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1.
Bioorg Chem ; 144: 107134, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38237389

RESUMO

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.


Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Proteína-Tirosina Quinases de Adesão Focal , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia
2.
Brain Res ; 1800: 148187, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36463957

RESUMO

PURPOSE: Neuropathic pain represents a significant public health problem and its effective management remains a challenge. The present study is designed to evaluate the analgesic effect of the spirocyclopiperazinium salt compound DXL-A-24 in spinal nerve ligation (SNL) model, and further to explore the possible molecular mechanisms. METHODS: SNL model was established on rats, and mechanical allodynia and thermal hyperalgesia were estimated with the von Frey and hot plate tests; the expression of CaMKIIα, CREB, JAK2, STAT3 and c-fos was determined by western blotting; the protein level of TNF-α was analysed by ELISA; the mRNA expression of TNF-α and c-fos was detected using qRT-PCR analysis and the receptor blocking test was used for target searching. RESULTS: Administration of DXL-A-24 (1, 0.5, 0.25 mg/kg, i.g.) obviously relieved SNL-induced mechanical allodynia and thermal hyperalgesia in rats (P < 0.01), with the percentage of pain threshold elevation (PTE%) was 103 %, 68 % and 47 %, respectively, in mechanical allodynia; the percentage of maximal possible effect (MPE%) was 56 %, 34 % and 21 %, respectively, in thermal hyperalgesia on day 7 after SNL. Pretreatment with peripheral α7 nicotinic or M4 muscarinic receptor antagonist, the effect of DXL-A-24 was completely blocked (P > 0.05). DXL-A-24 significantly reduced the upregulated pCaMKIIα, pCREB, pJAK2, pSTAT3 and TNF-α protein (P < 0.01), which could be blocked by α7 nicotinic receptor or M4 muscarinic receptor antagonist. In addition, administration of DXL-A-24 attenuated the mRNA and protein expression of c-fos and TNF-α mRNA in DRG of SNL rat. We did not observe significant acute toxicity and chronic hepatorenal impairment at effective dose and high dose. CONCLUSIONS: We report firstly that administration of DXL-A-24 displays obvious antineuropathic pain effects in SNL rats. The underlying mechanism may involve the reduction of the CaMKIIα/CREB and JAK2/STAT3 signalling pathways, and the suppression of TNF-α and c-fos expression, which may be mediated by activating peripheral α7 nicotinic and M4 muscarinic receptors. This study may provide a new perspective for developing new antineuralgic drug.


Assuntos
Hiperalgesia , Neuralgia , Ratos , Animais , Hiperalgesia/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Nervos Espinhais/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Cloreto de Sódio , Cloreto de Sódio na Dieta , Antagonistas Muscarínicos , RNA Mensageiro , Ligadura
3.
Eur J Med Chem ; 226: 113859, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34601246

RESUMO

Urea transporters (UTs) have been identified as new targets for diuretics. Functional deletion of UTs led to urea-selective urinary concentrating defects with relative salt sparing. In our previous study, a UT inhibitor with a diarylamide scaffold, which is denoted as 11a, was demonstrated as the first orally available UT inhibitor. However, the oral bioavailability of 11a was only 4.38%, which obstructed its clinical application. In this work, by replacing the nitro group of 11a with an acetyl group, 25a was obtained. Compared with 11a, 25a showed a 10 times stronger inhibitory effect on UT-B (0.14 µM vs. 1.41 µM in rats, and 0.48 µM vs. 5.82 µM in mice) and a much higher inhibition rate on UT-A1. Moreover, the metabolic stability both in vitro and in vivo and the drug-like properties (permeability and solubility) of 25a were obviously improved compared with those of 11a. Moreover, the bioavailability of 25a was 15.18%, which was 3 times higher than that of 11a, thereby resulting in significant enhancement of the diuretic activities in rats and mice. 25a showed excellent potential for development as a promising clinical diuretic candidate for targeting UTs to treat diseases that require long-term usage of diuretics, such as hyponatremia.


