Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26.864
Filtrar
1.
J Med Chem ; 67(4): 2570-2583, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38301207

RESUMO

Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil (1), the prodrug of baloxavir (2) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.


Assuntos
Dibenzotiepinas , Influenza Humana , Morfolinas , Tiepinas , Humanos , Influenza Humana/tratamento farmacológico , Oxazinas/farmacologia , Piridinas/farmacologia , Endonucleases , Antivirais/farmacologia , Antivirais/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
2.
Sci Rep ; 14(1): 2738, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302640

RESUMO

Pyridine compounds are one of the most important heterocyclic derivatives showing wide ranges in biological and pharmacological activities. Green chemistry eliminates or reduces the generation of hazardous compounds. It prevents pollution at a molecular level. The microwave technique used in heterocyclic compound synthesis is also an important branch of green chemistry techniques. In this study, we report designing and synthesizing a new pyridine-bearing pentose moiety via a one-pot multicomponent reaction using D-glucose and also investigate its behavior and reactivity toward some simple and heterocyclic amino derivatives. The chemical structures of the synthesized compounds were characterized and tested for their cytotoxic activities. Some of the test compounds exhibited slight to high cytotoxic activities against Caco2 (colon cancer) cells, HepG2 (hepatocellular carcinoma) cells and MCF-7 (human breast cancer) cells by MTT assay. The results showed clearly that compound 4 and compound 8 displayed strongest to moderate cytotoxic activity against the HepG2, Caco2 and MCF-7 respectively and compound 1 showed good activity against MCF-7 in comparison to the standard anticancer drug doxorubicin. These data were by cytopathological examination. An in-vivo radioactive tracing study of compound 4 proved its targeting ability to sarcoma cells in a tumor-bearing mice model. Our findings suggest that the synthesized compounds may be promising candidates as novel anticancer agents.


Assuntos
Antineoplásicos , Radioisótopos do Iodo , Humanos , Animais , Camundongos , Radioisótopos do Iodo/farmacologia , Células MCF-7 , Células CACO-2 , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Piridinas/farmacologia , Piridinas/química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Desenho de Fármacos , Simulação de Acoplamento Molecular
3.
Bioorg Med Chem ; 100: 117631, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38330848

RESUMO

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Apoptose , Linhagem Celular Tumoral , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Piridinas/farmacologia
4.
J Agric Food Chem ; 72(8): 3872-3883, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38358096

RESUMO

Herein, a series of chitosan oligosaccharide copper complexes modified with pyridine groups (CPSx-Cu complexes) were successfully prepared via the Schiff base reaction and ion complexation reaction for slow-release fungicide. The structures of the synthesized derivatives were characterized via Fourier transform infrared spectroscopy and 1H and 13C nuclear magnetic resonance spectroscopy, and the unit configuration of the complexes was calculated using Gaussian software. The slow-release performance experiment demonstrated that the cumulative copper ion release rate of CPSx-Cu complexes was dependent on the type of substituents on the pyridine ring. Furthermore, the in vitro and in vivo antifungal activities of the CPSx-Cu complexes were investigated. At a concentration of 0.4 mg/mL, CPSx-Cu complexes completely inhibited the growth of Pythium vexans and Phytophthora capsici. Results indicated that CPSx-Cu complexes with slow-release ability exhibited better antifungal activity than thiodiazole-copper and copper sulfate basic. This study confirmed that combining chitosan oligosaccharide with bioactive pyridine groups and copper ions is an effective approach to further developing slow-release copper fungicides, providing new possibilities for the application of copper fungicides in green agriculture. This study lays the foundation for further studies on biogreen copper fungicides.


