RESUMO
TAK-875 (compound 1) was the only GPR40 agonist with promising oral glucose-lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK-875 sulfoxide analog 2, which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK-875. Herein, in order to further evaluate the druglikeness of TAK-875 sulfoxide analogs, the pharmacokinetic properties of compounds 2, 3, and 4 in rats were investigated and compared with that of TAK-875. The results showed that sulfoxide (2, 3, and 4) and sulfone (TAK-875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK-875, 2 and 4. In order to further investigate the in vivo glucose-lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose-lowering effect in vivo than 6 (R, S, 71.0% de) and TAK-875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5) relative to sulfoxide 4 (the main component of 6) and TAK-875.
Assuntos
Sulfóxidos/farmacocinética , Animais , Benzofuranos/farmacocinética , Benzofuranos/farmacologia , Dieta Hiperlipídica , Açúcares da Dieta/administração & dosagem , Teste de Tolerância a Glucose , Masculino , Ratos Wistar , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/farmacocinética , Sulfonas/farmacologia , Sulfóxidos/farmacologiaRESUMO
The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC50 value of 0.089⯱â¯0.007⯵M, which was two orders of magnitude lower than that of bestatin (IC50â¯=â¯9.4⯱â¯0.5⯵M). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10⯵M), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100⯵M in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.
Assuntos
Antineoplásicos/química , Antígenos CD13/antagonistas & inibidores , Leucina/análogos & derivados , Inibidores de Proteases/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Antígenos CD13/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Click , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucina/farmacologia , Leucina/uso terapêutico , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Simulação de Acoplamento Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t1/2=630min) was over 5-fold improved than its parent 1 (t1/2=103min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model.
Assuntos
Benzimidazóis/química , Inibidores de Histona Desacetilases/química , Tetra-Hidroisoquinolinas/química , Animais , Benzimidazóis/uso terapêutico , Benzimidazóis/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/uso terapêutico , Transplante Heterólogo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Compounds 10 (ND-322) and 15 (ND-364) are potent selective inhibitors for gelatinases, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). However, both of them are racemates. Herein we report facile synthesis of optically active (R)- and (S)-enantiomers of compounds 10 and 15. And the sulfonyl of 15 was transformed to sulfinyl to obtain four epimeric mixtures. All synthesized thiirane-based compounds were evaluated in MMP2 and MMP9 inhibitory assays. Our results indicated that the configuration of thiirane moiety had little effects on gelatinase inhibition, but the substitution of sulfinyl for sulfonyl was detrimental to gelatinase inhibition. Besides, all target compounds exhibited no inhibition against other two Zn(2+) dependant metalloproteases, aminopeptidase N (APN) and histone deacetylases (HDACs), which confirmed the unique Zn(2+) chelation mechanism of thiirane moiety against gelatinases.
Assuntos
Arginina/análogos & derivados , Gelatinases/antagonistas & inibidores , Inibidores de Metaloproteinases de Matriz/farmacologia , Éteres Fenílicos/farmacologia , Sulfonas/farmacologia , Arginina/síntese química , Arginina/química , Arginina/farmacologia , Relação Dose-Resposta a Droga , Gelatinases/metabolismo , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/química , Estrutura Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/químicaRESUMO
Rice sheath blight, caused by Rhizoctonia solani Kihn (R. solani), poses a significant threat to rice production and quality. Autotetraploid rice, developed through chromosome doubling of diploid rice, holds great potential for enhancing biological and yield traits. However, its resistance to sheath blight in the field has remained unclear. In this study, the field resistance of 35 autotetraploid genotypes and corresponding diploids was evaluated across three environments from 2020 to 2021. The booting stage was optimal for inoculating period based on the inoculation and analysis of R. solani at five rice growth stages. We found autotetraploids generally exhibited lower disease scores than diploids, indicating enhanced resistance after chromosome doubling. Among the 35 genotypes, 16 (45.71%) displayed increased resistance, 2 (5.71%) showed decreased resistance, and 17 (48.57%) displayed unstable resistance in different sowing dates. All combinations of the genotype, environment and ploidy, including the genotype-environment-ploidy interaction, contributed significantly to field resistance. Chromosome doubling increased sheath blight resistance in most genotypes, but was also dependent on the genotype-environment interaction. To elucidate the enhanced resistance mechanism, RNA-seq revealed autotetraploid recruited more down-regulated differentially expressed genes (DEGs), additionally, more resistance-related DEGs, were down-regulated at 24 h post inoculation in autotetraploid versus diploid. The ubiquinone/terpenoid quinone and diterpenoid biosynthesis pathways may play key roles in ploidy-specific resistance mechanisms. In summary, our findings shed light on the understanding of sheath blight resistance mechanisms in autotetraploid rice.
RESUMO
Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.
