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1.
Dalton Trans ; 51(45): 17263-17276, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36317406

RESUMO

In recent years, Ru(II) complexes have gained high importance in medicinal chemistry due to their significant anti-cancer activities, which are directly related to their DNA binding ability. In this report, the chemistry and cytotoxicity of two new Ru(II) complexes containing imidazole pyridine (Ru-1) and imidazole quinoline (Ru-2) have been studied. The prepared compounds were characterized using infrared (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS), isothermal titration calorimetry (ITC), UV-Vis, and fluorescence spectral techniques. The structural analyses show that the Ru(II) complexes exhibit a 'piano stool' coordination geometry and they are composed of one bound arene, two sigma bonded benzil nitrogen atoms, and labile chlorine linked to Ru(II). The photo-physical properties of these complexes were examined, and they exhibit absorption peaks at 260 nm and 380 nm, which are due to the involvement of intra-ligand charge transitions (ILCT) and metal-to-ligand charge transitions (MLCT), respectively. The binding process of the Ru(II) complexes with DNA and BSA is non-covalent in nature and the binding constants of Ru-1 and Ru-2 complexes with DNA and BSA were found to be 1 × 105 M-1 and 1 × 103 M-1, respectively. In the presence of the Ru(II) complexes, ethidium bromide (EtBr) is competitively displaced from DNA by intercalation of the Ru(II) complexes in DNA and it is well corroborated by viscosity and in silico studies. Both the ligands and Ru(II) complexes were carefully investigated in vitro for cytotoxicity against HeLa, MCF-7, and MDA-MB-231 cells. Surprisingly, both Ru(II) complexes exhibit superior cytotoxicity to cisplatin with a low LD50 value against the examined cancer cells. Besides, an insignificant effect on HEK normal cells (LD50 > 140 µM) was observed.


Assuntos
Antineoplásicos , Complexos de Coordenação , Quinolinas , Rutênio , Humanos , Rutênio/química , Ligantes , Complexos de Coordenação/química , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , DNA/química , Imidazóis/farmacologia , Quinolinas/farmacologia , Piridinas/farmacologia , Linhagem Celular Tumoral
2.
Int J Mol Sci ; 23(21)2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36361971

RESUMO

Quinoline derivatives have been reported to possess a wide range of pharmaceutical activities. Our group previously synthesized a series of quinoline compounds, in which compound 91b1 showed a significant anticancer effect. The purpose of this study was to evaluate the anticancer activity of compound 91b1 in vitro and in vivo, and screen out its regulated target. A series of cancer cell lines and nontumor cell lines were treated with compound 91b1 by MTS cytotoxicity assay and cell-cycle assay. In vivo anticancer activity was evaluated by a xenografted model on nude mice. Target prediction of 91b1 was assessed by microarray assay and confirmed by pancancer analysis. Relative expression of the target gene Lumican was measured by qRT-PCR. 91b1 significantly reduced tumor size in the nude mice xenograft model. Lumican was downregulated after 91b1 treatment. Lumican was proven to increase tumorigenesis in vivo, as well as cancer cell migration, invasion, and proliferation in vitro. The results of this study suggest that the anticancer activity of compound 91b1 probably works through downregulating the gene Lumican.


Assuntos
Antineoplásicos , Quinolinas , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Lumicana/efeitos dos fármacos , Lumicana/metabolismo , Camundongos Nus , Quinolinas/farmacologia
3.
J Med Chem ; 65(21): 14792-14808, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36254462

RESUMO

Enterovirus D68 (EV-D68) is a nonpolio enterovirus that is mainly transmitted through respiratory routes and poses a potential threat for large-scale spread. EV-D68 infections mostly cause moderate to severe respiratory diseases in children and potentially induce neurological diseases. However, there are no specific antiviral drugs or vaccines against EV-D68. Herein, through virtual screening and rational design, a series of novel quinoline analogues as anti-EV-D68 agents targeting VP1 were identified. Particularly, 19 exhibited potent antiviral activity with an EC50 value ranging from 0.05 to 0.10 µM against various EV-D68 strains and showed inhibition of viral replication verified by Western blot, immunofluorescence, and plaque formation assay. Mechanistic studies indicated that the anti-EV-D68 agents work mainly by interacting with VP1. The acceptable bioavailability of 23.9% in rats and significant metabolic stability in human liver microsome (Clint = 10.8 mL/min/kg, t1/2 = 148 min) indicated that compound 19 with a novel scaffold was worth further investigation.


