Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.168
Filtrar
1.
Molecules ; 27(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35458755

RESUMO

Tuberculosis remains a global health problem that affects millions of people around the world. Despite recent efforts in drug development, new alternatives are required. Herein, a series of 27 N-(4-(benzyloxy)benzyl)-4-aminoquinolines were synthesized and evaluated for their ability to inhibit the M. tuberculosis H37Rv strain. Two of these compounds exhibited minimal inhibitory concentrations (MICs) similar to the first-line drug isoniazid. In addition, these hit compounds were selective for the bacillus with no significant change in viability of Vero and HepG2 cells. Finally, chemical stability, permeability and metabolic stability were also evaluated. The obtained data show that the molecular hits can be optimized aiming at the development of drug candidates for tuberculosis treatment.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Aminoquinolinas/farmacologia , Antituberculosos/química , Humanos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
2.
Exp Parasitol ; 236-237: 108249, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35318066

RESUMO

Significant overlaps in the geographical distribution of malaria and leishmaniasis increase the risk for comorbidity, which can affect treatment efficacy, cotreatment compatibility and disease progression. These concerns are also exacerbated by the existing shortcomings of malaria and leishmaniasis treatments. There is, therefore, a pressing need for new anti-infective drugs for both individual diseases and coinfections. The in vitro antileishmanial activity of previously synthesized antiplasmodial aminoquinoline-chalcone hybrids was evaluated. Hybrid 6, featuring a N-methyl-1,3-propylene diamine linker between pharmacophores, was 11-fold more potent in anti-amastigote activity against Leishmania major, responsible for cutaneous leishmaniasis, the most common form of the disease, in comparison to chloroquine. Hybrid 7, with a 2,2-(ethylenedioxy)bis(ethylamine) linker, was nearly 7-fold more active in anti-amastigote activity against Leishmania donovani, responsible for visceral leishmaniasis, the most lethal form of the infection. Although these two hybrids were less potent than the clinically used antileishmanial, amphotericin B, they still qualify as hits against both Plasmodium and Leishmania strains. Accordingly, this may lend them as potential agents against Leishmania-Plasmodium coinfections, which will require further investigation using in vitro co-cultures and subsequent in vivo testing for confirmation.


Assuntos
Antimaláricos , Antiprotozoários , Chalcona , Chalconas , Coinfecção , Leishmania donovani , Leishmaniose Cutânea , Malária , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Chalconas/uso terapêutico , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Malária/tratamento farmacológico
3.
Int J Mol Sci ; 23(3)2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35163699

RESUMO

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.


Assuntos
Aminoquinolinas/farmacologia , Proliferação de Células , Endometriose/tratamento farmacológico , Células-Tronco Mesenquimais/efeitos dos fármacos , Adulto , Aminoquinolinas/uso terapêutico , Agonistas de Dopamina/farmacologia , Endometriose/fisiopatologia , Endométrio/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
4.
Molecules ; 27(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163977

RESUMO

COVID-19 has spread around the world and caused serious public health and social problems. Although several vaccines have been authorized for emergency use, new effective antiviral drugs are still needed. Some repurposed drugs including Chloroquine, Hydroxychloroquine and Remdesivir were immediately used to treat COVID-19 after the pandemic. However, the therapeutic effects of these drugs have not been fully demonstrated in clinical studies. In this paper, we found an antimalarial drug, Naphthoquine, showed good broad-spectrum anti-coronavirus activity. Naphthoquineinhibited HCoV-229E, HCoV-OC43 and SARS-CoV-2 replication in vitro, with IC50 = 2.05 ± 1.44 µM, 5.83 ± 0.74 µM, and 2.01 ± 0.38 µM, respectively. Time-of-addition assay was also performed to explore at which stage Naphthoquine functions during SARS-CoV-2 replication. The results suggested that Naphthoquine may influence virus entry and post-entry replication. Considering the safety of Naphthoquine was even better than that of Chloroquine, we think Naphthoquine has the potential to be used as a broad-spectrum drug for coronavirus infection.