Assuntos
Quitosana , Complexos de Coordenação , Fungicidas Industriais , Cobre/química , Antifúngicos/química , Fungicidas Industriais/farmacologia , Quitosana/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Bases de Schiff , Espectroscopia de Infravermelho com Transformada de Fourier , Piridinas/farmacologia , Oligossacarídeos/farmacologia
5.
CNS Neurosci Ther ; 30(2): e14637, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38380702

RESUMO

AIMS: Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet they are still insufficiently considered in the management of stroke patients, and the mechanisms by which they occur remain unclear. There is evidence that boosting phasic GABA signaling with zolpidem during the repair phase improves stroke recovery by enhancing neural plasticity; however, as a non-benzodiazepine hypnotic, the effects of zolpidem on post-stroke sleep disorders remain unclear. METHOD: Transient ischemic stroke in male rats was induced with a 30-minute middle cerebral artery occlusion. Zolpidem or vehicle was intraperitoneally delivered once daily from 2 to 7 days after the stroke, and the electroencephalogram and electromyogram were recorded simultaneously. At 24 h after ischemia, c-Fos immunostaining was used to assess the effect of transient ischemic stroke and acute zolpidem treatment on neuronal activity. RESULTS: In addition to the effects on reducing brain damage and mitigating behavioral deficits, repeated zolpidem treatment during the subacute phase of stroke quickly ameliorated circadian rhythm disruption, alleviated sleep fragmentation, and increased sleep depth in ischemic rats. Immunohistochemical staining showed that in contrast to robust activation in para-infarct and some remote areas by 24 h after the onset of focal ischemia, the activity of the ipsilateral suprachiasmatic nucleus, the biological rhythm center, was strongly suppressed. A single dose of zolpidem significantly upregulated c-Fos expression in the ipsilateral suprachiasmatic nucleus to levels comparable to the contralateral side. CONCLUSION: Stroke leads to suprachiasmatic nucleus dysfunction. Zolpidem restores suprachiasmatic nucleus activity and effectively alleviates post-stroke sleep disturbances, indicating its potential to promote stroke recovery.


Assuntos
AVC Isquêmico , Transtornos do Sono-Vigília , Acidente Vascular Cerebral , Humanos , Masculino , Ratos , Animais , Zolpidem/farmacologia , Zolpidem/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Transtornos do Sono-Vigília/etiologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Sono , AVC Isquêmico/tratamento farmacológico
6.
Arch Virol ; 169(2): 29, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216710

RESUMO

Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.


Assuntos
Dibenzotiepinas , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A , Influenza Humana , Morfolinas , Orthomyxoviridae , Piridonas , Tiepinas , Triazinas , Animais , Cães , Humanos , Suínos , Vírus da Influenza A/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Virus da Influenza A Subtipo H5N1/genética , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Orthomyxoviridae/genética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Substituição de Aminoácidos , Endonucleases/genética , Farmacorresistência Viral/genética
7.
Sci Rep ; 14(1): 1152, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38212472

RESUMO

Computer-aided drug design has been employed to get the medicinal effects against Corona virus from different pyridine derivatives after synthesizing the new compounds. Additionally, various computational studies are also employed between the newly prepared pyridine derivatives and three controls against three proteins (6Y2E, 6M71 and 6M3M). Different methods were employed to synthesize new pyridine derivatives according to the literature using different reaction mediums. MTT was performed for cytotoxicity study and IC50 for inhibitory concentration. Additionally, in-silico studies including DFT, molecular docking, molecular dynamics, MMPBSA, ADME, pharmacokinetics and Lipinski rules were evaluated. The chemical structures of all new compounds were elucidated based on spectroscopic investigation. A molecular docking study demonstrated that compounds 5, 11, and 12 have the best binders of the SARS-CoV-2 main protease enzyme, with energy scores of - 7.5 kcal/mol, - 7.2 kcal/mol, and - 7.9 kcal/mol, respectively. The net binding energy values of the 11-Mpro, 12-Mpro, and 5-Mpro complexes revealed their highly stable nature in terms of both intermolecular interactions and docked conformation across the simulation time. ADME properties, besides the pharmacokinetics and Lipinski rules, showed that all seven newly synthesized compounds follow Lipinski rules with high GI absorption. The In Vitro antiviral study against SARS-CoV-2 using MTT methods confirms that compound 5 has more potential and is safer than other tested compounds. The study shows that the newly synthesized pyridine derivatives have medicinal properties against SARS-CoV-2 without violating Lipinski rules. Compounds 5, 11, and 12, particularly compound 5, may serve as promising potential candidate for COVID-19.