Assuntos
Enterovirus Humano D , Infecções por Enterovirus , Enterovirus , Quinolinas , Infecções Respiratórias , Criança , Humanos , Ratos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Infecções por Enterovirus/tratamento farmacológico , Quinolinas/farmacologia , Quinolinas/uso terapêutico
4.
Int J Mol Sci ; 23(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36232754

RESUMO

Due to the role of cancer stem cells (CSCs) in tumor resistance and glycosphingolipid (GSL) involvement in tumor pathogenesis, we investigated the effect of a newly synthesized compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide 1 on the percentage of CSCs and the expression of six GSLs on CSCs and non-CSCs on breast cancer cell lines (MDA-MB-231 and MCF-7). We also investigated the effect of 1 on the metabolic profile of these cell lines. The MTT assay was used for cytotoxicity determination. Apoptosis and expression of GSLs were assessed by flow cytometry. A GC-MS-coupled system was used for the separation and identification of metabolites. Compound 1 was cytotoxic for both cell lines, and the majority of cells died by treatment-induced apoptosis. The percentage of CSCs was significantly lower in the MDA-MB-231 cell line. Treatment with 1 caused a decrease of CSC IV6Neu5Ac-nLc4Cer+ MDA-MB-231 cells. In the MCF-7 cell line, the percentage of GalNAc-GM1b+ CSCs was increased, while the expression of Gg3Cer was decreased in both CSC and non-CSC. Twenty-one metabolites were identified by metabolic profiling. The major impact of the treatment was in glycolysis/gluconeogenesis, pyruvate and inositol metabolism. Compound 1 exhibited higher potency in MBA-MB-231 cells, and it deserves further examination.


Assuntos
Antineoplásicos , Neoplasias da Mama , Quinolinas , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Glucose/metabolismo , Glicoesfingolipídeos/metabolismo , Humanos , Inositol/farmacologia , Células-Tronco Neoplásicas/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Piruvatos/metabolismo , Quinolinas/farmacologia
5.
Int J Mol Sci ; 23(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36233226

RESUMO

Natural products play an important role in drug development and lead compound synthesis. Neocryptolepine is a polycyclic quinoline compound isolated from Cryptolepis sanguinolent. The cytotoxicity of neocryptolepine to gastric cancer cells AGS, MKN45, HGC27, and SGC7901 was not very strong, and it also had certain toxicity to gastric mucosa cells GES-1. Therefore, a series of neocryptolepine derivatives were synthesized by the modification of the structure of neocryptolepine, and their cytotoxicity was evaluated. The results showed that compounds C5 and C8 exhibited strong cytotoxicity to AGS cells. The cell colony formation and cell migration experiments suggested that compounds C5 and C8 could inhibit the proliferation and cell migration of AGS and HGC27 cells. Cell cycle and apoptosis experiments showed that compounds C5 and C8 did not cause the apoptosis of AGS and HGC27 cells but, mainly, caused cell necrosis. Compound C5 had no significant effect on AGS and HGC27 cell cycles at low concentration. After treatment with AGS cells for 24 h at high concentration, compound C5 could significantly arrest the AGS cell cycle in the G2/M phase. Compound C8 had no significant effect on the AGS and HGC27 cell cycles. The results of molecular docking and Western blot showed that compounds C5 and C8 might induce cytotoxicity through the PI3K/AKT signaling pathway. Therefore, compounds C5 and C8 may be promising lead compounds for the treatment of gastric cancer.


