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1.
Bioorg Chem ; 142: 106916, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37913584

RESUMO

Development of Multitarget-Directed Ligands (MTDLs) is a promising approach to combat the complex etiologies of Alzheimer's disease (AD). Herein we report the design, synthesis, and characterization of a new series of 1,4-bisbenzylpiperazine-2-carboxylic acid derivatives 3-5(a-g), 7a-f, 8a-s, and their piperazine-2-yl-1,3,4-oxadiazole analogs 6a-g. In vitro inhibitory effect against Electrophorus electricus acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from Equine serum was evaluated using modified Ellman's method, considering donepezil and tacrine as reference drugs. Lineweaver-Burk plot analysis of the results proved competitive inhibition of AChE and BChE with Ki values, in low micromolar range. The free carboxylic acid series 4a-g showed enhanced selectivity for AChE. Hence, 4c, 1,4-bis (4-chlorobenzyl)-piperazinyl-2-carboxylic acid), was the most active member of this series (Ki (AChE) = 10.18 ± 1.00 µM) with clear selectivity for AChE (SI âˆ¼ 17.90). However, the hydroxamic acids 7a-f and carboxamides 8a-s congeners were more potent and selective inhibitors of BChE (SI âˆ¼ 5.38 - 21862.5). Extraordinarily, 1,4-bis (2-chlorobenzyl)-piperazinyl-2-hydroxamic acid 7b showed promising inhibitory activity against BChE enzyme (Ki = 1.6 ± 0.08 nM, SI = 21862.5), that was significantly superior to that elicited by donepezil (Ki = 12.5 ± 2.6 µM) and tacrine (Ki = 17.3 ± 2.3 nM). Cytotoxicity assessment of 4c and 7b, on human neuroblastoma (SH-SY5Y) cell lines, revealed lower toxicity than staurosporine and was nearly comparable to that of donepezil. Molecular docking and molecular dynamics simulation afforded unblemished insights into the structure-activity relationships for AChE and BChE inhibition. The results showed stable binding with fair H-bonding, hydrophobic and/or ionic interactions to the catalytic and peripheral anionic sites of the enzymes. In silico predicted ADME and physicochemical properties of conjugates showed good CNS bioavailability and safety parameters. In this regard, compound (7b) might be considered as a promising inhibitor of BChE with an innovative donepezil-based anti-Alzheimer activity. Further assessments of the most potent AChE and BChE inhibitors as potential MTDLs anti-Alzheimer's agents are under investigation with our research group and will be published later.


Assuntos
Doença de Alzheimer , Neuroblastoma , Animais , Cavalos , Humanos , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Donepezila/farmacologia , Acetilcolinesterase/metabolismo , Tacrina/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/farmacologia , Ácidos Carboxílicos , Relação Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico , Simulação de Dinâmica Molecular , Estrutura Molecular
2.
Signal Transduct Target Ther ; 8(1): 405, 2023 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-37875500

RESUMO

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors demonstrated activity in terms of progression-free survival (PFS) in advanced dedifferentiated liposarcoma (DD-LPS), a sarcoma with CDK4 amplification. CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors. Preclinical investigators of this study found that CDK4 overexpression, while not of CDKN2A, was the most consistent predictive factor for palbociclib efficacy in sarcomas. Advanced adult-type soft-tissue sarcoma, excluding DD-LPS, or bone sarcoma patients, progressing after at least one systemic line, whose tumors overexpressed CDK4, but not CDKN2A at baseline biopsy, were accrued in this single-arm phase II trial (EudraCT number: 2016-004039-19). With the main endpoint of a 6-month PFS rate, 40% was considered promising in this population. Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles. A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening, archival material (141), and screening, baseline biopsy (95). There were 28 (29%) with favorable mRNA profiles from 95 screened patients at baseline. From 23 enrolled patients, 21 evaluable, the 6-month PFS rate was 29% (95% CI 9-48), and there were 6 patients out of 21 with a PFS longer than 6 months. The median PFS and overall survival were 4.2 (95% CI 3.6-4.8) and 12 (95% CI 8.7-15.4) months, respectively. Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.