Assuntos
COVID-19 , Compostos Heterocíclicos , Humanos , SARS-CoV-2 , Simulação de Acoplamento Molecular , Compostos Heterocíclicos/farmacologia , Piridinas/farmacologia , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia
8.
Sci Rep ; 14(1): 1307, 2024 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-38225243

RESUMO

In this study, we examined a mathematical model of breast cancer (BC) treatment that combines an oral oestrogen receptor inhibitor, AZD9496 with Palbociclib, a selective inhibitor of cyclin- dependent kinases CDK4 and CDK6. Treatment is described by analytical functions that enable us to control the dosage and time interval of the treatment, thus personalising the treatment for each patient. Initially, we investigated the effect of each treatment separately, and finally, we investigated the combination of both treatments. By applying numerical simulations, we confirmed that the combination of AZD9496 with palbociclib was the optimal treatment for BC. The dosage of AZD9496 increased and decreased throughout the treatment period, while the intervals were constant between treatments. Palbociclib changed almost cyclically, whereas the time intervals remained constant. To investigate the mathematical model, we applied the singularly perturbed homotopy analysis method, which is a numerical algorithm. The significant advantage of this method is that the mathematical model does not have to contain a small parameter (as is standard in perturbation theory). However, it is possible to artificially introduce a small parameter into the system of equations, making it possible to study the model using asymptotic methods.


Assuntos
Neoplasias da Mama , Cinamatos , Indóis , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Piridinas/farmacologia , Piridinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
9.
Cell Physiol Biochem ; 58(1): 1-13, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38219048

RESUMO

BACKGROUND/AIMS: Factors influencing gene expression through chemical modifications of histones may play an important role in the regulation of the autophagy process in cancers. RING1A or RING1B are responsible for the catalytical activity of Polycomb repressive complex 1 (PRC1) which monoubiquitylate histone H2A. The aim of the study was to determine the effect of the RING1A/B protein inhibition on the autophagy process in endometrial cancer cells and the anticancer effectiveness of RING1 inhibitor PRT4165 in combination with autophagy inhibitors. METHODS: The expression of autophagy genes and proteins were analyzed in endometrial cancer cells HEC-1A and Ishikawa grown in different glucose concentrations and treated with PRT4165. To assess the effectiveness of PRT4165 used alone or in combination with HCQ or Lys05, IC50 and the combination index (CI) were calculated. Flow cytometry method was used to estimate apoptotic cells after treatment. RESULTS: The results confirm the impact of RINGs on autophagy and apoptosis in endometrial cancer cells. PRT4165 inhibitor causes changes in the expression of ATG genes and autophagy markers and the effect depends on glucose concentration and cell types. However, the anticancer effectiveness of PRT4165 was lower when it was used in combination with autophagy inhibitors, suggesting that such a combination is not a promising anticancer strategy. CONCLUSION: The results indicate the importance of the RINGs in the process of autophagy and apoptosis. Further potentially more effective combinations of PRT4165 with autophagy modulators should be sought.