Assuntos
1-Naftilamina/análogos & derivados , Aminoquinolinas/farmacologia , Antivirais/farmacologia , Coronavirus/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , 1-Naftilamina/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano NL63/efeitos dos fármacos , Coronavirus Humano OC43/efeitos dos fármacos , Humanos , Técnicas In Vitro , Células Vero , Replicação Viral/efeitos dos fármacos
5.
Sci Rep ; 12(1): 2928, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190588

RESUMO

Biomarkers for treatment sensitivity or drug resistance used in precision medicine include prognostic and predictive molecules, critical factors in selecting appropriate treatment protocols and improving survival rates. However, identification of accurate biomarkers remain challenging due to the high risk of false-positive findings and lack of functional validation results for each biomarker. Here, we discovered a mechanical correlation between leucine proline-enriched proteoglycan 1 (LEPRE1) and pelitinib drug sensitivity using in silico statistical methods and confirmed the correlation in acute myeloid leukemia (AML) and A549 lung cancer cells. We determined that high LEPRE1 levels induce protein kinase B activation, overexpression of ATP-binding cassette superfamily G member 2 (ABCG2) and E-cadherin, and cell colonization, resulting in a cancer stem cell-like phenotype. Sensitivity to pelitinib increases in LEPRE1-overexpressing cells due to the reversing effect of ABCG2 upregulation. LEPRE1 silencing induces pelitinib resistance and promotes epithelial-to-mesenchymal transition through actin rearrangement via a series of Src/ERK/cofilin cascades. The in silico results identified a mechanistic relationship between LEPRE1 and pelitinib drug sensitivity, confirmed in two cancer types. This study demonstrates the potential of LEPRE1 as a biomarker in cancer through in-silico prediction and in vitro experiments supporting the clinical development of personalized medicine strategies based on bioinformatics findings.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminoquinolinas/farmacologia , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Transição Epitelial-Mesenquimal/genética , Regulação Leucêmica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Prolil Hidroxilases/genética , Prolil Hidroxilases/fisiologia , Proteoglicanas/genética , Proteoglicanas/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Neoplasias Pulmonares/diagnóstico
6.
EMBO Mol Med ; 14(3): e14501, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35107878

RESUMO

The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication-associated DNA damage and genomic instability, a signature of BRCA1/2-mutated tumours. Targeted therapies against BRCA1/2-mutated tumours exploit this vulnerability by introducing additional DNA lesions. Because homologous recombination (HR) repair is abrogated in the absence of BRCA1 or BRCA2, these lesions are specifically lethal to tumour cells, but not to the healthy tissue. Ligands that bind and stabilise G-quadruplexes (G4s) have recently emerged as a class of compounds that selectively eliminate the cells and tumours lacking BRCA1 or BRCA2. Pyridostatin is a small molecule that binds G4s and is specifically toxic to BRCA1/2-deficient cells in vitro. However, its in vivo potential has not yet been evaluated. Here, we demonstrate that pyridostatin exhibits a high specific activity against BRCA1/2-deficient tumours, including patient-derived xenograft tumours that have acquired PARP inhibitor (PARPi) resistance. Mechanistically, we demonstrate that pyridostatin disrupts replication leading to DNA double-stranded breaks (DSBs) that can be repaired in the absence of BRCA1/2 by canonical non-homologous end joining (C-NHEJ). Consistent with this, chemical inhibitors of DNA-PKcs, a core component of C-NHEJ kinase activity, act synergistically with pyridostatin in eliminating BRCA1/2-deficient cells and tumours. Furthermore, we demonstrate that pyridostatin triggers cGAS/STING-dependent innate immune responses when BRCA1 or BRCA2 is abrogated. Paclitaxel, a drug routinely used in cancer chemotherapy, potentiates the in vivo toxicity of pyridostatin. Overall, our results demonstrate that pyridostatin is a compound suitable for further therapeutic development, alone or in combination with paclitaxel and DNA-PKcs inhibitors, for the benefit of cancer patients carrying BRCA1/2 mutations.