Assuntos
Furanos/farmacologia , Hiponatremia/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Administração Oral , Animais , Cães , Relação Dose-Resposta a Droga , Furanos/administração & dosagem , Hiponatremia/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Transportadores de Ureia
4.
Acta Pharm Sin B ; 11(1): 181-202, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33532188

RESUMO

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate, N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide (1H), with excellent in vitro UT inhibitory activity at the submicromolar level. The half maximal inhibitory concentrations of 1H against UT-B in mouse, rat, and human erythrocyte were 1.60, 0.64, and 0.13 µmol/L, respectively. Further investigation suggested that 8 µmol/L 1H more powerfully inhibited UT-A1 at a rate of 86.8% than UT-B at a rate of 73.9% in MDCK cell models. Most interestingly, we found for the first time that oral administration of 1H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats. Additionally, 1H did not exhibit apparent toxicity in vivo and in vitro, and possessed favorable pharmacokinetic characteristics. 1H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

5.
Bioorg Chem ; 108: 104653, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33517002

RESUMO

Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC50 = 0.136 µM) and 8k (AC50 = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC50 = 0.228 µM), and they (IC50 < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC50 > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Piperazina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas de Transporte/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas de Membrana/metabolismo , Estrutura Molecular , Piperazina/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
6.
Acta Pharmacol Sin ; 41(1): 65-72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31213671

RESUMO

Urea transporters (UTs) are transmembrane proteins selectively permeable to urea and play an important role in urine concentration. UT-knockout mice exhibit the urea-selective urine-concentrating defect, without affecting electrolyte balance, suggesting that UT-B inhibitors have the potential to be developed as novel diuretics. In this study, we characterized a novel compound 5-ethyl-2-methyl-3-amino-6-methylthieno[2,3-b]pyridine-2,5-dicarboxylate (CB-20) with UT inhibitory activity as novel diuretics with excellent pharmacological properties. This compound was discovered based on high-throughput virtual screening combined with the erythrocyte osmotic lysis assay. Selectivity of UT inhibitors was assayed using transwell chambers. Diuretic activity of the compound was examined in rats and mice using metabolic cages. Pharmacokinetic parameters were detected in rats using LC-MS/MS. Molecular docking was employed to predict the potential binding modes for the CB-20 with human UT-B. This compound dose-dependently inhibited UT-facilitated urea transport with IC50 values at low micromolar levels. It exhibited nearly equal inhibitory activity on both UT-A1 and UT-B. After subcutaneous administration of CB-20, the animals showed polyuria, without electrolyte imbalance and abnormal metabolism. CB-20 possessed a good absorption and rapid clearance in rat plasma. Administration of CB-20 for 5 days did not cause significant morphological abnormality in kidney or liver tissues of rats. Molecular docking showed that CB-20 was positioned near several residues in human UT-B, including Leu364, Val367, and so on. This study provides proof of evidence for the prominent diuretic activity of CB-20 by specifically inhibiting UTs. CB-20 or thienopyridine analogs may be developed as novel diuretics.


Assuntos
Diuréticos/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Tienopiridinas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diuréticos/administração & dosagem , Diuréticos/química , Cães , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tienopiridinas/administração & dosagem , Tienopiridinas/química , Transportadores de Ureia
7.
Neurochem Res ; 44(12): 2786-2795, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31691883

RESUMO

The antinociceptive effects of spirocyclopiperazinium salt compound DXL-A-24 on neuropathic pain and chemical-stimulated pain were investigated in this study. After the administration of DXL-A-24, the paw withdrawal latency (PWL) and mechanical withdrawal threshold (MWT) were increased in rats suffering from neuropathic pain (chronic constriction injury, CCI) on days 1, 3, 5, 7 and 14 after surgery, and pain responses were inhibited in mice stimulated with chemicals (formalin or acetic acid). In the analysis of antinociceptive targets, the effect of DXL-A-24 was blocked by a peripheral nicotinic acetylcholine receptor (nAChR) antagonist (hexamethonium, Hex) or α7 nAChR antagonist (methyllycaconitine, MLA) in the formalin test. Meanwhile, the effect of DXL-A-24 was also blocked by a peripheral muscarinic acetylcholine receptor (mAChR) antagonist (atropine methylnitrate, Amn) or M4 mAChR antagonist (tropicamide, TRO). The antinociceptive signalling pathway was explored using molecular biology methods in ipsilateral dorsal root ganglions (DRGs) of CCI rats after the administration of DXL-A-24 for 7 days. Western blot analyses showed that the increased levels of phosphorylation of calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) and cAMP response element-binding protein (CREB) were eliminated, and the qRT-PCR assay showed that the increase in the expression of Tumor necrosis factor alpha (TNF-α) mRNA was reduced. Meanwhile, immunofluorescence staining revealed that the increase in calcitonin gene related peptide (CGRP) expression was inhibited by the administration of DXL-A-24, and the effect was blocked by MLA or TRO. In conclusion, DXL-A-24 exerts significant antinociceptive effects on neuropathic pain and chemical-stimulated pain. The antinociceptive effect of DXL-A-24 is probably attributed to the activation of peripheral α7 nAChR and M4 mAChR, the subsequent inhibition of the CaMKIIα/CREB signalling pathway, and finally the inhibition of TNF-α and CGRP expression.