Assuntos
Neoplasias do Endométrio , Indanos , Feminino , Humanos , Autofagia , Linhagem Celular Tumoral , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Glucose/farmacologia , Histonas/farmacologia , Piridinas/farmacologia
10.
Dalton Trans ; 53(6): 2475-2486, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38174938

RESUMO

Twelve (N^N^N)platinum pyridyl complexes, (N^N^N)Pt(pyF), were synthesised and investigated for their singlet oxygen generation and potential biological activities. They exhibited 1IL and 1MLCT absorption transitions at approximately 325 and 360 nm, identified through TD-DFT calculations. Luminescence was observed only in the L1-derived compounds in solution, with a dual emission with the main contribution of phosphorescence under deaerated conditions. Room temperature phosphorescence was detected in all solid-state cases. Electron-withdrawing substituents at specific positions (R1 and X) and the number of fluorine atoms in R2 were found to enhance the photosensitizing capabilities of these compounds. Biological assessments, including cytotoxicity and photocytotoxicity, were conducted to evaluate their potential as chemotherapeutic agents and photosensitizers. Complexes with chloro substitution in the N^N^N tridentate ligand of the central pyridine ring exhibited promising chemotherapeutic properties. Ancillary pyridine ring substitution became significant under irradiation conditions, with fluoromethylated substituents enhancing cytotoxicity. Complex 2-CF3 was the most efficient singlet oxygen producer and a highly effective photosensitizer. CHF2-substituted complexes also showed improved photosensitizing activity. DNA binding studies indicated moderate interactions with DNA, offering insights into potential biological applications.


Assuntos
Fármacos Fotossensibilizantes , Oxigênio Singlete , DNA , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Platina/química , Piridinas/farmacologia , Piridinas/química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia
11.
Colloids Surf B Biointerfaces ; 234: 113750, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38244482

RESUMO

In this contribution, a novel AIE monomers 2-(4-styrylphenyl)- 1,2-diphenylvinyl)styryl)pyridine (SDVPY) with smart fluorescent pH-sensitivity basing on tetraphenylethylene-pyridine were successfully synthesized for the first time, subsequently, a series of amphiphilic copolymers PEG-PY were achieved by reversible addition-fragmentation chain transfer (RAFT) polymerization of SDVPY and poly(ethylene glycol) methacrylate (PEGMA), which would self-assemble in water solution to form core-shell nanoparticles (PEG-PY FONs) with about 150 nm diameter. The PEG-PY FONs showed obvious fluorescence response to Fe3+, HCO3- and CO32- ions in aqueous solution owing to their smart pH-sensitivity and AIE characteristics, and their maximum emission wavelength could reversibly change from 525 nm to 624 nm. The as-prepared PEG-PY FONs showed also prospective application in cells imaging with the variable fluorescence for different pH cells micro-environment. When PEG-PY copolymers self-assembled with the anti-tumor drug paclitaxel (PTX), the obtained PY-PTX FONs could effectively deliver and release PTX with pH-sensitivity, and could be easily internalized by A549 cells and located at the cytoplasm with high cytotoxicity, which was further confirmed by the Calcein-AM/PI staining of dead and alive A549 cells. Moreover, the flow cytometry results indicated that the PY-PTX FONs could obviously induce the apoptosis of A549 cells, which further showed the great potential of PY-PTX FONs in the application of tumors therapy.


Assuntos
Metacrilatos , Nanopartículas , Neoplasias , Estilbenos , Humanos , Polietilenoglicóis , Polímeros , Corantes , Paclitaxel/farmacologia , Concentração de Íons de Hidrogênio , Piridinas/farmacologia , Microambiente Tumoral
12.
Stem Cell Res Ther ; 15(1): 26, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38287366

