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2.
Mol Med Rep ; 25(5)2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35362542

RESUMO

Evodiamine (Evo) is an alkaloid that can be extracted from the berry fruit Evodia rutaecarpa and has been reported to exert various pharmacological effects, such as antidiarrheal, antiemetic and antiulcer effects. In vivo, the potential effects of Evo were investigated in a mouse model of dextran sodium sulfate (DSS)­induced ulcerative colitis (UC) and in adenomatous polyposis coli (Apc)MinC/Gpt C57BL/6 mice with colorectal cancer (CRC), where the latter harbours a point­mutation in the Apc gene. Evo suppressed the degree of weight loss and colon shortening induced by DSS, decreased the disease activity index value and ameliorated the pathological alterations in the colon of mice with UC as examined via H&E staining of colon tissues. In addition, Evo decreased the number and size of colonic tumors in ApcMinC/Gpt mice. Proteomics (colon tissues), ELISA (colon tissues and serum) and western blotting (colon tissues) results revealed that Evo inhibited NF­κB to mediate the levels of various cytokines, including, in the DSS­induced UC model, IL­1ß, IL­2, IL­6, IL­8, TNF­α, IFN­Î³ (ELISA of colon tissues and serum), NF­κB, IKKα+ß, IκBα, S100a9, TLR4 and MyD88 (western blotting of colon tissues), and, in the colorectal cancer model, IL­1ß, IL­2, IL­6, IL­15, IL­17, IL­22, TNF­α (ELISA of colon tissues and serum), NF­κB, IKKα+ß, IκBα and S100a9 (western blotting of colon tissues), to achieve its anti­inflammatory and antitumor effects. In vitro, Evo also reduced the viability of the colon cancer cell line SW480, inhibited mitochondrial membrane potential (MMP detection), caused G2/M­phase arrest (cell cycle detection) and suppressed the translocation of phosphorylated­NF­κB from the cytoplasm into the nucleus (immunofluorescence of p­NF­κB). Theoretical evidence (MD simulations) suggest that Evo may bind to the ordered domain (α­helix) of NF­κB to influence this protein. The protein secondary structure changes were analyzed by the cpptraj module in Amber. In addition, these data provide experimental evidence that Evo may be an effective agent for treating UC and CRC.


Assuntos
Colite Ulcerativa , Neoplasias Colorretais , Animais , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/patologia , Neoplasias Colorretais/patologia , Sulfato de Dextrana/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Quinazolinas
3.
J Bioinform Comput Biol ; 20(2): 2240003, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35430948

RESUMO

In this paper, the authors present and describe, in detail, an original software-implemented numerical methodology used to determine the effect of mutations on binding to small chemical molecules, on the example of gefitinib, AMPPNP, CO-1686, ASP8273, erlotinib binding with EGFR protein, and imatinib binding with PPARgamma. Furthermore, the developed numerical approach makes it possible to determine the stability of a molecular complex, which consists of a protein and a small chemical molecule. The description of the software package that implements the presented algorithm is given in the website: https://binomlabs.com/.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Mutação , Quinazolinas
4.
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
5.
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
6.
ACS Biomater Sci Eng ; 8(5): 1907-1920, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35482571

RESUMO

Single-modality tumor therapy confronts many challenges, such as incomplete tumor ablation, tumor metastasis, and limited tumor tissue penetration. Combination therapy simultaneously achieves deep drug delivery to fully exert synergistic effects and has received increasing attention. Herein, based on the excellent efficacy of anti-angiogenesis therapy combined with chemotherapy and the specific size of the poly-amidoamine dendrimer (PAMAM), we developed a pH-triggered size-converted nano-drug delivery system to co-deliver fruquintinib (FRU) and doxorubicin (DOX). This study used cyclic Arg-Gly-Asp (cRGD) as the target, pH-responsive liposomes (PRLs), and PAMAM as the drug carrier. The FRU and DOX-loaded small-particle-size complex polyamide-amine-doxorubicin (PD) was encapsulated into PRLs with the target to construct a size-converted nano-drug delivery system, PRL-PD/FRU-cRGD. This nanoparticle (∼120 nm) actively targeted tumor tissues and used the acidic microenvironment outside tumor cells to release FRU and small-particle-size complex PD (∼15 nm), enabling the conversion of large-size nanoparticles to small-size nanoparticles and resulting in efficient tumor accumulation. In addition, the released PD could realize the deep delivery of DOX, showing efficient deep tumor penetration and further enhancing the tumor-suppressing effect. The results of in vivo and in vitro experiments showed that PRL-PD/FRU-cRGD exhibited the excellent synergistic effects of anti-angiogenesis therapy combined with chemotherapy and effectively inhibited tumor cell proliferation and metastasis, thereby achieving efficient tumor therapy. Thus, PRL-PD/FRU-cRGD shows great potential for combined tumor therapy.