Assuntos
Quadruplex G , Neoplasias , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2 , Reparo do DNA , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Ácidos Picolínicos
7.
J Biol Chem ; 298(3): 101658, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35101449

RESUMO

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.


Assuntos
Aminoquinolinas , Antivirais , COVID-19 , Proteases 3C de Coronavírus , SARS-CoV-2 , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Internalização do Vírus/efeitos dos fármacos
8.
Parasit Vectors ; 15(1): 10, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34991686

RESUMO

BACKGROUND: Drug resistance and toxic side effects are major challenges in the treatment of babesiosis. As such, new drugs are needed to combat the emergence of drug resistance in Babesia parasites and to develop alternative treatment strategies. A combination of naphthoquine (NQ) and artemisinin is an antimalarial therapy in pharmaceutical markets. The present study repurposed NQ as a drug for the treatment of babesiosis by evaluating the anti-Babesia activity of naphthoquine phosphate (NQP) alone. METHODS: An in vitro growth inhibition assay of NQP was tested on Babesia gibsoni cultures using a SYBR Green I-based fluorescence assay. In addition, the in vivo growth inhibitory effect of NQP was evaluated using BALB/c mice infected with Babesia rodhaini. The parasitemia level and hematocrit values were monitored to determine the therapeutic efficacy of NQP and the clinical improvements in NQP-treated mice. RESULTS: The half maximal inhibitory concentration of NQP against B. gibsoni in vitro was 3.3 ± 0.5 µM. Oral administration of NQP for 5 consecutive days at a dose of 40 mg/kg of body weight resulted in significant inhibition of B. rodhaini growth in mice as compared with that of the control group. All NQP-treated mice survived, whereas the mice in the control group died between days 6 and 9 post-infection. CONCLUSION: This is the first study to evaluate the anti-Babesia activity of NQP in vitro and in vivo. Our findings suggest that NQP is a promising drug for treating Babesia infections, and drug repurposing may provide new treatment strategies for babesiosis.


Assuntos
1-Naftilamina/análogos & derivados , Aminoquinolinas/farmacologia , Antiprotozoários/farmacologia , Babesia/efeitos dos fármacos , Babesiose/tratamento farmacológico , 1-Naftilamina/farmacologia , 1-Naftilamina/uso terapêutico , Aminoquinolinas/sangue , Aminoquinolinas/uso terapêutico , Animais , Antiprotozoários/sangue , Antiprotozoários/uso terapêutico , Babesia/crescimento & desenvolvimento , Babesiose/sangue , Babesiose/parasitologia , Hematócrito , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/parasitologia , Distribuição Aleatória
9.
Curr Top Med Chem ; 22(6): 436-472, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34986771

RESUMO

Apicomplexian parasite of the genus Plasmodium is the causative agent of malaria, one of the most devastating, furious and common infectious disease throughout the world. According to the latest World malaria report, there were 229 million cases of malaria in 2019 majorly consist of children under 5 years of age. Some of known analogues viz. quinine, quinoline-containing compounds have been used for last century in the clinical treatment of malaria. Past few decades witnessed the emergence of multi-drug resistance (MDR) strains of Plasmodium species to existing antimalarials pressing the need for new drug candidates. Thus, in those decades bioorganometallic approach to malaria therapy has been introduced which led to the discovery of noval metalcontaining aminoquinolines analogues viz. ferroquine (FQ or 1), Ruthenoquine (RQ or 2) and other related potent metalanalogues. It observed that some metal containing analogues (Fe-, Rh-, Ru-, Re-, Au-, Zn-, Cr-, Pd-, Sn-, Cd-, Ir-, Co-, Cu-, and Mn-aminoquines) were more potent; however, some were equally potent as Chloroquine (CQ) and 1. This is probably due to the intertion of metals in the CQ via various approaches, which might be a very attractive strategy to develop a SAR of novel metal containing antimalarials. Thus, this review aim to summarize the SAR of metal containing aminoquines towards the discovery of potent antimalarial hybrids to provide an insight for rational designs of more effective and less toxic metal containing amonoquines.