Assuntos
Lipopolissacarídeos , Sarcoma , Adulto , Humanos , Sarcoma/genética , Piperazinas/uso terapêutico , Piperazinas/farmacologia , RNA Mensageiro , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo
3.
J Nat Prod ; 86(10): 2342-2347, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37807846

RESUMO

Four new aranotin-type epipolythiodioxopiperazines, graphiumins K-N (1-4), along with four known analogues (5-8), were isolated from the deep-sea-derived fungus Exophiala mesophila MCCC 3A00939. Their structures were elucidated by detailed interpretation of NMR and mass spectrometric data. The absolute configuration of the isolates was deduced by a single-crystal X-ray diffraction analysis and the comparisons of experimental electronic circular dichroism (ECD) data with calculated ECD spectra. Graphiumins K (1) and L (2) exhibited cytotoxic activities against the K562, H69AR, and MDA-MB-231 cancer cells with IC50 values ranging from 2.3 to 5.9 µM.


Assuntos
Antineoplásicos , Antineoplásicos/química , Piperazinas/farmacologia , Fungos/química , Estrutura Molecular
4.
Int J Mol Sci ; 24(19)2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37834044

RESUMO

Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,ß-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.


Assuntos
Ferroptose , Animais , Humanos , Apoptose , Piperazinas/farmacologia , Peroxidação de Lipídeos/fisiologia , Mamíferos
5.
Org Biomol Chem ; 21(42): 8554-8562, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37853800

RESUMO

Studying the viscosity of lipid droplets (LDs) provides insights into various diseases associated with LD viscosity. Ferroptosis is one such process in which LD viscosity increases due to the abnormal accumulation of lipid ROS (reactive oxygen species) caused by peroxidation. For investigating the LD imaging and ferroptosis, we developed two molecules (NNS and DNS) that show significant Stokes shifts (182-232 nm) and utilized them for sub-cellular imaging. Excellent localization is noted with the lipid droplets. Subsequently, DNS was used to monitor the variations in the LD viscosity during erastin-induced ferroptosis followed by ferroptosis inhibition. Additionally, we explored variations in the LD quantity, size, and accumulation when subjected to oleic acid stimulation. Extensive DFT and TDDFT investigations have been employed to understand the effect of NO2 substitution on the linear and branched molecular derivatives. Our results with the improved lipophilic fluorophore, exhibiting excellent colocalization with LDs, offer valuable insights into sensing erastin-induced ferroptosis and have the potential for real-time diagnostic applications.


Assuntos
Ferroptose , Gotículas Lipídicas , Peroxidação de Lipídeos , Piperazinas/farmacologia , Espécies Reativas de Oxigênio
6.
Molecules ; 28(20)2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37894502

RESUMO

This study investigated the effects of aseptic inflammation and heavy metal exposure on immune responses, as well as the potential immunomodulatory properties of the newly synthesized 1-[1-(2,5-dimethoxyphenyl)-4-(naphthalene-1-yloxy)but-2-ynyl]-4-methylpiperazine complexed with ß-cyclodextrin (ß-CD). Aseptic inflammation was induced by a subcutaneous injection of turpentine in rats, while heavy metal exposure was achieved through a daily administration of cadmium chloride and lead acetate. The levels of immune cell populations, including cytotoxic T lymphocytes (CTL), monocytes, and granulocytes, were assessed in the spleen. The results showed that aseptic inflammation led to decreased levels of CTL, monocytes, and granulocytes on the 14th day, indicating an inflammatory response accompanied by a migration of effector cells to the inflamed tissues. The exposure to cadmium chloride and lead acetate resulted in systemic immunotoxic effects, with reduced levels of B cells, CD4+ Th cells, monocytes, and granulocytes in the spleen. Notably, piperazine complexed with ß-CD (the complex) exhibited significant stimulatory effects on CD4+, CD8+, and myeloid cell populations during aseptic inflammation, even in the presence of heavy metal exposure. These findings suggest the potential immunomodulatory properties of the complex in the context of aseptic inflammation and heavy metal exposure.