RESUMO

BACKGROUND: The stem cell characteristic makes basal cells desirable for ex vivo modeling of airway diseases. However, to date, approaches allowing them extensively in vitro serial expansion and maintaining bona fide stem cell property are still awaiting to be established. This study aims to develop a feeder-free culture system of mouse airway basal stem cells (ABSCs) that sustain their stem cell potential in vitro, providing an experimental basis for further in-depth research and mechanism exploration. METHODS: We used ROCK inhibitor Y-27632-containing 3T3-CM, MEF-CM, and RbEF-CM to determine the proper feeder-free culture system that could maintain in vitro stem cell morphology of mouse ABSCs. Immunocytofluorescence was used to identify the basal cell markers of obtained cells. Serial propagation was carried out to observe whether the stem cell morphology and basal cell markers could be preserved in this cultivation system. Next, we examined the in vitro expansion and self-renewal ability by evaluating population doubling time and colony-forming efficiency. Moreover, the differentiation potential was detected by an in vitro differentiation culture and a 3D tracheosphere assay. RESULTS: When the mouse ABSCs were cultured using 3T3-CM containing ROCK inhibitor Y-27632 in combination with Matrigel-coated culture dishes, they could stably expand and maintain stem cell-like clones. We confirmed that the obtained clones comprised p63/Krt5 double-positive ABSCs. In continuous passage and maintenance culture, we found that it could be subculture to at least 15 passages in vitro, stably maintaining its stem cell morphology, basal cell markers, and in vitro expansion and self-renewal capabilities. Meanwhile, through in vitro differentiation culture and 3D tracheosphere culture, we found that in addition to maintaining self-renewal, mouse ABSCs could differentiate into other airway epithelial cells such as acetylated tubulin (Act-Tub) + ciliated and MUC5AC + mucus-secreting cells. However, they failed to differentiate into alveoli epithelial cells, including alveolar type I and alveolar type II. CONCLUSION: We established an in vitro feeder-free culture system that allows mouse ABSCs to maintain their stem cell characteristics, including self-renewal and airway epithelium differentiation potential, while keeping up in vitro expansion stability.


Assuntos
Células-Tronco , Quinases Associadas a rho , Animais , Camundongos , Amidas/farmacologia , Piridinas/farmacologia , Diferenciação Celular , Proliferação de Células
13.
Biochemistry ; 63(3): 264-272, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38190441

RESUMO

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.


Assuntos
Dibenzotiepinas , Influenza Humana , Morfolinas , Tiepinas , Humanos , Oxazinas , Piridinas/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Endonucleases/genética , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Piridonas/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Zanamivir/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
14.
Bioorg Chem ; 144: 107122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38278049

RESUMO

Non-platinum metal-based complexes have good potential for cancer treatment. Here, we designed and synthesized five hydrazone copper(II) complexes, [Cu2(HL)2Cl2] 1A, [Cu2(HL)2(NO3)H2O]·NO3 2A, [Cu2(HL)2Br2] 3A, [Cu(L)pyridine] 1B and [Cu(HL)(pyridine)Br] 3B, and evaluated their anti-lung cancer activities. MTT experiments revealed that these copper(II) complexes exhibit higher anticancer activity than cisplatin. Mechanism studies revealed that complex 3A induced G1 phase cell cycle arrest, and induced cell apoptosis via reactive oxygen species (ROS)-mediated mitochondrial dysfunction. Scratch wound healing assay was also performed, revealing that complex 3A have good anti-cell migration activity. Hemolysis assays showed good blood biocompatibility of complex 3A. Furthermore, complex 3A can significantly inhibit the proliferation of A549 3D tumor spheroid. An in vivo anticancer study showed that complex 3A could delays the growth of A549 tumor xenografts with lower systemic toxicity. These results highlight the great possibility of developing highly active copper complexes as anti-lung cancer agents.


Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias Pulmonares , Humanos , Cobre/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Modelos Moleculares , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Piridinas/farmacologia , Apoptose , Linhagem Celular Tumoral
15.
J Med Chem ; 67(2): 1061-1078, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38198226

RESUMO

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-µM IC50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays.


Assuntos
Proteínas Hedgehog , Proteínas Hedgehog/metabolismo , Piridinas/química , Piridinas/farmacologia
16.
J Enzyme Inhib Med Chem ; 39(1): 2286939, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38083880

RESUMO

A series of cis-restricted 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines as novel tubulin polymerisation inhibitors was designed based on molecular docking. Compound 9p, exhibited potent antiproliferative activity against HeLa, MCF-7, and A549 cell lines. Mechanism studies indicated that 9p potently inhibited tubulin polymerisation and disrupted the microtubule dynamics of tubulin in HeLa cells. Moreover, 9p could cause G2/M phase cell cycle arrest and apoptosis in HeLa cells. In addition, the prediction of physicochemical properties disclosed that 9p conformed well to the Lipinski's rule of five. The initial results suggest that the 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines could serve as a promising scaffold for the development of novel anticancer drugs.