Assuntos
Antimaláricos , Malária , Plasmodium , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Criança , Pré-Escolar , Cloroquina/farmacologia , Humanos , Malária/tratamento farmacológico , Plasmodium falciparum
10.
Eur J Pharmacol ; 916: 174659, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34871559

RESUMO

The development of sub-type selective α1 adrenoceptor ligands has been hampered by the high sequence similarity of the amino acids forming the orthosteric binding pocket of the three α1 adrenoceptor subtypes, along with other biogenic amine receptors. One possible approach to overcome this issue is to target allosteric sites on the α1 adrenoceptors. Previous docking studies suggested that one of the quinoline moieties of a bis(4-aminoquinoline), comprising a 9-carbon methylene linker attached via the amine groups, could interact with residues outside of the orthosteric binding site while, simultaneously, the other quinoline moiety bound within the orthosteric site. We therefore hypothesized that this compound could act in a bitopic manner, displaying both orthosteric and allosteric binding properties. To test this proposition, we investigated the allosteric activity of a series of bis(4-aminoquinoline)s with linker lengths ranging from 2 to 12 methylene units (designated C2-C12). A linear trend of increasing [3H]prazosin dissociation rate with increasing linker length between C7 and C11 was observed, confirming their action as allosteric modulators. These data suggest that the optimal linker length for the bis(4-aminoquinoline)s to occupy the allosteric site of the α1A adrenoceptor is between 7 and 11 methylene units. In addition, the ability of C9 bis(4-aminoquinoline) to modulate the activation of the α1A adrenoceptor by norepinephrine was subsequently examined, showing that C9 acts as a non-competitive antagonist. Our findings indicate that the bis(4-aminoquinolines) are acting as allosteric modulators of orthosteric ligand binding, but not efficacy, in a bitopic manner.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Regulação Alostérica/efeitos dos fármacos , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Aminoquinolinas/farmacocinética , Animais , Sítios de Ligação , Células COS , Chlorocebus aethiops , Cinética , Norepinefrina/farmacologia , Prazosina/farmacologia
11.
J Am Chem Soc ; 143(49): 20988-21002, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34855372

RESUMO

Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s). G4s can form from a single DNA strand (intramolecular) or from multiple DNA strands (intermolecular), but studies on their biological functions have been often limited to intramolecular G4s, owing to the low probability of intermolecular G4s to form within genomic DNA. Herein, we report the first example of an endogenous protein, Cockayne Syndrome B (CSB), that can bind selectively with picomolar affinity toward intermolecular G4s formed within rDNA while displaying negligible binding toward intramolecular structures. We observed that CSB can selectively resolve intermolecular over intramolecular G4s, demonstrating that its selectivity toward intermolecular structures is also reflected at the resolvase level. Immunostaining of G4s with the antibody BG4 in CSB-impaired cells (CS1AN) revealed that G4-staining in the nucleolus of these cells can be abrogated by transfection of viable CSB, suggesting that intermolecular G4s can be formed within rDNA and act as binding substrate for CSB. Given that loss of function of CSB elicits premature aging phenotypes, our findings indicate that the interaction between CSB and intermolecular G4s in rDNA could be of relevance to maintain cellular homeostasis.