Assuntos
Cádmio , Metais Pesados , Ratos , Animais , Cádmio/toxicidade , Cloreto de Cádmio/toxicidade , Inflamação/induzido quimicamente , Piperazinas/farmacologia
7.
Am J Cardiol ; 209: 92-103, 2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-37844876

RESUMO

Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.


Assuntos
Insuficiência Cardíaca , Piperazinas , Humanos , Ranolazina/uso terapêutico , Piperazinas/uso terapêutico , Piperazinas/farmacologia , Acetanilidas/farmacologia , Acetanilidas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Sódio
8.
Bioorg Med Chem Lett ; 93: 129425, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37557926

RESUMO

This work describes about the synthesis and evaluation of substituted benzofuran piperazines as potential anticancer agents. The synthesized candidates have been evaluated for their cell proliferation inhibition properties in six murine and human cancer cell lines. In vitro evaluation of apoptosis and cell cycle analysis with the lead candidate 1.19 reveals that necrosis might be an important pathway for the candidate compounds to cause cell death. Further, in vivo evaluation of the lead compound shows that this candidate is well tolerated in healthy mice. Additionally, an in vivo anticancer efficacy study in mice using a MDA-MB-231 xenograft model with the lead compound provides good anti-cancer efficacy.


Assuntos
Antineoplásicos , Benzofuranos , Humanos , Animais , Camundongos , Antineoplásicos/farmacologia , Piperazinas/farmacologia , Linhagem Celular , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Proliferação de Células , Apoptose , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade
9.
Angiogenesis ; 26(4): 481-483, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37530975

RESUMO

Imatinib, an ABL tyrosine-kinase inhibitor, shows promise in restoring endothelial barrier function in patients with COVID-19, thus, preventing cytokine leakage from the alveolar compartment to the systemic compartment. COVID-19 is characterized by an alveolar cytokine storm, and imatinib has been shown to strengthen the endothelial barrier and mitigate alveolar inflammatory responses by modulating NF-κB signaling. Incorporating imatinib into COVID-19 treatment strategies offers a novel approach to safeguard the endothelial barrier and address the complex pathophysiology of the disease, including its potential implications in long COVID. Given that endothelial dysfunction plays a central role in COVID-19 progression and long COVID development, protecting the endothelial barrier during acute infection is crucial in preventing the persistent endothelial dysfunction associated with long COVID.


Assuntos
COVID-19 , Síndrome Pós-COVID-19 Aguda , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Tratamento Farmacológico da COVID-19 , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Piperazinas/farmacologia , Benzamidas/uso terapêutico , Benzamidas/farmacologia
10.
Bioorg Chem ; 139: 106749, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37517157

RESUMO

Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aß-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aß aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aß-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aß-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.


Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Ratos , Animais , Doença de Alzheimer/metabolismo , Donepezila/farmacologia , Tionas , Simulação de Acoplamento Molecular , Piperazinas/farmacologia , Simulação de Dinâmica Molecular , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Desenho de Fármacos , Relação Estrutura-Atividade
11.
J Nat Prod ; 86(7): 1786-1792, 2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37450763

RESUMO

Bioassay-guided fractionation of the essential oil of Santalum album led to the identification of α-santalol (1) and ß-santalol (2) as new chemotypes of cannabinoid receptor type II (CB2) ligands with Ki values of 10.49 and 8.19 µM, respectively. Nine structurally new α-santalol derivatives (4a-4h and 5) were synthesized to identify more selective and potent CB2 ligands. Compound 4e with a piperazine structural moiety demonstrated a Ki value of 0.99 µM against CB2 receptor and did not show binding activity against cannabinoid receptor type I (CB1) at 10 µM. Compounds 1, 2, and 4e increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that were attenuated by CB2 antagonism or inverse agonism, supporting the results that these compounds are CB2 agonists. Molecular docking showed that 1 and 4e had similar binding poses, exhibiting a unique interaction with Thr114 within the CB2 receptor, and that the piperazine structural moiety is required for the binding affinity of 4e. A 200 ns molecular dynamics simulation of CB2 complexed with 4e confirmed the stability of the complex. This structural insight lays a foundation to further design and synthesize more potent and selective α-santalol-based CB2 ligands for drug discovery.