Assuntos
Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Dor Nociceptiva/tratamento farmacológico , Piperazinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Ácido Acético , Analgésicos/toxicidade , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Formaldeído , Masculino , Camundongos Endogâmicos ICR , Dor Nociceptiva/induzido quimicamente , Piperazinas/toxicidade , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Compostos de Espiro/toxicidade , Fator de Necrose Tumoral alfa/genética
8.
Stroke Vasc Neurol ; 4(1): 3-7, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31105972

RESUMO

OBJECTIVE: Intravenous tissue plasminogen activator (tPA) is the standard therapy for patients with acute ischaemic stroke (AIS) within 4.5 hours of onset. Recent trials have expanded the endovascular treatment window to 24 hours. We investigated the efficacy and safety of using multimodal MRI to guide intravenous tPA treatment for patients with AIS of unknown time of onset (UTO). METHODS: Data on patients with AIS with UTO and within 4.5 hours of onset were reviewed. Data elements collected and analysed included: demographics, National Institutes of Health Stroke Scale (NIHSS) score at baseline and 2 hours, 24 hours, 7 days after thrombolysis and before discharge, the modified Rankin Scale (mRS) score at 3 months after discharge, imaging findings and any adverse event. RESULTS: Forty-two patients with UTO and 62 in control group treated within 4.5 hours of onset were treated with intravenous tPA. The NIHSS scores after thrombolysis and/or before discharge in UTO group were significantly improved compared with the baseline (p<0.05). Between the two groups, no significant differences in NIHSS score were observed (p>0.05). Utilising the non-inferiority test, to compare mRS scores (0-2) at 3 months between the two groups, the difference was 5.2% (92% CI, OR 0.196). Patients in the UTO group had mRS scores of 0-2, which were non-inferior to the control group. Their incidence of adverse events was similar. CONCLUSIONS: Utilising multimodal MRI to guide intravenous only thrombolysis for patients with AIS with UTO was safe and effective. In those patients with AIS between 6 and 24 hours of time of onset but without large arterial occlusion, intravenous thrombolysis could be considered an option.


Assuntos
Imagem de Difusão por Ressonância Magnética , Fibrinolíticos/administração & dosagem , AVC Isquêmico/tratamento farmacológico , Angiografia por Ressonância Magnética , Imagem de Perfusão , Terapia Trombolítica , Tempo para o Tratamento , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Fibrinolíticos/efeitos adversos , Estado Funcional , Humanos , Infusões Intravenosas , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Estudos Retrospectivos , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento
9.
Eur J Med Chem ; 172: 131-142, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959323

RESUMO

Urea transporters (UTs) play an important role in the urine concentrating mechanism and are recognized as novel targets for developing small molecule inhibitors with salt-sparing diuretic activity. Thienoquinoline derivatives, a class of novel UT-B inhibitors identified by our group, play a significant diuresis in animal model. However, the poor solubility and low bioavailability limited its further development. To overcome these shortcomings, the structure modification of thienoquinoline was carried out in this study, which led to the discovery of novel thienopyridine derivatives as specific urea transporter inhibitors. Further optimization obtained the promising preclinical candidate 8n with not only excellent inhibition effect on urea transporters and diuretic activity on rat model, but also suitable water solubility and Log P value.