Assuntos
Antineoplásicos , Produtos Biológicos , Quinolinas , Neoplasias Gástricas , Alcaloides , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
6.
Eur J Med Chem ; 244: 114799, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36209632

RESUMO

Novel dihydrobenzo[h]quinolines (DHBQs), the products of an efficient catalyst-free three-component reaction (3CR) recently developed by us, possess useful and strong aggregation-induced emission (AIE) characteristic. Here, a series of new dihydrobenzo[h]quinolines (h-DHBQs 4-1-34) and dihydrobenzo[f]quinolines (f-DHBQs 5a-e) were designed and synthesized by the 3CR to study their bioactivities as novel inhibitors against the influenza A (H1N1) virus. The structure-activity relationship (SAR) indicates that the antiviral activities of DHBQs depend on the combination of substituents and three of h-DHBQs (4-12, 4-25 and 4-27) show potent antiviral activity with IC50 = 2.52-3.79 µM. These potent h-DHBQs have low toxicity to MDCK and A549 cells (CC50 > 100 µM for 4-12 and > 50/100 µM for 4-25 and 4-27). The primary mechanism of the antiviral activities of DHBQs was studied using the most potent h-DHBQ 4-12, which indicated that 4-12 could efficiently inhibit virus-induced plaque formation and NP/PB2 protein expression in a dose-dependent way. DHBQs with simple synthetic method, useful AIE characteristic and antiviral activities are expected to be developed into potential inhibitors against influenza A virus, at the same time acting as chemical/biological fluorescent probe.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Quinolinas , Animais , Cães , Antivirais/farmacologia , Relação Estrutura-Atividade , Quinolinas/farmacologia , Células Madin Darby de Rim Canino
7.
Curr Cancer Drug Targets ; 22(11): 865-878, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36267045

RESUMO

Lenvatinib is a multikinase inhibitor which mainly hinders liver cancer proliferation by inhibiting angiogenesis. In 2018, Lenvatinib was approved for the first-line treatment of patients with advanced hepatocellular carcinoma [HCC] in the United States, the European Union, Japan, and China. Lenvatinib has been established as a sorafenib replacement drug with a higher objective response rate [ORR], longer progression-free survival [PFS], and time to progression [TTP]. Lenvatinib resistance during hepatocellular carcinoma treatment has become increasingly common in recent years. Accordingly, it is necessary to determine factors associated with Lenvatinib resistance and explore solutions. In this review, we sought to explore the drug resistance mechanisms of Lenvatinib in liver cancer and methods to reduce drug resistance and summarized the recent achievements of Lenvatinib in liver cancer treatment.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Antineoplásicos/farmacologia , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Quinolinas/uso terapêutico
8.
J Pharmacol Exp Ther ; 383(2): 157-171, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36279397

RESUMO

A series of dipicolyl amine pyrimidines (DPPs) were previously identified as potential α7 agonists by means of a calcium influx assay in the presence of the positive allosteric modulator (PAM) 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596). The compounds lack the quaternary or strongly basic nitrogens of typical nicotinic agonists. Although differing in structure from typical nicotinic agonists, based on crystallographic data with the acetylcholine binding protein, they appeared to engage the site shared by such typical orthosteric agonists. Using oocytes expressing human α7 receptors, we found that the DPPs were efficacious activators of the receptor, with currents showing rapid desensitization characteristic of α7 receptors. However, we note that the rate of recovery from this desensitization depends strongly on structural features within the DPP family. Although the activation of receptors by DPP was blocked by the competitive antagonist methyllycaconitine (MLA), MLA had no effect on the DPP-induced desensitization, suggesting multiple modes of DPP binding. As expected, the desensitized conformational states could be reactivated by PAMs. Mutants made insensitive to acetylcholine by the C190A mutation in the agonist binding site were weakly activated by DPPs. The observation that activation of C190A mutants by the DPP compounds was resistant to the allosteric antagonist (-)cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide supports the hypothesis that the activity of these noncanonical agonists in the orthosteric binding sites was not entirely dependent on the classic epitopes controlling activation by typical agonists and that perhaps they may access alternative modes for promoting the conformational changes associated with activation and desensitization. SIGNIFICANCE STATEMENT: This study reports a family of nicotinic acetylcholine receptor agonists that break the rules about what the structure of a nicotinic acetylcholine receptor agonist should be. It shows that the activity of these noncanonical agonists in the orthosteric binding sites is not dependent on the classical epitopes controlling activation by typical agonists and that through different binding poses, they promote unique conformational changes associated with receptor activation and desensitization.


