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1.
Front Endocrinol (Lausanne) ; 13: 1083569, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36686417

RESUMO

Background: Renal cell carcinoma (RCC) is a highly metastatic urological cancer. RCC with liver metastasis (LM) carries a dismal prognosis. The objective of this study is to develop a machine learning (ML) model that predicts the risk of RCC with LM, which is used to assist clinical treatment. Methods: The retrospective study data of 42,547 patients with RCC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. ML includes algorithmic methods and is a fast-rising field that has been widely used in the biomedical field. Logistic regression (LR), Gradient Boosting Machine (GBM), Extreme Gradient Boosting (XGB), random forest (RF), decision tree (DT), and naive Bayesian model [Naive Bayes Classifier (NBC)] were applied to develop prediction models to predict the risk of RCC with LM. The six models were 10-fold cross-validated, and the best-performing model was selected based on the area under the curve (AUC) value. A web online calculator was constructed based on the best ML model. Results: Bone metastasis, lung metastasis, grade, T stage, N stage, and tumor size were independent risk factors for the development of RCC with LM by multivariate regression analysis. In addition, the correlation of the relative proportions of the six clinical variables was shown by a heat map. In the prediction models of RCC with LM, the mean AUC of the XGB model among the six ML algorithms was 0.947. Based on the XGB model, the web calculator (https://share.streamlit.io/liuwencai4/renal_liver/main/renal_liver.py) was developed to evaluate the risk of RCC with LM. Conclusions: This XGB model has the best predictive effect on RCC with LM. The web calculator constructed based on the XGB model has great potential for clinicians to make clinical decisions and improve the prognosis of RCC patients with LM.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Hepáticas , Humanos , Prognóstico , Teorema de Bayes , Modelos Estatísticos , Estudos Retrospectivos , Aprendizado de Máquina
2.
Cancer Manag Res ; 12: 4009-4016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547235

RESUMO

BACKGROUND: Germacrone, a natural product isolated from the traditional Chinese medicine Rhizoma Curcuma, has been reported to exhibit antitumor activities in vitro. To further understand the antitumor mechanism of germacrone, we investigated the growth inhibitory effect of germacrone on the human prostate cancer cell lines PC-3 (androgen independent) and 22RV1 (androgen dependent). MATERIALS AND METHODS: Prostate cancer cells were cultured with different concentrations of germacrone, and cell viability was measured by MTT assay. The levels of proteins were measured by Western blotting. Cell apoptosis was assessed by flow cytometry. Images of autophagy-related protein staining were captured by fluorescence microscopy. Autophagic flux was assessed by detecting the LC3B-II level. RESULTS: Our results indicated that germacrone treatment significantly inhibited cell proliferation by inducing apoptosis in a dose-dependent manner, with IC50 values of 259 µM for PC-3 cells and 396.9 µM for 22RV1 cells. Germacrone-treated cells also exhibited induction of autophagy, as evidenced by elevated LC3B-II protein expression levels and punctuate patterns. Additionally, an autophagy inhibitor enhanced the growth inhibitory effect of germacrone. Moreover, the phosphorylation of Akt and mTOR was inhibited in germacrone-treated prostate cancer cells. CONCLUSION: Germacrone induced apoptosis and autophagy in prostate cancer cells by inhibiting the Akt/mTOR signaling pathway. Germacrone treatment also led to the activation of protective autophagy. These findings suggest that germacrone may potentially contribute to the development of a new therapeutic agent for prostate cancer treatment.