Assuntos
Agonismo Inverso de Drogas , Neuroblastoma , Humanos , Simulação de Acoplamento Molecular , Ligantes , Receptores de Canabinoides , Piperazinas/farmacologia , Receptor CB2 de Canabinoide , Receptor CB1 de Canabinoide , Estrutura Molecular , Relação Estrutura-Atividade
12.
Int J Oncol ; 63(3)2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37503790

RESUMO

Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan­AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti­tumor activity in pre­clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the Lkb1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated­H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo­treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.


Assuntos
Neoplasias do Endométrio , Paclitaxel , Feminino , Animais , Humanos , Camundongos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Proteínas Proto-Oncogênicas c-akt , Piperazinas/farmacologia , Proliferação de Células , Neoplasias do Endométrio/patologia , Apoptose , Linhagem Celular Tumoral
13.
Oncogene ; 42(34): 2578-2588, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37468679

RESUMO

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+ mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Camundongos , Animais , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Fator de Células-Tronco/genética , Fator de Células-Tronco/farmacologia , Fator de Células-Tronco/uso terapêutico , Pirimidinas/farmacologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Benzamidas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Proto-Oncogênicas c-kit , Mutação , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
14.
Int J Mol Sci ; 24(11)2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37298236

RESUMO

Despite not dividing, senescent cells acquire the ability to synthesize and secrete a plethora of bioactive molecules, a feature known as the senescence-associated secretory phenotype (SASP). In addition, senescent cells often upregulate autophagy, a catalytic process that improves cell viability in stress-challenged cells. Notably, this "senescence-related autophagy" can provide free amino acids for the activation of mTORC1 and the synthesis of SASP components. However, little is known about the functional status of mTORC1 in models of senescence induced by CDK4/6 inhibitors (e.g., Palbociclib), or the effects that the inhibition of mTORC1 or the combined inhibition of mTORC1 and autophagy have on senescence and the SASP. Herein, we examined the effects of mTORC1 inhibition, with or without concomitant autophagy inhibition, on Palbociclib-driven senescent AGS and MCF-7 cells. We also assessed the pro-tumorigenic effects of conditioned media from Palbociclib-driven senescent cells with the inhibition of mTORC1, or with the combined inhibition of mTORC1 and autophagy. We found that Palbociclib-driven senescent cells display a partially reduced activity of mTORC1 accompanied by increased levels of autophagy. Interestingly, further mTORC1 inhibition exacerbated the senescent phenotype, a phenomenon that was reversed upon autophagy inhibition. Finally, the SASP varied upon inhibiting mTORC1, or upon the combined inhibition of mTORC1 and autophagy, generating diverse responses in cell proliferation, invasion, and migration of non-senescent tumorigenic cells. Overall, variations in the SASP of Palbociclib-driven senescent cells with the concomitant inhibition of mTORC1 seem to depend on autophagy.


Assuntos
Senescência Celular , Piperazinas , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Piperazinas/farmacologia , Carcinogênese , Autofagia
15.
Eur J Med Chem ; 258: 115539, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37321107

RESUMO

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesised and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 µM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.


Assuntos
Mycobacterium tuberculosis , Quinolonas , Quinolonas/farmacologia , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Piperazinas/farmacologia , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana
16.
CNS Neurosci Ther ; 29(10): 2998-3013, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37122156

RESUMO

AIM: Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats. METHODS: Neural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity. RESULTS: We detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia. CONCLUSION: Excessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.


