12D, G12V) mutated cancer cells. Utilizing a KRAS-GTP pull-down assay, it was demonstrated that K20 decreased the active form of KRAS (KRAS-GTP) in NCI-H358 cells. In addition, K20 reduced the level of phosphorylated Erk and caused cancer cell apoptosis. Further, K20 could inhibit the formation of H358 or H23 tumor colonies. Moreover, K20 displayed significant tumor-suppressing effects in NCI-H358 xenograft-bearing nude mice with a TGI (tumor growth inhibition) of 41%, comparable to that of ARS-1620 (47%). Lastly, K20 exhibited benign toxicity profiles without causing bone marrow suppression and any other apparent toxicity to major organs of mice. Collectively, these results indicate that K20 is a KRas G12C inhibitor deserving further investigation.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Animais , Guanosina Trifosfato , Humanos , Camundongos , Camundongos Nus , Mutação , Piperazinas , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinas/farmacologia
18.
Pharm Biol ; 60(1): 359-373, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35171063

RESUMO

CONTEXT: Patients with non-alcoholic steatohepatitis (NASH) may have a simultaneous intake of pravastatin and evodiamine-containing herbs. OBJECTIVE: The effect of evodiamine on the pharmacokinetics of pravastatin and its potential mechanisms were investigated in NASH rats. MATERIALS AND METHODS: The NASH model was conducted with feeding a methionine choline-deficient (MCD) diet for 8 weeks. Sprague-Dawley rats were randomised equally (n = 6) into NASH group, evodiamine group (10 mg/kg), pravastatin group (10 mg/kg), and evodiamine (10 mg/kg) + pravastatin (10 mg/kg) group. Normal control rats were fed a standard diet. Effects of evodiamine on the pharmacokinetics, distribution, and uptake of pravastatin were investigated. RESULTS: Evodiamine decreased Cmax (159.43 ± 26.63 vs. 125.61 ± 22.17 µg/L), AUC0-t (18.17 ± 2.52 vs. 14.91 ± 2.03 mg/min/L) and AUC0-∞ (22.99 ± 2.62 vs. 19.50 ± 2.31 mg/min/L) of orally administered pravastatin in NASH rats, but had no significant effect in normal rats. Evodiamine enhanced the uptake (from 154.85 ± 23.17 to 198.48 ± 26.31 pmol/mg protein) and distribution (from 736.61 ± 108.07 to 911.89 ± 124.64 ng/g tissue) of pravastatin in NASH rat liver. The expression of Oatp1a1, Oatp1a4, and Oatp1b2 was up-regulated 1.48-, 1.38-, and 1.51-fold by evodiamine. Evodiamine decreased the levels of IL-1ß, IL-6, and TNF-α by 27.82%, 24.76%, and 29.72% in NASH rats, respectively. DISCUSSION AND CONCLUSIONS: Evodiamine decreased the systemic exposure of pravastatin by up-regulating the expression of OATPs. These results provide a reference for further validation of this interaction in humans.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transportadores de Ânions Orgânicos/genética , Pravastatina/farmacocinética , Quinazolinas/farmacologia , Animais , Área Sob a Curva , Interações Ervas-Drogas , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
19.
Sci Rep ; 12(1): 2505, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169179

RESUMO

Mpro, the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify Mpro inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to Mpro and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured Mpro and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of Mpro. The most active compound from this chemotype inhibited Mpro in vitro with an IC50 value of 1 µM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to Mpro was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/química , SARS-CoV-2/enzimologia , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Cristalografia por Raios X , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Nitrilas/química , Nitrilas/metabolismo , Nitrilas/farmacologia , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Quinazolinas/química , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
20.
Mar Drugs ; 20(2)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35200684

RESUMO

The tricyclic quinazoline alkaloid deoxyvasicinone (DOV, 1) was isolated from a marine-derived Streptomyces sp. CNQ-617, and its anti-melanogenic effects were investigated. Deoxyvasicinone was shown to decrease the melanin content of B16F10 and MNT-1 cells that have been stimulated by α-melanocyte-stimulating hormone (α-MSH). In addition, microscopic images of the cells showed that deoxyvasicinone attenuated melanocyte activation. Although, deoxyvasicinone did not directly inhibit tyrosinase (TYR) enzymatic activity, real-time PCR showed that it inhibited the mRNA expression of TYR, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2). In the artificial 3D pigmented skin model MelanodermTM, deoxyvasicinone brightened the skin significantly, as confirmed by histological examination. In conclusion, this study demonstrated that the marine microbial natural product deoxyvascinone has an anti-melanogenic effect through downregulation of melanogenic enzymes.


Assuntos
Melaninas/metabolismo , Quinazolinas/farmacologia , Pele/efeitos dos fármacos , Streptomyces/metabolismo , Animais , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanoma/metabolismo , Melanoma Experimental/metabolismo , Camundongos , Quinazolinas/isolamento & purificação , Pele/metabolismo
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