3.
Cancer Manag Res ; 12: 1751-1757, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210616

RESUMO

BACKGROUND: lncRNA-SNHG16 was identified as an oncogene in many cancers, but its involvement in prostate carcinoma is unknown. MATERIAL AND METHOD: Expression of lncRNA-SNHG16 and glucose transporter 1 (GLUT-1) in 52 prostate carcinoma tissues and 36 normal prostate tissues was analyzed by RT-qPCR. Transfections were performed to analyze gene interactions. Cell proliferation was analyzed by cell proliferation assay. RESULTS: Overexpression of lncRNA-SNHG16 effectively distinguished prostate carcinoma patients from normal ones. Expression levels of lncRNA-SNHG16 and GLUT-1 mRNA were significantly and positively correlated across prostate carcinoma tissues. In vitro cancer cell experiments revealed that lncRNA-SNHG16 siRNA silencing downregulated the expressions of GLUT-1 and reduced glucose uptake. lncRNA-SNHG16 siRNA silencing also significantly inhibited prostate carcinoma cell proliferation. However, lncRNA-SNHG16 siRNA silencing did not affect the normal prostate. CONCLUSION: In conclusion, lncRNA-SNHG16 might be a possible treatment target for prostate cancer.

4.
Adv Clin Exp Med ; 27(11): 1469-1475, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30085424

RESUMO

BACKGROUND: Diabetic cardiomyopathy (DCM) is one of the most harmful diseases with high morbidity and mortality rates. However, the underlying pathological mechanism of the disorder still remains unclear. OBJECTIVES: The purpose of our study was to identify differentially expressed proteins associated with DCM. MATERIAL AND METHODS: C57BLKS/J db/db (diabetes mellitus group - DM group) and db/m mice (normal control group - NC group) were acclimated in cages for 15 weeks. The general state was recorded. After 15 weeks, the heart tissues were used for histological examination. In addition, quantitative mass spectrometry using isobaric tags for relative and absolute quantitation (iTRAQ) was used to identify differentially expressed proteins in the heart tissues. SEQUEST software was used to identify proteins with data derived from liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectra by searching ipi.MOUSE.v3.72.REVERSED. fasta database. Expert Protein Analysis System (ExPASy) was used to calculate the theoretical parameters. One upregulated protein (sorbin and SH3 domain containing 2 - Sorbs2) and 1 downregulated protein (myosin-3) was measured by western blot to validate the iTRAQ data. RESULTS: The mice in the NC group were active and grew well, while the mice in the DM group presented with obvious polydipsia, polyphagia and polyuria. The results of histological examination revealed that, compared to the NC group, the DM group showed significant myocardial hypertrophy and myofiber disarray accompanied by damaged nuclei. A total of 73 differentially expressed proteins were identified, including 44 upregulated and 29 downregulated proteins. Western blot analysis confirmed that the expression of Sorbs2 was significantly increased (p < 0.01), while the expression of myosin-3 was statistically decreased in the DM group compared to the NC group (p < 0.05). CONCLUSIONS: These results suggest that DCM shows differences in its proteomics compared to normal controls. Our quantitative proteomic analysis may provide a new insight into the distinct molecular profile of DCM.


Assuntos
Cromatografia Líquida/métodos , Cardiomiopatias Diabéticas/metabolismo , Miocárdio/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Cardiomiopatias Diabéticas/patologia , Miocárdio/patologia
5.
Sci Rep ; 8(1): 5273, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29588471

RESUMO

Janus tyrosine kinase 3 (JAK3) is expressed in lymphoid cells and is involved in the signalling of T cell functions. The development of a selective JAK3 inhibitor has been shown to have a potential benefit in the treatment of autoimmune disorders. In this article, we developed the 4-aminopiperidine-based compound RB1, which was highly selective for JAK3 inhibition, with an IC50 of value of 40 nM, but did not inhibit JAK1, JAK2 or tyrosine kinase 2 (TYK2) at concentrations up to 5 µM. Furthermore, RB1 also exhibited favourable selectivity against a panel of representative kinases. In a battery of cytokine-stimulated cell-based assays, this potent inhibitor of JAK3 activity with good selectivity against other kinases could potently inhibit JAK3 activity over the activity of JAK1 or JAK2 (over at least 100-fold). A combination of liquid chromatography-mass spectrometry (LC-MS) experiments validated that RB1 covalently modified the unique cysteine 909 residue in JAK3. In vivo, RB1 exerted significantly improved pathology in the joints of a collagen-induced arthritis mouse model. The reasonable pharmacokinetics properties (F = 72.52%, T1/2 = 14.6 h) and favourable results of toxicology experiments (LD50 > 2 g/kg) suggest that RB1 has the potential to be an efficacious treatment for RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Janus Quinase 3/antagonistas & inibidores , Articulações/efeitos dos fármacos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Descoberta de Drogas , Feminino , Humanos , Janus Quinase 3/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
6.
Mol Divers ; 22(2): 343-358, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29411195