Assuntos
Nanopartículas , Neoplasias , Benzofuranos , Doxorrubicina/uso terapêutico , Portadores de Fármacos , Humanos , Lipossomos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Quinazolinas , Microambiente Tumoral
7.
Bioorg Med Chem ; 62: 116727, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35366437

RESUMO

In the search for novel more effective insecticides, natural products could be used as ideal template compounds due to their good environmental compatibility, various bioactivities, unique scaffolds and mode of action. We have found that natural product evodiamine, the main active component from the fruits of Evodia rutaecarpa (Juss.) Benth, displayed obvious insecticidal activities against lepidoptera pests. To continue our research, a series of evodiamine derivatives 3a-3aa were rationally designed and synthesized. The larvicidal activities results indicated that most of target compounds displayed better efficacy than evodiamine, matrine, and rotenone against Mythimna separata, Plutella xylostella and Helicoverpa armigera, among which 3z exhibited excellent larvicidal activities (65% at 2.5 mg/L against M. separata, 75% at 1.0 mg/L against P. xylostella, and 85% 10 mg/L against H. armigera, respectively), much better than evodiamine (0%), matrine (0%), and rotenone (0%). The preliminary structure activity relationships demonstrated that the fluorine atom at the E ring of evodiamine had a positive influence on the larvicidal activity. The calcium imaging experiment studies indicated that 3z could act on the ryanodine receptor (RyR) of M. separata and was an effective calcium activator for RyR.


Assuntos
Inseticidas , Mariposas , Animais , Cálcio , Inseticidas/química , Inseticidas/farmacologia , Larva , Estrutura Molecular , Mariposas/metabolismo , Quinazolinas , Rotenona , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
8.
J Microbiol ; 60(5): 550-559, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35437625

RESUMO

Adjuvants are substances added to vaccines to enhance antigen-specific immune responses or to protect antigens from rapid elimination. As pattern recognition receptors, Toll-like receptors 7 (TLR7) and 8 (TLR8) activate the innate immune system by sensing endosomal single-stranded RNA of RNA viruses. Here, we investigated if a 2,4-diaminoquinazoline-based TLR7/8 agonist, (S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexan-1-ol (named compound 31), could be used as an adjuvant to enhance the serological and mucosal immunity of an inactivated influenza A virus vaccine. The compound induced the production of proinflammatory cytokines in macrophages. In a dose-response analysis, intranasal administration of 1 µg compound 31 together with an inactivated vaccine (0.5 µg) to mice not only enhanced virus-specific IgG and IgA production but also neutralized influenza A virus with statistical significance. Notably, in a virus-challenge model, the combination of the vaccine and compound 31 alleviated viral infection-mediated loss of body weight and increased survival rates by 40% compared with vaccine only-treated mice. We suggest that compound 31 is a promising lead compound for developing mucosal vaccine adjuvants to protect against respiratory RNA viruses such as influenza viruses and potentially coronaviruses.


Assuntos
Vírus da Influenza A , Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Adjuvantes Imunológicos/farmacologia , Administração Intranasal , Animais , Anticorpos Antivirais , Humanos , Imunidade nas Mucosas , Camundongos , Camundongos Endogâmicos BALB C , Quinazolinas , Receptor 7 Toll-Like
9.
Sci Rep ; 12(1): 7002, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488047