Assuntos
Ácido Araquidônico , Transformação Celular Neoplásica , Montagem e Desmontagem da Cromatina , Classe I de Fosfatidilinositol 3-Quinases , Mutação , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Ácido Araquidônico/metabolismo , Animais , Mutação/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Montagem e Desmontagem da Cromatina/genética , Camundongos , Linhagem Celular Tumoral , Colo/patologia , Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Exossomos/metabolismo , Exossomos/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Histonas/metabolismo , Histonas/genéticaRESUMO
BACKGROUND: Many studies have shown that glycated hemoglobin (HbA1c) is associated with coronary artery disease (CAD). HbA1c was independently related to angiographic severity in Chinese patients with CAD after adjusting for other covariates. Some traditional cardiovascular drugs may have an impact on this relationship. METHODS: This retrospective study enrolled a total of 572 CAD patients who underwent their coronary angiography and had their HbA1c levels measured at the Chinese Hospital. The complexity of the coronary artery lesions was evaluated using the Syntax score, and the subjects were divided into 4 inter quartiles according to HbA1c levels. Covariates included history of traditional cardiovascular drugs. RESULTS: The average age of selected participants was 61.00 ± 9.15 years old, and about 54.72% of them were male. Result of fully adjusted linear regression showed that HbA1c was positively associated with Syntax score after adjusting confounders (ß = 1.09, 95% CI: 0.27, 1.91, P = 0.0096). By interaction and stratified analyses, the interactions were observed based on our specification including with the medication history of statins and angiotensin receptor blockers (ARBs) (P values for interaction <0.05). CONCLUSION: In this study, we found a positive correlation between the HbA1c levels and the SYNTAX score among CAD individuals, and oral statins and ARBs medication could affect the correlation. Thus, HbA1c measurement could be used for the evaluation of the severity and complexity of coronary lesions among CAD patients.
RESUMO
In the title compound, C(14)H(16)ClN(3)O(2)S, the dihedral angle between the 4-chloro-phenyl and 1,3,4-oxadiazole rings is 67.1â (1)° and the orientation of the amide N-H and C=O bonds is anti. In the crystal, mol-ecules are linked by N-Hâ¯O and N-Hâ¯S hydrogen bonds.
RESUMO
Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.
Assuntos
Diabetes Mellitus Experimental/terapia , Fibrose/terapia , Fatores de Transcrição MEF2/antagonistas & inibidores , Miocárdio/patologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Transição Epitelial-Mesenquimal , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores de Transcrição MEF2/biossíntese , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Transdução de Sinais , TransfecçãoRESUMO
Myocyte enhancer factor 2A (MEF2A) functions in muscle-specific and/or growth factor-related transcription and is involved in cell growth, survival, and apoptosis. To evaluate the role of this transcription factor in cardiac fibroblasts (CFs) in diabetes mellitus, we performed a series of in vitro and in vivo experiments. We used short hairpin RNA (shRNA) to inhibit the expression of MEF2A in CFs in vitro. Inhibition of MEF2A significantly reduced hyperglycemia-induced CF proliferation and migration, myofibroblast differentiation, matrix metalloproteinase (MMP) activities, and collagen production. Furthermore, MEF2A inhibition attenuated HG-induced activation of the mitogen-activated protein kinase (MAPK), Akt, and TGF-ß1/Smad signaling pathways. For in vivo analysis in a mouse model, type-1 diabetes was induced by streptozotocinand MEF2A expression was knocked down by myocardial injection with lentivirus carrying shRNA-MEF2A. Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. Knockdown of MEF2A ameliorated diabetes-induced cardiac dysfunction and collagen deposition. Our study suggests that inhibition of MEF2A could alleviate HG-induced extracellular matrix accumulation by blocking the activation of Akt and TGF-ß1/Smad signaling pathway in CFs. Thus, inhibition of MEF2A has therapeutic potential in the treatment of diabetic-induced cardiac remodeling.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Matriz Extracelular/metabolismo , Hiperglicemia/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/patologia , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Glucose/fisiologia , Ventrículos do Coração/patologia , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Miocárdio/química , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
A series of new 1,3,4-oxadiazole and 1,2,4-triazole derivatives were synthesized. The structures were confirmed by IR, (1)H-NMR, and MS. The compounds were evaluated for their antiproliferative activity against K562 (human erythromyeloblastoid leukemia cell line), MDA-MB-231 (human breast adenocarcinoma cell line), HT29 (human colon adenocarcinoma grade II cell line) and HepG2 (human hepatocellular liver carcinoma cell line) in vitro. The result showed that 7 compounds displayed inhibitory activities against K562 with the inhibition rate more than 50%. Especially, compound 5f exhibited the most potent activity against K562 with 85% inhibition ratio and could be used as lead compound to search new 1,3,4-oxadiazole derivatives as antiproliferative agent.