RESUMO

Here, we report the design and synthesis of pyrimidinyl heterocyclic compounds containing terminal electrophiles as irreversible covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of the structure-activity relationship utilizing kinase assays resulted in the identification of potent and selective JAK3 inhibitors such as T1, T8, T15, T22, and T29. Among them, T29 was verified as a promising JAK3 irreversible inhibitor that possessed the best bioactivity and selectivity against JAKs and kinases containing a cysteine in the residue analogous to Cys909 in JAK3, suggesting that covalent modification of this Cys residue allowed the identification of a highly selective JAK3 inhibitor. Moreover, T29 also displayed a significant anti-inflammatory effect in ICR mice through the inhibition of increased paw thickness, which is worth further optimization to increase its potency and medicinal properties.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Técnicas de Química Sintética , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Domínios Proteicos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade
7.
Mol Med Rep ; 17(3): 4832-4838, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29328450

RESUMO

Cardiovascular diseases have become one of the major public health problems in many countries. The downregulation of MYBL2 was found in H9c2 and native cardiomyocytes cells after hypoxia treatment. The present study aimed to investigate the effects of MYB proto­oncogene like 2 (MYBL2) on H9c2 injury induced by hypoxia. Reverse transcription­quantitative polymerase chain reaction and western blot were performed on H9c2 cells to determine the mRNA and protein levels of MYBL2, respectively. Small interfering RNA (siRNA) was employed to downregulate MYBL2 expression in H9c2 cells to investigate changes in cell proliferation and apoptosis. Cell proliferation was assessed by a Cell Counting kit­8 assay and the percentage of apoptotic cells was determined using an Annexin V­fluorescein isothiocyanate/propidium iodide apoptosis detection kit. The nuclear factor­κB (NF­κB) and AKT signaling pathways in H9c2 cells were investigated by western blot analysis. The results demonstrated that the overexpression of MYBL2 promoted cell proliferation and suppressed apoptosis. Furthermore, overexpression of MYBL2 suppressed the expression of phosphorylated (p)­AKT, p­NF­κB inhibitor α, p­p65 and B­cell CLL/lymphoma 3 (Bcl­3). The results indicated that MYBL2 may improve cell viability and inhibit H9c2 apoptosis via the inhibition of AKT and NF­κB pathways. Therefore, MYBL2 may be a potential therapeutic target for the treatment of myocardial infarction.


Assuntos
Hipóxia Celular , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose , Proteína 3 do Linfoma de Células B , Linhagem Celular , Proliferação de Células , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética
8.
Eur J Med Chem ; 145: 96-112, 2018 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-29324347

RESUMO

Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16. B16 preferentially inhibited Btk (IC50 = 21.70 ±â€¯0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto-phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC50 values over 30 µM. Moreover, B16 showed very weak potential to block the hERG channel (IC50 = 11.10 µM) in comparison to ibrutinib (IC50 = 0.97 µM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t1/2 = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Tirosina Quinase da Agamaglobulinemia , Animais , Artrite Reumatoide/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Int J Nanomedicine ; 12: 7121-7130, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29026305