RESUMO

Gefitinib and erlotinib are the first-line tyrosine kinase inhibitors (TKI) for advanced non-small-cell lung cancer. However, co-administration of either drug with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) may reduce TKI's bioavailability. Therefore, we aimed to investigate the effects of these drug-drug interactions. We surveyed nationwide population-based databases between Jan 1, 2010, and Dec 30, 2018. Newly diagnosed patients with advanced lung adenocarcinoma who received first-line gefitinib or erlotinib were identified. Effects on overall survival (OS) and time to next treatment (TTNT) association between PPIs or H2RAs and co-administrated gefitinib or erlotinib were evaluated. PPIs or H2RAs users were defined if the period overlapped with TKIs by ≥ 20%. A total of 4340 gefitinib and 1635 erlotinib users were included. PPI group had the shortest median OS and TTNT compared to the H2RA and non-user groups (in gefitinib cohort: OS: 14.35 vs. 17.67 vs. 21.87 months; P < 0.0001, TTNT: 8.47 vs. 10.78 vs. 10.33 months; P < 0.0001); (in erlotinib cohort: OS: 16.97 vs. 20.07 vs. 23.92 months; P < 0.0001, TTNT: 9.06 vs. 11.85 vs. 10.90 months; P = 0.0808). Compared with the non-user group, the adjusted hazard ratio (aHR) of the PPI group in the gefitinib was 1.58 on OS (95% CI 1.42-1.76), 1.37 on TTNT (95% CI 1.24-1.52); in the erlotinib was 1.54 on OS (95% CI 1.30-1.82) and 1.19 on TTNT (95% CI 1.01-1.39). Concurrent use of PPIs with first-line gefitinib or erlotinib therapy was associated with a worse OS and TTNT in patients with lung adenocarcinoma harboring EGFR mutations.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/induzido quimicamente , Adenocarcinoma de Pulmão/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB , Cloridrato de Erlotinib , Gefitinibe/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases , Inibidores da Bomba de Prótons/uso terapêutico , Quinazolinas
10.
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
11.
J Enzyme Inhib Med Chem ; 37(1): 1212-1226, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35450499

RESUMO

A series of novel derivatives of isaindigotone, which comes from the root of isaits indinatca Fort, were synthesised (Compound 1-26). Four human gastrointestinal cancer cells (HCT116, PANC-1, SMMC-7721, and AGS) were employed to evaluate the anti-proliferative activity. Among them, Compound 6 displayed the most effective inhibitory activity on AGS cells with an IC50 (50% inhibitory concentration) value of 2.2 µM. The potential mechanism study suggested that Compound 6 induced apoptosis in AGS cells. The collapse of mitochondrial membrane potential (MMP) in AGS cells was proved. In docking analysis, good affinity interaction between Compound 6 and AKT1 was discovered. Treatment of AGS cells with Compound 6 also resulted in significant suppression of PI3K/AKT/mTOR signal pathway. The collapse of MMP and suppression of PI3K/AKT/mTOR signal pathway may be responsible for induction of apoptosis. This derivative Compound 6 could be useful as an underlying anti-tumour agent for treatment of gastric cancer.


Assuntos
Antineoplásicos , Neoplasias Gástricas , Alcaloides , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Metaloproteinases da Matriz , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , Quinazolinas , Neoplasias Gástricas/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo
12.
Int J Mol Sci ; 23(8)2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35457081

RESUMO

DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy.


Assuntos
Proteína Quinase Ativada por DNA , Neoplasias , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , DNA , Reparo do DNA , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fosfatidilinositol 3-Quinases/metabolismo , Piridazinas , Quinazolinas
13.
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
14.
Molecules ; 27(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35408762

RESUMO

The halogen bond has been widely used as an important supramolecular tool in various research areas. However, there are relatively few studies on halogen bonding related to molecular chirality. 3-(2-Halophenyl)quinazoline-4-thione derivatives have stable atropisomeric structures due to the rotational restriction around an N-C single bond. In X-ray single crystal structures of the racemic and optically pure N-C axially chiral quinazoline-4-thiones, we found that different types of intermolecular halogen bonds (C=S⋯X) are formed. That is, in the racemic crystals, the intermolecular halogen bond between the ortho-halogen atom and sulfur atom was found to be oriented in a periplanar conformation toward the thiocarbonyl plane, leading to a syndiotactic zig-zag array. On the other hand, the halogen bond in the enantiomerically pure crystals was oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. These results indicate that the corresponding racemic and optically pure forms in chiral molecules are expected to display different halogen bonding properties, respectively, and should be separately studied as different chemical entities.