Assuntos
Antineoplásicos , Tubulina (Proteína) , Humanos , Tubulina (Proteína)/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Células HeLa , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Linhagem Celular Tumoral
17.
Bioorg Med Chem Lett ; 97: 129543, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37939863

RESUMO

Heparanase-1 (HPSE1) is an endo-ß-d-glucuronidase that catalyzes degradation of heparan sulfate proteoglycans. Inhibition of HPSE1 appears to be a useful therapeutic target against cancer and proteinuric kidney diseases. We previously reported tetrahydroimidazo[1,2-a]pyridine 2 as a potent HPSE1 inhibitor after optimization of the synthetic reaction. However, synthesis of 2 involves a total of 19 steps, including a cyclization process that accompanies a strong odor due to the use of Lawesson's reagent and an epimerization reaction; furthermore, 2 exhibited insufficient selectivity for HPSE1 over exo-ß-d-glucuronidase (GUSß) and glucocerebrosidase (GBA), which also needed to be addressed. First, the cyclization reaction was optimized to synthesize tetrahydroimidazo[1,2-a]pyridine without using Lawesson's reagent or epimerization, with reference to previous reports. Next, 16 and 17 containing a bulkier substituent at position 6 than the 6-methoxyl group in 2 were designed and synthesized using the improved cyclization conditions, so that the synthetic route of 16 and 17 was shortened by five steps as compared with that of 2. The inhibitory activities of 16 and 17 against GUSß and GBA were reduced as compared with those of 2, that is, the compounds showed improved selectivity for HPSE1 over GUSß and GBA. In addition, 16 showed enhanced inhibitory activity against HPSE1 as compared with that of 2. Compound 16 appears promising as an HPSE1 inhibitor with therapeutic potential due to its highly potent inhibitory activity against HPSE1 with high selectivity for HPSE1.


Assuntos
Glucuronidase , Piridinas , Glucuronidase/antagonistas & inibidores , Compostos Organotiofosforados , Piridinas/química , Piridinas/farmacologia
18.
J Immunol ; 212(4): 689-701, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38149922

RESUMO

The classical pathway (CP) is a potent mechanism for initiating complement activity and is a driver of pathology in many complement-mediated diseases. The CP is initiated via activation of complement component C1, which consists of the pattern recognition molecule C1q bound to a tetrameric assembly of proteases C1r and C1s. Enzymatically active C1s provides the catalytic basis for cleavage of the downstream CP components, C4 and C2, and is therefore an attractive target for therapeutic intervention in CP-driven diseases. Although an anti-C1s mAb has been Food and Drug Administration approved, identifying small-molecule C1s inhibitors remains a priority. In this study, we describe 6-(4-phenylpiperazin-1-yl)pyridine-3-carboximidamide (A1) as a selective, competitive inhibitor of C1s. A1 was identified through a virtual screen for small molecules that interact with the C1s substrate recognition site. Subsequent functional studies revealed that A1 dose-dependently inhibits CP activation by heparin-induced immune complexes, CP-driven lysis of Ab-sensitized sheep erythrocytes, CP activation in a pathway-specific ELISA, and cleavage of C2 by C1s. Biochemical experiments demonstrated that A1 binds directly to C1s with a Kd of ∼9.8 µM and competitively inhibits its activity with an inhibition constant (Ki) of ∼5.8 µM. A 1.8-Å-resolution crystal structure revealed the physical basis for C1s inhibition by A1 and provided information on the structure-activity relationship of the A1 scaffold, which was supported by evaluating a panel of A1 analogs. Taken together, our work identifies A1 as a new class of small-molecule C1s inhibitor and lays the foundation for development of increasingly potent and selective A1 analogs for both research and therapeutic purposes.