RESUMO

PURPOSE: Schisandrin B (Sch B) is clinically applied for the treatment of hepatitis and ischemic disease. However, its clinical efficacy is limited due to the poor solubility and low bioavailability. This study aimed to develop matrix metalloproteinase (MMP)-sensitive peptide-modified, polyethylene glycol (PEG)-modified (PEGylated) solid lipid nanoparticles (SLNs) for loading Sch B (MMP-Sch B SLNs), and to evaluate the therapeutic effect in the myocardial infarction model. METHODS: PEG lipid and MMP-targeting peptide conjugate were synthesized. MMP-Sch B SLNs were prepared by solvent displacement technique. The physicochemical properties and pharmacokinetics of SLNs were investigated. In vivo effects on infarct size was evaluated in rats. RESULTS: The successful synthesis of lipid-peptide conjugate was confirmed. MMP-Sch B SLNs had a particle size of 130 nm, a zeta potential of 18.3 mV, and a sustained-release behavior. Higher heart drug concentration and longer blood circulation times were achieved by Sch B loaded SLNs than the drug solution according to the pharmacokinetic and biodistribution results. The best therapeutic efficacy was exhibited by MMP-Sch B SLNs by reducing the infarction size to the greatest extent. CONCLUSION: The modified SLNs may be a good choice for delivery of Sch B for the treatment of myocardial infarction.


Assuntos
Cardiotônicos/uso terapêutico , Lignanas/uso terapêutico , Lipídeos/química , Metaloproteinases da Matriz/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Nanopartículas/química , Peptídeos/química , Compostos Policíclicos/uso terapêutico , Polietilenoglicóis/química , Animais , Disponibilidade Biológica , Cardiotônicos/farmacologia , Morte Celular/efeitos dos fármacos , Ciclo-Octanos/sangue , Ciclo-Octanos/farmacocinética , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Lignanas/sangue , Lignanas/farmacocinética , Lignanas/farmacologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Tamanho da Partícula , Compostos Policíclicos/sangue , Compostos Policíclicos/farmacocinética , Compostos Policíclicos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos
10.
Bioorg Med Chem Lett ; 27(17): 4051-4055, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28765013

RESUMO

Histone acetylation marks play important roles in controlling gene expressions and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins, whose targeted inhibitors are under clinical investigation. BET and HDAC inhibitors have been demonstrated to be synergistically killing in Mycinduced murine lymphoma. Herein, we combine the inhibitory activities of BET and HDAC into one molecule through structure-based design method and evaluate its function. The majority of these synthesized compounds showed inhibitory activity against second bromdomains(BRD) of BRD4 and HDAC1. Among them, 16ae presented anti-proliferative effects against human acute myelogenous leukemia (AML) cell lines in vitro, and 16ae is confirmed to reduce the expression of Myc by Western blot analysis. Those results indicated that 16ae is a potent dual BRD4/HDAC inhibitor and deserves further investigation.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Nucleares/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
11.
Eur J Med Chem ; 138: 1114-1125, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28763646

RESUMO

A series of novel 4-anilinoquinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, 14h exhibited the most potent cytotoxic activity with IC50 values ranging from 1.5 to 3.9 nM against all tested cancer cell lines, and showed promising efficacy in multidrug resistant cancer cells. Flow cytometry assay, immune-fluorescence staining, microtubule dynamics assays and competition assays with EBI identified that 14h was a novel tubulin depolymerization agent by binding to the colchicine site. Importantly, in vivo efficacy evaluation of HCT116 xenograft model, 14h showed efficient antitumor activity without significant loss in body weight. All the results indicated that 14h could be a promising candidate for the treatment of cancer.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Quinolinas/farmacologia , Tubulina (Proteína)/metabolismo , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
12.
J Colloid Interface Sci ; 493: 181-189, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28092816