Assuntos
Quinolinas , Receptores Nicotínicos , Animais , Humanos , Agonistas Nicotínicos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Acetilcolina/farmacologia , Regulação Alostérica , Cálcio/metabolismo , Xenopus laevis , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Pirimidinas , Epitopos , Receptores Nicotínicos/metabolismo
9.
J Neuroinflammation ; 19(1): 265, 2022 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-36309753

RESUMO

Encephalopathy of prematurity (EoP) affects approximately 30% of infants born < 32 weeks gestation and is highly associated with inflammation in the foetus. Here we evaluated the efficacy of montelukast, a cysteinyl leukotriene receptor antagonist widely used to treat asthma in children, to ameliorate peripheral and central inflammation, and subsequent grey matter neuropathology and behaviour deficits in a mouse model of EoP. Male CD-1 mice were treated with intraperitoneal (i.p.) saline or interleukin-1beta (IL-1ß, 40 µg/kg, 5 µL/g body weight) from postnatal day (P)1-5 ± concomitant montelukast (1-30 mg/kg). Saline or montelukast treatment was continued for a further 5 days post-injury. Assessment of systemic and central inflammation and short-term neuropathology was performed from 4 h following treatment through to P10. Behavioural testing, MRI and neuropathological assessments were made on a second cohort of animals from P36 to 54. Montelukast was found to attenuate both peripheral and central inflammation, reducing the expression of pro-inflammatory molecules (IL-1ß, IL-6, TNF) in the brain. Inflammation induced a reduction in parvalbumin-positive interneuron density in the cortex, which was normalised with high-dose montelukast. The lowest effective dose, 3 mg/kg, was able to improve anxiety and spatial learning deficits in this model of inflammatory injury, and alterations in cortical mean diffusivity were not present in animals that received this dose of montelukast. Repurposed montelukast administered early after preterm birth may, therefore, improve grey matter development and outcome in EoP.


Assuntos
Encefalopatias , Nascimento Prematuro , Quinolinas , Recém-Nascido , Humanos , Feminino , Masculino , Animais , Camundongos , Substância Cinzenta , Nascimento Prematuro/tratamento farmacológico , Acetatos/uso terapêutico , Acetatos/farmacologia , Quinolinas/uso terapêutico , Quinolinas/farmacologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico
10.
Molecules ; 27(20)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36296513

RESUMO

Based on the Warburg effect and the increased demand for glucose by tumor cells, a targeted drug delivery strategy was developed. A series of new glycoconjugates with increased ability to interact with GLUT transporters, responsible for the transport of sugars to cancer cells, were synthesized. Glycoconjugation was performed using the C-6 position in the sugar unit, as the least involved in the formation of hydrogen bonds with various aminoacids residues of the transporter. The carbohydrate moiety was connected with the 8-hydroxyquinoline scaffold via a 1,2,3-triazole linker. For the obtained compounds, several in vitro biological tests were performed using HCT-116 and MCF-7 cancer cells as well as NHDF-Neo healthy cells. The highest cytotoxicity of both cancer cell lines in the MTT test was noted for glycoconjugates in which the triazole-quinoline was attached through the triazole nitrogen atom to the d-glucose unit directly to the carbon at the C-6 position. These compounds were more selective than the analogous glycoconjugates formed by the C-1 anomeric position of d-glucose. Experiments with an EDG inhibitor have shown that GLUTs can be involved in the transport of glycoconjugates. The results of apoptosis and cell cycle analyses by flow cytometry confirmed that the new type of glycoconjugates shows pro-apoptotic properties, without significantly affecting changes in the distribution of the cell cycle. Moreover, glycoconjugates were able to decrease the clonogenic potential of cancer cells, inhibit the migration capacity of cells and intercalate with DNA.


