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PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.
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Hipoglucemiantes , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteolisis , Animales , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Descubrimiento de Drogas , Células Hep G2 , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.
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Enfermedades Neurodegenerativas , Proteolisis , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Proteolisis/efectos de los fármacos , Animales , Descubrimiento de Drogas , Estructura Molecular , Quimera Dirigida a la ProteólisisRESUMEN
Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.
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Benzofuranos , Indanos , Fármacos Neuroprotectores , Piperidinas , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Piperidinas/farmacología , Piperidinas/síntesis química , Piperidinas/química , Indanos/farmacología , Indanos/síntesis química , Indanos/química , Benzofuranos/farmacología , Benzofuranos/síntesis química , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Masculino , Supervivencia Celular/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológicoRESUMEN
The objective of this study was to investigate the anticancer activities of biodegradable polymeric micelles composed of monomethoxy poly(ethylene glycol), polylactic acid, and nitric oxide (mPEG-PLA-NO) loaded with paclitaxel (PTX) as a nanomedicine delivery system. We aimed to compare the anticancer effects of these NO/PTX micelles with PTX alone and elucidate their mechanism of action. We evaluated the impact of NO/PTX and PTX on cell viability using Cell Counting Kit-8 (CCK8) assays conducted on the Bel-7402 liver cancer cell line. Additionally, we employed H22 xenografted mice to assess the in vivo tumor growth inhibitory activity of NO/PTX. To examine the cytotoxicity of NO/PTX, the intracellular levels of reactive oxygen species (ROS), and the expression of ferroptosis-related proteins, we conducted experiments in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) or the ROS inhibitor N-acetyl cysteine (NAC). Furthermore, we investigated the expression of endoplasmic reticulum stress (ERS) and apoptosis-associated proteins. Our results demonstrated that NO/PTX exhibited enhanced anticancer effects compared to PTX alone in both Bel-7402 cells and H22 xenografted mice. The addition of Fer-1 or NAC reduced the anticancer activity of NO/PTX, indicating the involvement of ferroptosis and ROS in its mechanism of action. Furthermore, NO/PTX modulated the expression of proteins related to ERS and apoptosis, indicating the activation of these cellular pathways. The anticancer effects of NO/PTX in liver cancer cells were mediated through the induction of ferroptosis, pyroptosis, ERS, and apoptosis-associated networks. Ferroptosis and pyroptosis were activated by treatment of NO/PTX at low concentration, whereas ERS was induced to trigger apoptosis at high concentration. The superior anti-tumor effect of NO/PTX may be attributed to the downregulation of a multidrug resistance transporter and the sensitization of cells to PTX chemotherapy. In summary, our study highlights the potential of mPEG-PLA-NO micelles loaded with PTX as a nanomedicine delivery system for liver cancer treatment. The observed enhancement in anticancer activity, combined with the modulation of key cellular pathways, provides valuable insights into the therapeutic potential of NO/PTX in overcoming resistance and improving treatment outcomes in liver cancer patients.
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[This corrects the article DOI: 10.1039/D3RA04861F.].
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There are no highly effective and safe medicines for clinical treatment of ischemic stroke, although the natural product 3-n-butylphthalide (NBP) has been approved in China for mild and moderate ischemic stroke. To discover more potent anti-cerebral ischemic agents and overcome the low stability by phthalide derivatives, benzofuran-3-one was selected as a core moiety and two types of nitric oxide (NO)-donating groups were incorporated into the structure. In this work, a series of 2,6-disubstituted benzofuran-3-one derivatives were designed and synthesised as NBP analogues, and tested as neuroprotective and antioxidative agents. Compounds 5 (without an NO donor) and 16 (with an NO donor) displayed more potent neuroprotective effects than the established clinical drugs Edaravone and NBP. More importantly, 5 and 16 also exhibited good antioxidative activity without cytotoxicity in rat primary neuronal and PC12 cells. Most active compounds showed good blood-brain barrier permeability in a parallel artificial membrane permeability assay. Furthermore, compound 5 reduced the ischemic infarct area significantly in rats subjected to ischemia/reperfusion injury, downregulated ionised calcium-binding adaptor molecule 1 and glial fibrillary acidic protein in inflammatory cells, and upregulated nerve growth factor.