Assuntos
DNA Helicases/metabolismo , Enzimas Reparadoras do DNA/metabolismo , DNA/metabolismo , Quadruplex G , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Recombinases/metabolismo , Aminoquinolinas/farmacologia , Animais , Benzotiazóis/farmacologia , Nucléolo Celular/metabolismo , DNA/genética , Células HeLa , Humanos , Naftiridinas/farmacologia , Ácidos Picolínicos/farmacologia , Ligação Proteica/efeitos dos fármacos , Células Sf9 , Spodoptera
12.
Int J Biol Sci ; 17(15): 4474-4492, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803511

RESUMO

BET bromodomain BRD4 and RAC1 oncogenes are considered important therapeutic targets for cancer and play key roles in tumorigenesis, survival and metastasis. However, combined inhibition of BRD4-RAC1 signaling pathways in different molecular subtypes of breast cancer including luminal-A, HER-2 positive and triple-negative breast (TNBC) largely remains unknown. Here, we demonstrated a new co-targeting strategy by combined inhibition of BRD4-RAC1 oncogenic signaling in different molecular subtypes of breast cancer in a context-dependent manner. We show that combined treatment of JQ1 (inhibitor of BRD4) and NSC23766 (inhibitor of RAC1) suppresses cell growth, clonogenic potential, cell migration and mammary stem cells expansion and induces autophagy and cellular senescence in molecular subtypes of breast cancer cells. Mechanistically, JQ1/NSC23766 combined treatment disrupts MYC/G9a axis and subsequently enhances FTH1 to exert antitumor effects. Furthermore, combined treatment targets HDAC1/Ac-H3K9 axis, thus suggesting a role of this combination in histone modification and chromatin modeling. C-MYC depletion and co-treatment with vitamin-C sensitizes different molecular subtypes of breast cancer cells to JQ1/NSC23766 combination and further reduces cell growth, cell migration and mammosphere formation. Importantly, co-targeting RAC1-BRD4 suppresses breast tumor growth in vivo using xenograft mouse model. Clinically, RAC1 and BRD4 expression positively correlates in breast cancer patient's samples and show high expression patterns across different molecular subtypes of breast cancer. Both RAC1 and BRD4 proteins predict poor survival in breast cancer patients. Taken together, our results suggest that combined inhibition of BRD4-RAC1 pathways represents a novel and potential therapeutic approach in different molecular subtypes of breast cancer and highlights the importance of co-targeting RAC1-BRD4 signaling in breast tumorigenesis via disruption of C-MYC/G9a/FTH1 axis and down regulation of HDAC1.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Ferritinas/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona Desacetilase 1/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Oxirredutases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Aminoquinolinas/farmacologia , Animais , Azepinas/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Ferritinas/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade/genética , Histona Desacetilase 1/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Camundongos , Camundongos Nus , Oxirredutases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Pirimidinas/farmacologia , Fatores de Transcrição/genética , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rac1 de Ligação ao GTP/genética
13.
Sci Rep ; 11(1): 19905, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620901

RESUMO

Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.


Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Fígado/parasitologia , Malária Vivax/parasitologia , Testes de Sensibilidade Parasitária , Plasmodium vivax/efeitos dos fármacos , Aminoquinolinas/química , Aminoquinolinas/uso terapêutico , Antimaláricos/química , Antimaláricos/uso terapêutico , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Descoberta de Drogas/métodos , Sinergismo Farmacológico , Humanos , Estágios do Ciclo de Vida , Malária Vivax/tratamento farmacológico , Estrutura Molecular , Testes de Sensibilidade Parasitária/métodos , Plasmodium vivax/crescimento & desenvolvimento , Curva ROC , Fatores de Tempo
14.
Nucleic Acids Res ; 49(19): 11323-11336, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34614161