Assuntos
Antineoplásicos , Quinolinas , Humanos , Antineoplásicos/química , Açúcares , Glicoconjugados/química , Oxiquinolina/química , Quinolinas/farmacologia , Quinolinas/química , Carboidratos , Triazóis/farmacologia , Glucose , Carbono , Nitrogênio , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade
11.
Sci Rep ; 12(1): 16988, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-36216981

RESUMO

Two new classes of hybrid quinoline-imidazole/benzimidazole derivatives (the hybrid QIBS salts and QIBC cycloadducts) were designed and synthesized to evaluate their anticancer and antimicrobial activity. The strategy adopted for synthesis is straight and efficient, in four steps: N-acylation, N-alkylation, quaternization and a Huisgen 3 + 2 cycloaddition. The in vitro single-dose anticancer assay of forty six hybrid quinoline-benzimidazole compounds reveal that one QIBS salt (11h), has an excellent quasi nonselective activity against all type of cancer cell with an excellent PGI in the area of 90-100% and very good lethality. Three others quinoline-imidazole/benzimidazole hybrids (8h, 12h, 12f) has an excellent selective activity against some cancer cell lines: breast cancer MDA-MB-468 and Leukemia HL-60 TB). The five-dose assay screening confirms that compound 11h possesses excellent anti-proliferative activity, with GI50 in the range of nano-molar, against some cancer cell lines: Leukemia HL-60 TB, Leukemia K-526, Leukemia RPMI-8226, Breast cancer MDA-MB-468, Lung cancer HOP-92 and Ovarian cancer IGROV1. The antibacterial assay indicates that three hybrid QIBS salts (12f, 12c, 12d) have an excellent activity against Gram-negative bacteria E. coli (superior to control Gentamicin) while against Gram-positive bacteria S. aureus only one compound 8i (R2 = -CF3) exhibits a significant activity (superior to control Gentamicin). The MIC assay indicates that two other compounds (11h, 12h) are biologically active to a very low concentration, in the range of nano-molar. We believe that all these excellent assets related to anticancer and antibacterial activities, make from our hybrid quinoline-imidazole/benzimidazole compounds bearing a phenyl group (R2 = -C6H5) in the para (4)-position of the benzoyl moiety a good candidate for future drug developing.


Assuntos
Antineoplásicos , Neoplasias da Mama , Fármacos Dermatológicos , Leucemia , Quinolinas , Inibidores de 14-alfa Desmetilase/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Fármacos Dermatológicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli , Feminino , Gentamicinas , Humanos , Imidazóis , Estrutura Molecular , Quinolinas/farmacologia , Sais , Staphylococcus aureus , Relação Estrutura-Atividade
12.
J Agric Food Chem ; 70(37): 11782-11791, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36067412

RESUMO

In this work, a series of derivatives with disulfide bonds containing pyridine, pyrimidine, thiophene, thiazole, benzothiazole, and quinoline were designed and synthesized based on the various biological activities of allicin disulfide bond functional groups. The antimicrobial activities of the target compounds were determined, and the structure-activity relationships were discussed. Among them, compound S8 demonstrated the most potent antifungal activity in vitro against Monilinia fructicola (M. fructicola), with an EC50 value of 5.92 µg/mL. Furthermore, an in vivo bioassay revealed that compound S8 exhibited equivalent curative and higher protective effects as the positive drug thiophanate methyl at a concentration of 200 µg/mL. The preliminary mechanism experiments showed that compound S8 could inhibit the growth of M. fructicola' s hyphae in a time- and concentration-dependent manner, and compound S8 could induce the shrinkage of hyphae, disrupt the integrity of the plasma membrane, and cause the damage and leakage of cell contents. More than that, compound S5 also demonstrated an excellent antibacterial effect on Xanthomonas oryzae (X. oryzae), with a MIC90 value of 1.56 µg/mL, which was superior to the positive control, thiodiazole copper.


Assuntos
Oryza , Quinolinas , Xanthomonas , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Benzotiazóis/farmacologia , Cobre/farmacologia , Dissulfetos/farmacologia , Testes de Sensibilidade Microbiana , Oryza/microbiologia , Doenças das Plantas/microbiologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Relação Estrutura-Atividade , Ácidos Sulfínicos , Tiofanato , Tiofenos/farmacologia
13.
Int J Mol Sci ; 23(17)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36077268