Assuntos
Descoberta de Drogas , Proteínas de Membrana Transportadoras/metabolismo , Tienopiridinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Proteínas de Membrana Transportadoras/sangue , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/química , Transportadores de Ureia
10.
Eur J Med Chem ; 170: 1-15, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878825

RESUMO

Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound 5 and SAR study, the 7-azaindole moiety in compound 5 was systematically optimized. The results showed that compound 6f, which has a difluoroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375 cell lines. In a xenograft mouse model, oral administration of compound 6f led to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that 6f could influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375 cells. More importantly, compound 6f significantly inhibited migration of A375 cells in a concentration-dependent manner. Collectively, 6f may serve as a lead compound in the development of potent PKM2 activators for cancer therapy.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Proteínas de Transporte/agonistas , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Proteínas de Membrana/agonistas , Tiocarbamatos/farmacologia , Hormônios Tireóideos/agonistas , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Humanos , Indóis/síntese química , Indóis/química , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/química , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
11.
J Org Chem ; 84(3): 1310-1319, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607949

RESUMO

A direct C(sp2)-H amination of 2-furanones under metal-free conditions was realized. This unprecedented intermolecular C-H to C-N conversion provides rapid access to 4-amino-furanone derivatives and novel aza-heterocycle fused furanone skeletons. A redox mechanism based on a double-Michael-addition intermediate INT2 is proposed and detected by spectrometry.


Assuntos
Furanos/química , Elementos de Transição/química , Aminação , Catálise , Oxirredução
12.
Bioorg Med Chem Lett ; 28(14): 2459-2464, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29886021

RESUMO

Curcumin is a well-known pharmacophore and some of its derivatives are shown to target 20S proteasome recently. In this report, we designed and synthesized two series of curcumin derivatives modified with different α-amino boronic acids as potent proteasome inhibitors. The synthesized compounds were evaluated for their cytotoxic activities against HCT116 cells, and the results showed that all of them exhibited excellent cell growth inhibitory activity comparing with curcumin, with the IC50 values varying from 0.17 µM to 1.63 µM. Compound II-2F with free boronic acid was assayed for its proteasome inhibitory activity and the results indicated that II-2F exhibited more potent inhibitory activity against ChT-L with high subunit selectivity than any other reported curcumin derivatives.


Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Curcumina/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Borônicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/síntese química , Curcumina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 149: 1-9, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29486369

RESUMO

Based on our discovered novel lead compound 1 through phenotypic drug discovery (PDD) approaches, systematic structural optimization was performed. A series of 2-allylthio-5-amino substituted benzoquinones were synthesized and evaluated for their in-vitro anticancer activities against human prostate cancer cell line PC3. The compound 7a was found inhibit the growth of PC3 with an IC50 of 0.22 µM, which is over 20-fold improvement compared to lead compound 1. It is noteworthy that compound 7a also showed potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cell, as well as good water solubility.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Desenho de Fármacos , Antineoplásicos/química , Benzoquinonas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Solubilidade , Relação Estrutura-Atividade
14.
Regul Toxicol Pharmacol ; 94: 108-114, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29353067

RESUMO

The aim of this study was to investigate the analgesic effect of the spirocyclopiperazinium salt compound LXM-15 by intragastric administration in thermal and chemical pain models and further to elucidate the possible molecular mechanisms. The results showed that LXM-15 exerted significant antinociception in hot-plate test, formalin test and acetic acid writhing test. Western blot analysis showed that LXM-15 significantly reduced the upregulation of phosphorylation of calcium/calmodulin -dependent protein kinase IIα (CaMKIIα) and cAMP response element-binding protein (CREB), and further decreased the elevation of calcitonin gene related peptide (CGRP) in the dorsal root ganglion (DRG) and spinal cord in mice. ELISA analysis showed the level of cAMP in the spinal cord was decreased by LXM-15. All effects of LXM-15 could be blocked by methyllycaconitine citrate (MLA, a selective α7 nicotinic receptor antagonist) or tropicamide (TRO, a selective M4 muscarinic receptor antagonist). This study first reported that intragastric administration of LXM-15 produced significant analgesic effect, which may be related to the activation of α7 nicotinic acetylcholine receptor and M4 muscarine acetylcholine receptor, and thereby inhibiting CaMKIIα/cAMP/CREB/CGRP signalling pathway.


Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Dor/metabolismo , Compostos de Espiro/farmacologia , Ácido Acético , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Formaldeído , Temperatura Alta , Masculino , Camundongos Endogâmicos ICR , Receptor Muscarínico M4/metabolismo , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
15.
Inflamm Res ; 67(4): 363-370, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29302720

RESUMO

OBJECTIVE: This study aimed to investigate the anti-inflammatory effects of a novel spirocyclopiperazinium salt compound LXM-15, and explore the underlying mechanisms. METHODS: Xylene-induced mouse ear oedema and carrageenan-induced rat paw oedema tests were used to evaluate the anti-inflammatory effects of LXM-15. The protein levels of TNF-α, IL-6, phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were detected by ELISA or Western blot analysis. Additionally, receptor blocking test was performed to explore the possible target. RESULTS: Intragastric administration with LXM-15 (2, 1, 0.5 mg/kg in mice, and 6, 3, 1.5 mg/kg in rats) produced distinct anti-inflammatory effects in vivo, the highest inhibition percentage was 60 and 52%, respectively (P < 0.01). Following treatment with LXM-15 (6 mg/kg, i.g.), the levels of TNF-α and IL-6 in the rats paws were attenuated by 40 and 41%; and the phosphorylation of JAK2 and STAT3 was restrained by 35 and 45%, respectively (P < 0.01). All effects of LXM-15 were blocked by pretreatment with methyllycaconitine citrate or tropicamide. CONCLUSION: This study provides the first report that the spirocyclopiperazinium salt compound LXM-15 displays considerable anti-inflammatory effects. The underlying mechanism may be through activating the peripheral α7 nicotinic acetylcholine receptor and M4 muscarinic acetylcholine receptor, leading to the inhibition of the JAK2/STAT3 signalling pathway, eventually resulting in the reduction of TNF-α and IL-6.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Compostos de Espiro/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Edema/induzido quimicamente , Edema/metabolismo , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M4/metabolismo , Fator de Transcrição STAT3/metabolismo , Compostos de Espiro/química , Fator de Necrose Tumoral alfa/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
16.
Eur J Med Chem ; 143: 48-65, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29172082

RESUMO

Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC50 values from 0.46 µM to 0.81 µM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Descoberta de Drogas , Proteínas de Membrana/metabolismo , Tionas/farmacologia , Hormônios Tireóideos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/química , Proteínas de Ligação a Hormônio da Tireoide
17.
Front Pharmacol ; 8: 476, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28883791

RESUMO

Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome.

18.
Bioorg Med Chem ; 25(15): 4031-4044, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28634039

RESUMO

On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.


Assuntos
Ácidos Borônicos/farmacologia , Prolina/química , Inibidores de Proteassoma/farmacologia , Ácidos Borônicos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Humanos , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 127: 442-458, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28092860

RESUMO

A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50 of 7.4 nM and 82 nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468 cells. In vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100 mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900 mg/kg (single dose).


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Mostardas de Fosforamida/síntese química , Mostardas de Fosforamida/farmacologia , Quinazolinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Mostardas de Fosforamida/química , Mostardas de Fosforamida/farmacocinética , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Med Chem ; 125: 925-939, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27769033

RESUMO

A novel class of urea-containing peptide boronic acids as proteasome inhibitors was designed by introducing a urea scaffold to replace an amido bond. Compounds were synthesized and their antitumor activities were evaluated. After two rounds of optimizations, the compound I-14 was found to be a potent proteasome inhibitor. Compared with Bortezomib, I-14 showed higher potency against the chymotrypsin-like activity of human 20S proteasome (IC50 < 1 pM), similar potency against four different cancer cell lines (IC50 < 10 nM), and better pharmacokinetic profile. Furthermore, I-14 significantly inhibited tumor growth in Bel7404 mouse xenograft model. The excellent proteasome inhibition by I-14 was rationalized through docking and molecular dynamics studies.


Assuntos
Ácidos Borônicos/farmacologia , Peptídeos/farmacologia , Inibidores de Proteassoma/química , Animais , Antineoplásicos , Ácidos Borônicos/química , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/farmacocinética , Ureia/química , Ureia/farmacologia
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