RESUMO

RNA guanine quadruplexes (rG4) assume important roles in post-transcriptional regulations of gene expression, which are often modulated by rG4-binding proteins. Hence, understanding the biological functions of rG4s requires the identification and functional characterizations of rG4-recognition proteins. By employing a bioinformatic approach based on the analysis of overlap between peaks obtained from rG4-seq analysis and those detected in >230 eCLIP-seq datasets for RNA-binding proteins generated from the ENCODE project, we identified a large number of candidate rG4-binding proteins. We showed that one of these proteins, G3BP1, is able to bind directly to rG4 structures with high affinity and selectivity, where the binding entails its C-terminal RGG domain and is further enhanced by its RRM domain. Additionally, our seCLIP-Seq data revealed that pyridostatin, a small-molecule rG4 ligand, could displace G3BP1 from mRNA in cells, with the most pronounced effects being observed for the 3'-untranslated regions (3'-UTR) of mRNAs. Moreover, luciferase reporter assay results showed that G3BP1 positively regulates mRNA stability through its binding with rG4 structures. Together, we identified a number of candidate rG4-binding proteins and validated that G3BP1 can bind directly with rG4 structures and regulate the stabilities of mRNAs.


Assuntos
Regiões 3' não Traduzidas , Aminoquinolinas/farmacologia , DNA Helicases/genética , Quadruplex G , Ácidos Picolínicos/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , Aminoquinolinas/química , Sequência de Bases , Clonagem Molecular , Biologia Computacional/métodos , DNA Helicases/metabolismo , Conjuntos de Dados como Assunto , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Genes Reporter , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HEK293 , Células HeLa , Humanos , Ligantes , Luciferases/genética , Luciferases/metabolismo , Ácidos Picolínicos/química , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Ligação Proteica , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Estabilidade de RNA , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
15.
Bioorg Med Chem Lett ; 51: 128371, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34534673

RESUMO

Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood-brain barrier. Moreover, preliminary structure-activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Desenho de Fármacos , Glioblastoma/tratamento farmacológico , Aminoquinolinas/síntese química , Aminoquinolinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
16.
Molecules ; 26(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34577001

RESUMO

A new series of compounds was prepared from 6-methoxyquinolin-8-amine or its N-(2-aminoethyl) analogue via Ugi-azide reaction. Their linkers between the quinoline and the tert-butyltetrazole moieties differ in chain length, basicity and substitution. Compounds were tested for their antiplasmodial activity against Plasmodium falciparum NF54 as well as their cytotoxicity against L-6-cells. The activity and the cytotoxicity were strongly influenced by the linker and its substitution. The most active compounds showed good activity and promising selectivity.


Assuntos
Aminoquinolinas/química , Antimaláricos/química , Antimaláricos/farmacologia , Quinolinas/química , Tetrazóis/química , Aminoquinolinas/farmacologia , Animais , Antimaláricos/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Concentração Inibidora 50 , Plasmodium falciparum/efeitos dos fármacos , Primaquina/química , Quinolinas/farmacologia , Ratos , Tetrazóis/farmacologia
17.
Viruses ; 13(9)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34578365

RESUMO

Rhinoviruses (RVs) are the main cause of recurrent infections with rather mild symptoms characteristic of the common cold. Nevertheless, RVs give rise to enormous numbers of absences from work and school and may become life-threatening in particular settings. Vaccination is jeopardised by the large number of serotypes eliciting only poorly cross-neutralising antibodies. Conversely, antivirals developed over the years failed FDA approval because of a low efficacy and/or side effects. RV species A, B, and C are now included in the fifteen species of the genus Enteroviruses based upon the high similarity of their genome sequences. As a result of their comparably low pathogenicity, RVs have become a handy model for other, more dangerous members of this genus, e.g., poliovirus and enterovirus 71. We provide a short overview of viral proteins that are considered potential drug targets and their corresponding drug candidates. We briefly mention more recently identified cellular enzymes whose inhibition impacts on RVs and comment novel approaches to interfere with infection via aggregation, virus trapping, or preventing viral access to the cell receptor. Finally, we devote a large part of this article to adding the viral RNA genome to the list of potential drug targets by dwelling on its structure, folding, and the still debated way of its exit from the capsid. Finally, we discuss the recent finding that G-quadruplex stabilising compounds impact on RNA egress possibly via obfuscating the unravelling of stable secondary structural elements.