RESUMO

Patients with differentiated thyroid cancer (DTC) usually have good prognosis, while those with advanced disease have poor clinical outcomes. This study aimed to investigate the antitumor effects of combination therapy with lenvatinib and 131I (CTLI) using three different types of DTC cell lines with different profiling of sodium iodide symporter (NIS) status. The radioiodine accumulation study revealed a significantly increased radioiodine uptake in K1-NIS cells after lenvatinib treatment, while there was almost no uptake in K1 and FTC-133 cells. However, lenvatinib administration before radioiodine treatment decreased radioiodine uptake of K1-NIS xenograft tumor in the in vivo imaging study. CTLI synergistically inhibited colony formation and DTC cell migration, especially in K1-NIS cells. Finally, 131I treatment followed by lenvatinib administration significantly inhibited tumor growth of the NIS-expressing thyroid cancer xenograft model. These results provide important clinical implications for the combined therapy that lenvatinib should be administered after 131I treatment to maximize the treatment efficacy. Our synergistic treatment effects by CTLI suggested its effectiveness for RAI-avid thyroid cancer, which retains NIS function. This potential combination therapy suggests a powerful and tolerable new therapeutic strategy for advanced thyroid cancer.


Assuntos
Quinolinas , Simportadores , Neoplasias da Glândula Tireoide , Humanos , Radioisótopos do Iodo/metabolismo , Radioisótopos do Iodo/uso terapêutico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Simportadores/genética , Simportadores/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/radioterapia
14.
J Med Chem ; 65(17): 11776-11787, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-35993839

RESUMO

Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.


Assuntos
Quinolinas , Trypanosoma , Tripanossomíase Africana , Animais , Microscopia Crioeletrônica , Modelos Animais de Doenças , Humanos , Camundongos , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
15.
Sci Rep ; 12(1): 14019, 2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982225

RESUMO

In this study, 18 novel quinoline-based-benzo[d]imidazole derivatives were synthesized and screened for their α-glucosidase inhibitory potential. All compounds in the series except 9q showed a significant α-glucosidase inhibition with IC50 values in the range of 3.2 ± 0.3-185.0 ± 0.3 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). A kinetic study indicated that compound 9d as the most potent derivative against α-glucosidase was a competitive type inhibitor. Furthermore, the molecular docking study revealed the effective binding interactions of 9d with the active site of the α-glucosidase enzyme. The results indicate that the designed compounds have the potential to be further studied as new anti-diabetic agents.


Assuntos
Inibidores de Glicosídeo Hidrolases , Quinolinas , Acetamidas , Inibidores de Glicosídeo Hidrolases/química , Imidazóis/farmacologia , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
16.
Eur Rev Med Pharmacol Sci ; 26(14): 5210-5217, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35916819

RESUMO

OBJECTIVE: Cardiovascular diseases are responsible for the majority of deaths on a global scale. Atherosclerosis is the main risk factor for cardiovascular disorders and represents a complex phenomenon associated with endothelial dysfunction and inflammation. Statins, especially atorvastatin (ATV) and pitavastatin (PTV), are common agents used to control ongoing atherosclerotic events in the body to minimize cardiovascular disease-based deaths. MATERIALS AND METHODS: The present study aimed at comparing the efficacy of ATV and PTV in a cell line model of inflammation. Human saphenous vein cells were treated with TNF-alpha to mimic atherosclerotic conditions, and the cells were divided into 7 groups, including control, DMSO, TNF-alpha (10 ng/mL-6 hours), ATV (50 µM/24 hours), PTV (2 µM/24 hours), ATV (50 µM/24 hours)+TNF-alpha (10 ng/mL-6 hours) and PTV (2 µM/24 hours)+TNF-alpha (10 ng/mL-6 hours). The expression levels of 20 proinflammatory cytokines and chemokines were investigated in these groups using a human atherosclerosis antibody array. RESULTS: Possible pathway interactions were determined by STRING and PANTHER analyses. Comparison with the effect of ATV indicated that PTV reduced the levels of 4 proinflammatory cytokines: CCL11, CSF2, CCL20, and TGFB1 (p<0.05). CONCLUSIONS: Pleiotropic effects of pitavastatin against cardiovascular diseases appeared to be better; however, additional studies are required to compare statins and to identify new drugs that maintain broader protection from the risks of cardiovascular diseases.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Quinolinas , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Atorvastatina/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Citocinas , Células Endoteliais/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Projetos Piloto , Quinolinas/farmacologia , Veia Safena , Fator de Necrose Tumoral alfa/farmacologia
17.
J Appl Microbiol ; 133(5): 3059-3068, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35929359