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Benzofuranos , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Antioxidantes/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/química , Daño por Reperfusión/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Benzofuranos/químicaRESUMEN
A series of halogenated 1,5-diarylimidazole compounds were synthesized and their inhibitory effects on LPS-induced PGE2 production in RAW 264.7 cells were evaluated. A wide variety of 2,4-, 4-, and 2-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles were synthesized for SAR study via two different pathways. Overall, 4-halogenated 5-aryl-1-(4-methylsulfonylphenyl)imidazoles, regardless of the species of halogen, exhibited very strong inhibitory activities of PGE2 production. Among them, 4-chloro-5-(4-methoxyphenyl)-1-(4-methylsulfonylphenyl)imidazole (3, IC50 3.3 nM ± 2.93), and 4-chloro-5-(4-chlorophenyl)-1-(4-methylsulfonylphenyl)imidazole (13, IC50 5.3 nM ± 0.23) showed the best results.
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Dinoprostona/biosíntesis , Imidazoles , Células RAW 264.7/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Halogenación , Imidazoles/síntesis química , Imidazoles/farmacología , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A class of 2-aryl-4-aminoquinazoline derivatives (7a-7j, 8a-8h, 9a-9h and 10a-10k) were designed, synthesized and evaluated as EGFR inhibitors. The anti-proliferative activity of compounds in vitro showed that compound 9e was considered to be a promising derivative. Compared with the lead compound Angew2017-7634-1, 9e exhibited excellent inhibitory activity against A549, NCI-H460 and H1975 cell lines, with IC50 values of 14.33 ± 1.16 µM, 17.81 ± 1.25 µM and 13.41 ± 1.14 µM, respectively. Moreover, 9e could effectively inhibit against Ba/F3-EGFRDel19/T790M/C797S cell lines. In the kinase experiment, the most promising compound 9e exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M, with an IC50 value of 0.74 µM. Further activity studies showed that 9e could not only induce remarkable cell-apoptosis of A549, but also block A549 cell lines in S-phase in a concentration-dependent manner. Furthermore, molecular docking study revealed the binding mode of 9e. All in all, we analyzed the structure-activity relationship of the target compounds, and explored their mechanism of action.
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Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-ActividadRESUMEN
Introduction: Type 2 diabetes is a rapid-growing complex chronic metabolic disease characterized by hyperglycemia due to lessened insulin secretion, insulin resistance and hepatic glucose overproduction. GPR119 is a class A of G protein-coupled receptor, expressed on certain enteroendocrine L and K cells in the small intestine and by ß-cells within the islets of Langerhans of the pancreas. Activation of GPR119 stimulates the secretion of glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose-dependent release of insulin in pancreatic ß-cells.Area covered: This review summarized the reported patents on GPR119 agonists from 2014 to present. The authors described the structural features of these novel synthetic molecules and compared their biological activities (including in vitro and in vivo) as potent GPR119 agonists for the treatment of diabetes.Expert opinion: GPR119 agonists remain the advantage of stimulating both insulin and incretin release in a glucose-dependent manner over other hypoglycemic agents, although some GPR119 agonist clinical candidates have been discontinued in Phase Ð or Phase II. GPR119 agonists will succeed to be developed as anti-diabetic drugs after accumulated scaffolds of agonists are discovered and the crystallographic structure of GPR119 is elucidated. The synergic effect of GPR119 agonist and DPP-4 inhibitor will also elicit a benefit for the new therapeutic of diabetes.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Diabetes Mellitus Tipo 2/fisiopatología , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Desarrollo de Medicamentos , Sinergismo Farmacológico , Glucosa/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Incretinas/metabolismo , Insulina/metabolismo , Patentes como Asunto , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Epidermal growth factor receptor (EGFR) is a receptor for epithelial growth factor (EGF) cell proliferation and signaling, which is related to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and apoptosis. Thus, it has become an important target for the treatment of non-small cell lung cancer (NSCLC). The first to the third-generation EGFR inhibitors have demonstrated powerful efficacy and brought a prospect to patients. Unfortunately, after 9-15 months of treatment, they all developed resistance without exception. As for the resistance of third-generation inhibitors, no major breakthrough has been made in this field. In this review, we discussed the recent advances in medicinal chemistry of fourth-generation EGFR-TKIs, as well as further discussed the clinical challenges and future prospects of treating patients with EGFR mutations resistant to third-generation EGFR-TKIs.