Assuntos
Halogênios , Tionas , Halogênios/química , Modelos Moleculares , Conformação Molecular , Quinazolinas
15.
J Agric Food Chem ; 70(16): 5197-5206, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35435667

RESUMO

Pests threaten worldwide food security by decreasing crop yields and damaging their quality. Natural product-based molecular design and structural optimization have been one of the most effective ways to innovate pesticides for integrated insect management. To continue our previous studies on the discovery of insecticidal lead, a series of evodiamine derivatives were designed, synthesized, and evaluated for their insecticidal activities. The bioassay results demonstrated that compounds Ian and Iao exhibited 90 and 80% insecticidal activities against Mythimna separata at 2.5 mg/L, respectively, which were superior to evodiamine (10% at 10 mg/L), matrine (45% at 600 mg/L), and rotenone (30% at 200 mg/L). Compounds Ian-Iap showed 90% insecticidal activities against Plutella xylostella at 1.0 mg/L, far more potent than those of evodiamine, matrine, and rotenone. Compound Ian displayed 60% insecticidal activity against Helicoverpa armigera at 5.0 mg/L, while evodiamine, matrine, and rotenone showed very poor activities. The study on the insecticidal mechanism of action by a calcium imaging experiment indicated that the insect ryanodine receptors (RyRs) could be the potential target of Ian. Furthermore, the molecular docking indicated that Ian anchored in the binding site of the RyR of P. xylostella. The above results manifested the potential of evodiamine derivatives as potent insecticide candidates.


Assuntos
Inseticidas , Mariposas , Animais , Inseticidas/química , Larva , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas , Rotenona/metabolismo , Relação Estrutura-Atividade
16.
Int J Immunopathol Pharmacol ; 36: 3946320221086079, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35388733

RESUMO

BACKGROUND: Evodiamine (EVO) is one of the major components isolated from Evodia rutaecarpa (Juss.). Recent studies have shown that EVO has an anti-cancer effect. However, the pharmacological mechanism by which EVO impacts cancer is still poorly understood. OBJECTIVES: This study focused on asking the anti-cancer effect of EVO in human non-small cell lung carcinoma (NSCLC), and in particular to investigate whether EVO acts via modulating the endoplasmic reticulum stress (ERS)-mediated apoptosis pathway. MATERIALS AND METHODS: A Lewis lung carcinoma (LLC) tumor-bearing mouse model was treated with low-dose EVO (5 mg/kg) and high-dose EVO (10 mg/kg) intraperitoneally for 14 d. The effects of EVO on tumor growth, apoptosis, and ERS were assessed. In addition, NSCLC A549 and LLC cells were treated with EVO in vitro. The effects of EVO on cell proliferation, apoptosis, and ERS were investigated. Finally, 4-phenylbutyric acid (4-PBA), an ERS inhibitor, was used to validate whether EVO induced apoptosis of NSCLC cells by modulating ERS. RESULTS: EVO treatment significantly inhibited tumor growth in LLC tumor-bearing mice. H&E staining indicated that EVO treatment reduced the number of tumor cells and the nucleo-plasmic ratio. Immunostaining showed that EVO treatment significantly decreased the expression of Ki-67. TUNEL staining revealed that EVO induced apoptosis in the tumor. Likewise, EVO treatment up-regulated the expression of apoptosis-related genes and proteins and increased activation of the ERS pathway in the tumor. Additionally, EVO inhibited cell proliferation and increased cell apoptotic rates in A549 and LLC cells. EVO also increased the expression levels of genes and proteins associated with ERS-mediated apoptosis pathway in vitro. The effects of EVO on apoptosis were abolished by 4-PBA treatment. CONCLUSIONS: Our study demonstrated that EVO suppresses the progression of NSCLC by modulating the ERS-mediated apoptosis pathway.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático , Neoplasias Pulmonares/metabolismo , Camundongos , Quinazolinas
17.
Org Biomol Chem ; 20(17): 3558-3563, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35416228

RESUMO

Quinazoline compounds demonstrate a variety of physiological and pharmacological activities. However, the most common syntheses require large quantities of oxidants, high temperature, and other extreme conditions. In this study, quinazoline compounds were synthesized from the condensation of α-keto acid and 2-aminobenzylamine and then decarboxylation under blue LED irradiation at room temperature without transition metal catalysts or additives. Therefore, we demonstrated that by using α-keto acid as the acyl source, decarboxylation can be realized under blue LED without oxidants, in a simple, mild, and environmentally friendly process.