RESUMO

HYPOTHESIS: Exchange of the chloride ion (Cl-) ligands of cisplatin with carboxylates is widely used in fabricating cisplatin loaded nanoparticles for improved cancer therapy. However, the dynamic exchange may cause premature cisplatin release and even disintegration of the nanoparticles in Cl--containing medium such as in plasma. Molecules bearing carboxylates are capable of mediating the mineralization process of calcium phosphate; therefore, it is possible to overcome the disadvantage by sequestering cisplatin in a calcium phosphate nanoparticle (CPNP). EXPERIMENTS: With the hypothesis, precipitation reaction of calcium nitrate and disodium hydrogen phosphate was performed in a solution of poly(ethylene glycol)-poly(acrylic acid) block copolymers with their carboxylates partly conjugated with cisplatin. Then, structure, physicochemical properties, and bioactivity of the product were carefully investigated with multiple characterization methods. FINDINGS: It was revealed a pegylated, cisplatin encapsulated CPNP was prepared; and with appropriate mole ratio of cisplatin to carboxylates, the nanoparticle encapsulated cisplatin efficiently (>90%), was stable and almost entirely prevented the cisplatin release in Cl--containing medium at pH 7.4 but released them in an acidic condition, and showed moderately and greatly enhanced cytotoxicities to the lung cancer cell line A549 and its cisplatin resistance form A549R respectively in comparison with the free cisplatin.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Fosfatos de Cálcio/administração & dosagem , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Portadores de Fármacos/química , Nanopartículas/administração & dosagem , Polietilenoglicóis/química , Antineoplásicos/química , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Cisplatino/química , Portadores de Fármacos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/química , Polietilenoglicóis/administração & dosagem
13.
Chem Biol Drug Des ; 87(2): 290-5, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26426933

RESUMO

Type 2 diabetes (T2D) is classified as a major metabolic disorder, which has affected approximately 194 million people worldwide. DPP-IV inhibitors as a new therapy have shown several advantages over traditional antidiabetic drugs. Based on the similar binding modes of Alogliptin and Linagliptin, molecular operation was conducted via combining pharmacophore hybridization with structural optimization between the two market drugs and racemic compounds 40 and 43 were reported as DPP-IV inhibitors in our previous studies. But the majority of DPP-IV inhibitors have developed into a small molecule with certain conformation; in this study, we described the synthesis, biological evaluation, and molecular docking of corresponding enantiomers of compounds 40 and 43. The most potent inhibitor is (R)-40 (IC50  = 23.5 nm, F = 74.67%, T1/2  = 4 h), which exhibited moderate antihyperglycemic activity as compared to the standard antidiabetic drug Linagliptin in OGTT. In addition, compound (R)-40 effectively improved the pathological state of DIO mice. Molecular docking studies clarified the favorable binding affinity between compound (R)-40 and DPP-IV active site. Thus, compound (R)-40 would be entitled to further development as a drug candidate on the basis of the suitable pharmacokinetic (PK) and desirable pharmacodynamic (PD) profiles.


Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Hipoglicemiantes/síntese química , Nitrilas/química , Animais , Área Sob a Curva , Sítios de Ligação , Glicemia/análise , Domínio Catalítico , Dieta Hiperlipídica , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Teste de Tolerância a Glucose , Meia-Vida , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/etiologia , Curva ROC , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
14.
Bioorg Med Chem ; 23(13): 3337-50, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25937236

RESUMO

By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3',4',5'-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel-Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure-activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC50 values of 8.4-26.4nM in five human cancer cell lines, with comparable inhibition effects to CA-4. Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent.


Assuntos
Inibidores da Angiogênese/farmacologia , Antimitóticos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Tiazóis/farmacologia , Moduladores de Tubulina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Inibidores da Angiogênese/síntese química , Animais , Antimitóticos/síntese química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colchicina/metabolismo , Colchicina/farmacologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica , Estilbenos/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Moduladores de Tubulina/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Bioorg Med Chem Lett ; 25(11): 2429-33, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25881822

RESUMO

Twenty-eight pyrazoline derivatives, which originated from pyranochalcones, have been synthesized and evaluated for their inhibitory potency on the production of inflammatory mediator nitric oxide (NO) in LPS-stimulated RAW 264.7 cells. Among them, three compounds (1c, 11c, and 15c) exhibited potent inhibitory effects on NO production and iNOS activity superior to positive control Indomethacin, with 1c being most efficacious. Furthermore, 1c could suppress the progress of carrageenan-induced hind paw edema at a dosage of 50 mg/kg/day and dose-dependently ameliorate the development of adjuvant-induced arthritis (AIA). Docking study confirmed that 1c was an iNOS inhibitor with good binding into the active site of murine iNOS.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Carragenina/toxicidade , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Ratos
16.
Mol Divers ; 19(2): 333-46, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25672287

RESUMO

Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 [Formula: see text] exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.