Assuntos
Antivirais/farmacologia , RNA Viral/efeitos dos fármacos , Rhinovirus/efeitos dos fármacos , Aminoquinolinas/farmacologia , Animais , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Enterovirus/genética , Infecções por Enterovirus/virologia , Genoma Viral/efeitos dos fármacos , Humanos , Ácidos Picolínicos/farmacologia , Poliovirus/genética , Proteínas não Estruturais Virais/efeitos dos fármacos , Proteínas Virais/genética
18.
Cell Rep ; 36(11): 109689, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525350

RESUMO

Assessing drug response within live native tissue provides increased fidelity with regards to optimizing efficacy while minimizing off-target effects. Here, using longitudinal intravital imaging of a Rac1-Förster resonance energy transfer (FRET) biosensor mouse coupled with in vivo photoswitching to track intratumoral movement, we help guide treatment scheduling in a live breast cancer setting to impair metastatic progression. We uncover altered Rac1 activity at the center versus invasive border of tumors and demonstrate enhanced Rac1 activity of cells in close proximity to live tumor vasculature using optical window imaging. We further reveal that Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress and therefore improves overall anti-metastatic response to therapy during transit to secondary sites such as the lung. Collectively, this study demonstrates the utility of single-cell intravital imaging in vivo to demonstrate that Rac1 inhibition can reduce tumor progression and metastases in an autochthonous setting to improve overall survival.


Assuntos
Técnicas Biossensoriais/métodos , Neoplasias da Mama/patologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Aminoquinolinas/farmacologia , Animais , Neoplasias da Mama/diagnóstico por imagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Transferência Ressonante de Energia de Fluorescência , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/farmacologia , Resistência ao Cisalhamento , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
19.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34508006

RESUMO

P2X1 receptors are adenosine triphosphate (ATP)-gated cation channels that are functionally important for male fertility, bladder contraction, and platelet aggregation. The activity of P2X1 receptors is modulated by lipids and intracellular messengers such as cAMP, which can stimulate protein kinase A (PKA). Exchange protein activated by cAMP (EPAC) is another cAMP effector; however, its effect on P2X1 receptors has not yet been determined. Here, we demonstrate that P2X1 currents, recorded from human embryonic kidney (HEK) cells transiently transfected with P2X1 cDNA, were inhibited by the highly selective EPAC activator 007-AM. In contrast, EPAC activation enhanced P2X2 current amplitude. The PKA activator 6-MB-cAMP did not affect P2X1 currents, but inhibited P2X2 currents. The inhibitory effects of EPAC on P2X1 were prevented by triple mutation of residues 21 to 23 on the amino terminus of P2X1 subunits to the equivalent amino acids on P2X2 receptors. Double mutation of residues 21 and 22 and single mutation of residue 23 also protected P2X1 receptors from inhibition by EPAC activation. Finally, the inhibitory effects of EPAC on P2X1 were also prevented by NSC23766, an inhibitor of Rac1, a member of the Rho family of small GTPases. These data suggest that EPAC is an important regulator of P2X1 and P2X2 receptors.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/farmacologia , AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/farmacologia , Rim/metabolismo , Receptores Purinérgicos P2X1/metabolismo , Receptores Purinérgicos P2X2/metabolismo , Trifosfato de Adenosina , Aminoquinolinas/farmacologia , Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Pirimidinas/farmacologia , Receptores Purinérgicos P2X1/genética , Receptores Purinérgicos P2X2/genética , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
20.
Eur J Med Chem ; 225: 113763, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34419892

RESUMO

The tumor microenvironment contains high concentrations of TGFß, a crucial immunosuppressive cytokine. TGFß stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFßR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFßR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFßR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFßR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFßR1 inhibitor that has potential applications in immuno-oncology.


Assuntos
Aminoquinolinas/farmacologia , Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Estrutura Molecular , Receptor do Fator de Crescimento Transformador beta Tipo I/imunologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...