RESUMO

AIMS: Psychrotrophs are extremophilic microorganisms that grow optimally in low temperature having many unique bioactive molecules of biotechnological applications. In this study, we characterized a pigment from an arctic bacterium with protective activity towards UV exposure. METHODS AND RESULTS: The present research reports isolation and characterization of a psychrotrophic bacteria, RSAP2, from the soil sample of NyAlesund (78°56"N, 11°54"E), Svalbard, Norway. The strain showed closest 16S rRNA gene sequence similarity (99.9%) with Kocuria indica NIO-1021. RSAP2 is a Gram-positive, coccoid aerobe which produces a yellow pigment. The optimal parameters for pigment production while grown in LB medium were 3% (w/v) NaCl and 4 days of incubation of the culture at 20°C and pH 9 with shaking (180 rpm). The pigment was extracted in methanol and acetone (2:1) and further purified through column chromatography. It was characterized by mass spectrometry, UV-visible, fluorescence, IR, 1 H NMR, 13 C NMR spectroscopy and CHNS/O analysis. The pigment has a molecular weight of about 258 daltons and the molecular formula was determined as C15 H18 N2 O2 and is a quinoline derivative. We show that the pigment can protect Escherichia coli against UV-mediated mutagenesis. We further demonstrate that the pigment displays a significant antimicrobial effect and in sublethal concentrations it impairs biofilm formation ability of the model organism Staphylococcus aureus. CONCLUSIONS: The pigment of a psychrotrophic Arctic bacterium, most likely a strain of K. indica, was purified and its chemical structure was determined. The quinoline-based pigment has the ability to protect live cells from UV induced damage. SIGNIFICANCE AND IMPACT OF STUDY: Analysis and characterization of this newly isolated quinoline-based pigment is a potential candidate for future application in skin care products.


Assuntos
Anti-Infecciosos , Quinolinas , RNA Ribossômico 16S/genética , Cloreto de Sódio , Metanol , Acetona , Bactérias/genética , Quinolinas/farmacologia , Solo , Filogenia , Análise de Sequência de DNA , DNA Bacteriano/genética , Ácidos Graxos/análise , Regiões Árticas , Técnicas de Tipagem Bacteriana
18.
Cell Death Dis ; 13(8): 724, 2022 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-35985991

RESUMO

Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.


Assuntos
Inibidores da Angiogênese , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Compostos de Fenilureia , Quinolinas , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neovascularização Patológica/metabolismo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Transdução de Sinais , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Enzyme Inhib Med Chem ; 37(1): 2334-2347, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36043496

RESUMO

Based on the obtained SARs, further structural optimisation of compound BC2021-104511-15i was conducted in this investigation, and totally ten novel quinoline derivates were designed, synthesised and optimised for biological activity. Among them, compound 10a displayed significant in vitro anticancer activity against COLO 205 cells with an IC50 value of 0.11 µM which was over 90-fold more potent than that of Regorafenib (IC50>10.0 µM) and Fruquintinib (IC50>10.0 µM). Furthermore, compound 10a exhibited over 90-fold selectivity towards COLO 205 relative to human normal colorectal mucosa epithelial cell FHC cells. Flow cytometry study demonstrated that compound 10a could induce apoptosis in COLO 205 cells, however, it could not induce cell cycle arrest in COLO 205 cells. The results of preliminary kinase profile study showed that compound 10a was a potential HGFR and MST1R dual inhibitor, with IC50 values of 0.11 µM and 0.045 µM, respectively.


Assuntos
Antineoplásicos , Neoplasias , Quinolinas , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Quinolinas/farmacologia , Relação Estrutura-Atividade , Ureia/farmacologia
20.
J Enzyme Inhib Med Chem ; 37(1): 2191-2205, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35975321

RESUMO

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.


Assuntos
Antineoplásicos , Isatina , Quinolinas , Animais , Antineoplásicos/farmacologia , Células CACO-2 , Proliferação de Células , Chlorocebus aethiops , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isatina/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Células Vero
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