Assuntos
Cetoácidos , Quinazolinas , Catálise , Descarboxilação , Luz , Oxidantes , Oxirredução
18.
Mol Cancer Ther ; 21(5): 751-761, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35417017

RESUMO

Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the mAb, trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small-molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small-molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard-of-care trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER; HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Oxazóis , Fosfatidilinositol 3-Quinases/uso terapêutico , Piridinas , Quinazolinas , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/uso terapêutico , Trastuzumab
19.
Dalton Trans ; 51(13): 5024-5033, 2022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35274641

RESUMO

In this study, two novel curcumin (H-Cur)-tryptanthrin metal compounds-[Zn(TA)Cl2], i.e., Zn(TA), and [Zn(TA)(Cur)]Cl, i.e., Zn(TAC)-were synthesized and investigated using 5-(bis-pyridin-2-ylmethyl-amino)-pentanoic acid (6,12-dioxo-6,12-dihydro-indolo[2,1-b]quinazolin-8-yl)-amide (TA) and H-Cur as the targeting and high-activity anticancer chemotherapeutic moieties, respectively. They were then compared with the di-(2-picolyl)amine (PA) Zn(II) complex [Zn(PA)Cl2], i.e., Zn(PA). When compared with Zn(PA) and cisplatin, the IC50 values of Zn(TA) and Zn(TAC) indicated that the compounds had high cytotoxicity against A549/DDP cancer cells, implying that the H-Cur-tryptanthrin Zn(II) compounds have the potential for use as anticancer drugs. We propose the use of synthesized theragnostic H-Cur-tryptanthrin Zn(II) complexes with nuclear-targeting and DNA-damaging capabilities as a simple therapeutic strategy against tumors. The Zn(TA) and Zn(TAC) complexes could be traced via red fluorescence and were found to accumulate in the cell nuclei and induce DNA damage, cell cycle arrest, mitochondrial dysfunction, and cell apoptosis both in vitro and in vivo. In addition, Zn(TAC) exhibited a higher antiproliferative effect on A549/DDP than Zn(TA) and Zn(PA), which was undoubtedly associated with the key roles of the novel tryptanthrin derivative TA and H-Cur in the Zn(TAC) complex.


Assuntos
Antineoplásicos , Curcumina , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Curcumina/farmacologia , Ligantes , Quinazolinas , Zinco/farmacologia
20.
Pharm Biol ; 60(1): 621-626, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35289238

RESUMO

CONTEXT: Tucatinib (CYP2C8 substrate) and quercetin (CYP2C8 inhibitor) are two common drugs for the treatment of cancer. However, the effect of quercetin on the metabolism of tucatinib remains unknown. OBJECTIVE: We validated a sensitive method to quantify tucatinib levels in rat plasma based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which was successfully employed to explore the effect of quercetin on tucatinib pharmacokinetics in rats. MATERIALS AND METHODS: An Acquity UPLC BEH C18 column was applied to achieve the separation of tucatinib and internal standard (IS) talazoparib after protein precipitation with acetonitrile. Then, we used this assay to investigate the effect of different doses of quercetin (25, 50 and 100 mg/kg) on the exposure of orally administered tucatinib (30 mg/kg) in 24 Sprague-Dawley (SD) rats, which were randomly divided into three quercetin pre-treated groups and one control group (n = 6). RESULTS: Our developed assay was verified in all aspects of bioanalytical method validation, involving lower limit of quantification (LLOQ), selectivity, accuracy and precision, calibration curve, extraction recovery, matrix effect and stability. After pre-treatment with 100 mg/kg quercetin, AUC0→t, AUC0→∞ and Cmax of tucatinib were remarkably increased by 75.4%, 75.8% and 59.1% (p < 0.05), respectively, while CLz/F was decreased significantly by 47.3% (p < 0.05) when compared with oral administration of 30 mg/kg tucatinib alone. This change is dose-dependent. CONCLUSIONS: This study will help better understand the pharmacokinetic properties of tucatinib with concurrent use with quercetin, and more clinical verifications were inspired to confirm whether this interaction has clinical significance in humans.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Oxazóis/farmacocinética , Piridinas/farmacocinética , Quercetina/farmacologia , Quinazolinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Antineoplásicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Interações Medicamentosas , Limite de Detecção , Masculino , Oxazóis/administração & dosagem , Oxazóis/análise , Piridinas/administração & dosagem , Piridinas/análise , Quercetina/administração & dosagem , Quinazolinas/administração & dosagem , Quinazolinas/análise , Ratos , Ratos Sprague-Dawley
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