Assuntos
Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Desenho de Fármacos , Glucose/metabolismo , Homeostase , Xantina/química , Animais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Homeostase/efeitos dos fármacos , Camundongos , Fatores de Tempo , Xantina/farmacologia
17.
Mol Divers ; 18(2): 335-44, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24519385

RESUMO

PIM-1 kinase is an important therapeutic target in the treatment of cancer. Discovery and identification of PIM-1 Inhibitors with novel scaffolds are an effective way for developing potent therapeutic agents for the treatment of cancers. Here we proposed a hybrid screening approach which combines an optimal structure-based drug design strategy and a simple pharmacophore model to discover PIM-1 kinase inhibitors. With the proposed hybrid screening approach, the SPECS database containing 204,580 molecules was screened. In total, 89 hits were obtained. Forty three of them were purchased and tested in bioassays. Finally, 5 lead compounds with novel scaffolds were identified to exhibit promising antitumor activities against human leukemia cell line MV4-11, K-562 and human prostate cancer cell line PC-3 and DU145. Their IC(50) values range from 4.40 to 37.96 µM. Three hits with 3 different scaffolds were selected from these five hits for binding mode analysis. It was demonstrated that the subtle differences in the interactions of the representatives with PIM-1 kinase contribute to the different inhibitory activities. It was also demonstrated that the suggested hybrid screening approach is an effective method to discover PIM-1 inhibitors possessing different scaffolds. These leads have a strong likelihood to act as further starting points for us in the optimization and development of potent PIM-1 inhibitors.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo
18.
Zhonghua Xin Xue Guan Bing Za Zhi ; 37(11): 994-7, 2009 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-20137323

RESUMO

OBJECTIVE: To observe the outcome of percutaneous balloon mitral valvuloplasty (PBMV) in patients with rheumatic mitral valve stenosis. METHODS: From April 1992 to November 2008, 1768 patients underwent PBMV in our hospital.Clinical and echocardiographic follow up data were analyzed in 426 patients from April 1992 to August 1998. Left atrial pressure and the mitral valve gradient (MVG) were measured before and immediately after PBMV in all patients. RESULTS: PBMV was successful in 1748 out of 1768 patients (98.86%). Left atrial pressure decreased from (38 +/- 7) mm Hg (1 mm Hg = 0.133 kPa) to (12 +/- 4) mm Hg (P < 0.001), MVG decreased from (28 +/- 6) mm Hg to (8 +/- 3) mm Hg (P < 0.001) and the area of the mitral valve increased from (0.98 +/- 0.26) cm(2) to (1.97 +/- 0.39) cm(2) (P < 0.001) post PBMV. The main complications included death (n = 2), acute pericardial effusion (n = 1), severe mitral regurgitation (n = 12), cerebral embolism (n = 2) and pulmonary edema (n = 1). Ten years follow up was finished in 426 patients and 288 patients (67.6%) were still in NYHA class Ior II without mitral valve replace operation or repeated PBMV, restenosis was evidenced in 140 patients (33.3%) and 31 patients dead (7.5%). CONCLUSION: PBMV was an effective therapy option for patients with rheumatic mitral valve stenosis.


Assuntos
Cateterismo , Estenose da Valva Mitral/terapia , Cardiopatia Reumática/terapia , Cateterismo/efeitos adversos , Ecocardiografia , Seguimentos , Humanos , Resultado do Tratamento
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