Assuntos
Antiparkinsonianos , Discinesia Induzida por Medicamentos , Ritmo Gama , Levodopa , Piperazinas , Agonistas do Receptor de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Ritmo Gama/efeitos dos fármacos , Levodopa/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Antiparkinsonianos/efeitos adversos , Animais , Ratos , Modelos Animais de Doenças , Córtex Motor/efeitos dos fármacos , Córtex Motor/fisiopatologia
17.
Biochem Biophys Res Commun ; 668: 49-54, 2023 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-37244034

RESUMO

Salmonella is a widespread foodborne pathogen that can exhibit multidrug resistance (MDR; resistance to ≥3 antimicrobial classes). Therefore, the development of new preventative measures against MDR Salmonella is highly important. Bacterial antibiotic resistance is commonly mediated by efflux pumps. In this study, two compounds that block efflux pump activity, 1-(1-Naphthylmethyl)-Piperazine (NMP) and Phenylalanine-arginine ß-naphthylamide (PaßN), were tested with the antibiotic tetracycline to determine if a synergistic reduction in resistance could be achieved in tetracycline-resistant Salmonella. The efflux pump inhibitors (EPIs) reduced Salmonella resistance to tetracycline by 16 to 32-fold in several tetracycline resistant isolates. For example, the tetracycline minimum inhibitory concentration (MIC) for MDR Salmonella enterica serovar I 4,[5],12:i:- USDA15WA-1 (SX 238) was 256 µg/mL. However, in the presence of NMP (250 µg/mL), the MIC dropped to 8 µg/mL which is below the Clinical Laboratory Standards Institute (CLSI) breakpoint for tetracycline resistance in Salmonella (≥16 µg/mL). Confocal and transmission electron microscopy revealed NMP-mediated damage to Salmonella membranes at a higher concentration (1000 µg/mL), implying that the EPI disrupts membrane morphology which can lead to cell death; however, this effect was dependent on NMP concentration, as NMP blocked efflux activity with less of a membrane-disrupting effect at a lower concentration (250 µg/mL). These findings suggest that the use of EPIs can reduce the MIC of tetracycline and restore the effectiveness of the antibiotic against tetracycline-resistant Salmonella.


Assuntos
Anti-Infecciosos , Piperazinas , Piperazina/farmacologia , Piperazinas/farmacologia , Farmacorresistência Bacteriana Múltipla , Proteínas de Membrana Transportadoras , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Salmonella , Tetraciclinas/farmacologia , Testes de Sensibilidade Microbiana
18.
PLoS Pathog ; 19(5): e1011387, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37200402

RESUMO

Infections caused by members of the mycobacterium tuberculosis complex [MTC] and nontuberculous mycobacteria [NTM] can induce widespread morbidity and mortality in people. Mycobacterial infections cause both a delayed immune response, which limits rate of bacterial clearance, and formation of granulomas, which contain bacterial spread, but also contribute to lung damage, fibrosis, and morbidity. Granulomas also limit access of antibiotics to bacteria, which may facilitate development of resistance. Bacteria resistant to some or all antibiotics cause significant morbidity and mortality, and newly developed antibiotics readily engender resistance, highlighting the need for new therapeutic approaches. Imatinib mesylate, a cancer drug used to treat chronic myelogenous leukemia [CML] that targets Abl and related tyrosine kinases, is a possible host-directed therapeutic [HDT] for mycobacterial infections, including those causing TB. Here, we use the murine Mycobacterium marinum [Mm] infection model, which induces granulomatous tail lesions. Based on histological measurements, imatinib reduces both lesion size and inflammation of surrounding tissue. Transcriptomic analysis of tail lesions indicates that imatinib induces gene signatures indicative of immune activation and regulation at early time points post infection that resemble those seen at later ones, suggesting that imatinib accelerates but does not substantially alter anti-mycobacterial immune responses. Imatinib likewise induces signatures associated with cell death and promotes survival of bone marrow-derived macrophages [BMDMs] in culture following infection with Mm. Notably, the capacity of imatinib to limit formation and growth of granulomas in vivo and to promote survival of BMDMs in vitro depends upon caspase 8, a key regulator of cell survival and death. These data provide evidence for the utility of imatinib as an HDT for mycobacterial infections in accelerating and regulating immune responses, and limiting pathology associated with granulomas, which may mitigate post-treatment morbidity.