Assuntos
Complemento C1s , Via Clássica do Complemento , Animais , Ovinos , Peptídeo Hidrolases , Complemento C1/metabolismo , Endopeptidases , Piridinas/farmacologia
19.
Viruses ; 15(12)2023 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-38140689

RESUMO

Baloxavir marboxil (baloxavir) is an FDA-approved inhibitor of the influenza virus polymerase acidic (PA) protein. Here, we used next-generation sequencing to compare the genomic mutational profiles of IAV H1N1 and H3N2, and IBV wild type (WT) and mutants (MUT) viruses carrying baloxavir resistance-associated substitutions (H1N1-PA I38L, I38T, and E199D; H3N2-PA I38T; and IBV-PA I38T) during passaging in normal human bronchial epithelial (NHBE) cells. We determined the ratio of nonsynonymous to synonymous nucleotide mutations (dN/dS) and identified the location and type of amino acid (AA) substitutions that occurred at a frequency of ≥30%. We observed that IAV H1N1 WT and MUT viruses remained relatively stable during passaging. While the mutational profiles for IAV H1N1 I38L, I38T, and E199D, and IBV I38T MUTs were relatively similar after each passage compared to the respective WTs, the mutational profile of the IAV H3N2 I38T MUT was significantly different for most genes compared to H3N2 WT. Our work provides insight into how baloxavir resistance-associated substitutions may impact influenza virus evolution in natural settings. Further characterization of the potentially adaptive mutations identified in this study is needed.


Assuntos
Herpesvirus Cercopitecino 1 , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Tiepinas , Humanos , Oxazinas/farmacologia , Piridinas/farmacologia , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/metabolismo , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/metabolismo , Tiepinas/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Células Epiteliais/metabolismo , Genômica , Proteínas Virais/genética , Nucleotidiltransferases
20.
Int J Mol Sci ; 24(24)2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38138979

RESUMO

Cisplatin-type covalent chemotherapeutics are a cornerstone of modern medicinal oncology. However, these drugs remain encumbered with dose-limiting side effects and are susceptible to innate and acquired resistance. The bulk of platinum anticancer research has focused on Cisplatin and its derivatives. Here, we take inspiration from the design of platinum complexes and ligands used successfully with other metals to create six novel complexes. Herein, the synthesis, characterization, DNA binding affinities, and lipophilicity of a series of non-traditional organometallic Pt(II)-complexes are described. These complexes have a basic [Pt(PL)(AL)]Cl2 molecular formula which incorporates either 2-pyrrolidin-2-ylpyridine, 2-(1H-Imidazol-2-yl)pyridine, or 2-(2-pyridyl)benzimidazole as the PL; the AL is resolved diaminocyclohexane. Precursor [Pt(PL)(Cl)2] complexes were also characterized for comparison. While the cytotoxicity and DNA binding properties of the three precursors were unexceptional, the corresponding [Pt(PL)(AL)]2+ complexes were promising; they exhibited different DNA binding interactions compared with Cisplatin but with similar, if not slightly better, cytotoxicity results. Complexes with 2-pyrrolidin-2-ylpyridine or 2-(2-pyridyl)benzimidazole ligands had similar DNA binding properties to those with 2-(1H-Imidazol-2-yl)pyridine ligands but were not as cytotoxic to all cell lines. The variation in activity between cell lines was remarkable and resulted in significant selectivity indices in MCF10A and MCF-7 breast cancer cell lines, compared with previously described similar Pt(II) complexes such as 56MESS.


Assuntos
Antineoplásicos , Platina , Humanos , Platina/farmacologia , Platina/química , Cisplatino/farmacologia , Cisplatino/química , Antineoplásicos/química , Células MCF-7 , DNA/química , Piridinas/farmacologia , Ligantes , Linhagem Celular Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...