Assuntos
Piperazinas , Pirimidinas , Humanos , Animais , Camundongos , Mesilato de Imatinib/farmacologia , Pirimidinas/farmacologia , Piperazinas/farmacologia , Benzamidas , Antibacterianos/uso terapêutico , Granuloma/tratamento farmacológico
19.
Brain Res Bull ; 199: 110662, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37150328

RESUMO

BACKGROUND: The onset of schizophrenia is associated with both genetic and environmental risks during brain development. Environmental factors during pregnancy can represent risk factors for schizophrenia, and we have previously reported that several microRNA and mRNA expression changes in fetal brains exposed to haloperidol during pregnancy may be related to the onset of this disease. This study aimed to replicate that research and focused on apoptotic-related gene expression changes. METHODS: Haloperidol (1 mg/kg) or aripiprazole (1 mg/kg) was injected into pregnant mice. Using RNA sequencing for the hippocampus of each offspring born from pregnant mice exposed to haloperidol, we analyzed genes identified as changed in our previous report and validated two apoptosis-related genes (Cdkn1a and Apaf1) using quantitative polymerase chain reaction (qPCR) methods. Furthermore, we attempted to elucidate the direct effects of haloperidol and aripiprazole on those mRNA expressions in in vitro experiments. RESULTS: RNA sequencing successfully replicated 16 up-regulated and 5 down-regulated genes in this study. Of those, up-regulations of Cdkn1a and Apaf1 mRNA expression were successfully validated by direct quantification. Moreover, haloperidol and aripiprazole dose-dependent upregulation of both mRNA expressions were confirmed in a Neuro2a cell line. CONCLUSIONS: In the hippocampus of offspring, intraperitoneal injection of haloperidol to pregnant mice induced up-regulation of apoptotic genes that representing the phenotypic change without apoptosis. These findings will be useful for understanding the molecular biological mechanisms underlying the effects of antipsychotics on the fetal brain.


Assuntos
Antipsicóticos , Quinolonas , Camundongos , Animais , Haloperidol/farmacologia , Aripiprazol/farmacologia , Piperazinas/farmacologia , Quinolonas/farmacologia , Antipsicóticos/farmacologia , Hipocampo/metabolismo , RNA Mensageiro/metabolismo
20.
Gastric Cancer ; 26(5): 677-690, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37222910

RESUMO

BACKGROUND: KIT is frequently mutated in gastrointestinal stromal tumors (GISTs), and the treatment of GISTs largely relies on targeting KIT currently. In this study, we aimed to investigate the role of sprouty RTK signaling antagonist 4 (SPRY4) in GISTs and related mechanisms. METHODS: Ba/F3 cells and GIST-T1 cell were used as cell models, and mice carrying germline KIT/V558A mutation were used as animal model. Gene expression was examined by qRT-PCR and western blot. Protein association was examined by immunoprecipitation. RESULTS: Our study revealed that KIT increased the expression of SPRY4 in GISTs. SPRY4 was found to bind to both wild-type KIT and primary KIT mutants in GISTs, and inhibited KIT expression and activation, leading to decreased cell survival and proliferation mediated by KIT. We also observed that inhibition of SPRY4 expression in KITV558A/WT mice led to increased tumorigenesis of GISTs in vivo. Moreover, our results demonstrated that SPRY4 enhanced the inhibitory effect of imatinib on the activation of primary KIT mutants, as well as on cell proliferation and survival mediated by the primary KIT mutants. However, in contrast to this, SPRY4 did not affect the expression and activation of drug-resistant secondary KIT mutants, nor did it affect the sensitivity of secondary KIT mutants to imatinib. These findings suggested that secondary KIT mutants regulate a different downstream signaling cascade than primary KIT mutants. CONCLUSIONS: Our results suggested that SPRY4 acts as negative feedback of primary KIT mutants in GISTs by inhibiting KIT expression and activation. It can increase the sensitivity of primary KIT mutants to imatinib. In contrast, secondary KIT mutants are resistant to the inhibition of SPRY4.


Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Neoplasias Gástricas , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Mutação , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
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