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Química Farmacéutica , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Introduction: EGFR is the receptor for epidermal growth factor (EGF) and belongs to the protein tyrosine kinase (PTK) receptor. It is closely related to the inhibition of tumor cell proliferation, invasion, and apoptosis. Overexpression or mutation activation of EGFR is involved in the development of many human malignancies, especially non-small cell lung cancer (NSCLC). At present, numerous small molecule tyrosine kinase inhibitors (TKIs) have been developed to target the ATP-binding region of EGFR, aiming to develop selective and effective inhibitors for the treatment of NSCLC against EGFR mutants.Areas covered: This review covers the latest progress in the patented EGFR inhibitors and the inhibition activity against NSCLC from 2014 to present.Expert opinion: EGFR is an important anti-tumor target, and small molecule inhibitors targeting EGFR have become important biologically active compounds for the treatment of cancer, especially against NSCLC. Among the recent patents available, great majority of them focus on selective inhibitors of EGFR mutants. Although great achievements have been made in the development of selective EGFR inhibitors, there is still an urgent need to discover new EGFR inhibitors which are safe, efficient, selective, and low-toxic to avoid the adverse pharmacokinetics caused by wild-type EGFR feature.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Desarrollo de Medicamentos , Receptores ErbB/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Patentes como Asunto , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
A series of novel thiapyran-pyrimidine derivatives (10a-10h, 11a-11g, 12a-12f, 13a-13f, 14a-14f) were synthesized and their antiproliferative activities were tested. Most of the target compounds showed good activity on one or more cancer cell lines but low activity on human normal cell LO2. The most promising compound 13a exhibited the similar IC50 values on A549 and H1975 cell lines to the lead drug Olmutinib, and exhibited excellent activity and selectivity on EGFRT790M/L858R in the kinase experiment. AO and Hoechst33258 staining indicated that 13a could effectively induce H1975 cells apoptosis. Cell cycle and apoptosis analysis suggested that 13a could block cancer cells in G2/M phase and induce into late apoptosis in a manner of concentration-dependent. The structure-activity relationship of 13a was analyzed to explore its mechanism. All the results showed that 13a was a promising EGFR inhibitor.
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Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Piranos/farmacología , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piranos/química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 µM and 3.79 ± 0.57 µM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of apoptosis induced by the 13a was studied. The results showed that compound 13a induced late apoptosis of A431 cancer cells in a dose-dependent manner.
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Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Mutación/efectos de los fármacos , Pirimidinas/química , Pirimidinas/farmacología , Tiofenos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
Two series of novel triazolo-pyridazine/-pyrimidine derivatives were designed, synthesized, and evaluated for their inhibitory activity against c-Met kinase, as well as three c-Met overexpressed cancer cell lines (A549, MCF-7, and HeLa) and one normal human hepatocytes cell line LO2 in vitro. The pharmacological data indicated that most of the tested compounds showed moderate cytotoxicity, and the most promising compound 12e exhibited significant cytotoxicity against A549, MCF-7, and HeLa cell lines with IC50 values of 1.06 ± 0.16, 1.23 ± 0.18, and 2.73 ± 0.33 µM, respectively. Moreover, the inhibitory activity of compound 12e against c-Met kinase (IC50 = 0.090 µM) was equal to that of Foretinib (IC50 = 0.019 µM). The result of the acridine orange (AO) single staining test demonstrated that compound 12e could remarkably induce apoptosis of A549 cells. The results of apoptosis and cycle distribution of cells showed that compound 12e could induce late apoptosis of A549 cells and stimulate A549 cells arresting in the G0/G1 phase. Structure-activity relationships (SARs), pharmacological results, and docking studies indicated that the introduction of 5-methylthiazole fragment to the five-atom moiety was beneficial for the activity. So far, the existing data indicated that compound 12e may become a potential class II c-Met inhibitor.
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Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549â¯cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16â¯nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549â¯cells, Hela cells and H1975â¯cells proliferation at a low concentration, and the IC50 values were 0.057⯵M, 0.104⯵M and 0.916⯵M, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2]â¯=â¯0.765, r2â¯=â¯0.965) and CoMSIA (q [2]â¯=â¯0.875, r2â¯=â¯0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.
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Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Relación Estructura-Actividad Cuantitativa , Células A549 , Acrilamidas/síntesis química , Acrilamidas/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Células Tumorales CultivadasRESUMEN
Based on the approach of merged pharmacophores of GPR119 agonists and DPP-4 inhibitors, a series of tetrahydropyridopyrimidine compounds were designed as dual GPR119 and DPP-4 modulators with hypoglycemic activity. Seven fragments extracted from DPP-4 inhibitors were hybridized with the scaffold of tetrahydropyridopyrimidine. Among them, compound 51 displayed most potent GPR119 agonistic activity (EC50â¯=â¯8.7â¯nM) and good inhibition rate of 74.5% against DPP-4 at 10⯵M. Furthermore, the blood glucose AUC0-2h of 51 was reduced to 19.5% in the oral glucose tolerance test (oGTT) at the dose of 30â¯mg/kg in C57BL/6N mice, which was more potent than that of vildagliptin (16.4%) at the same dose. The docking study of compound 51 with DPP-4 indicated GPR119 agonists could inhibit DPP-4 to serve as dual GPR119 and DPP-4 modulators.
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Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hipoglucemiantes/farmacología , Pirimidinas/farmacología , Pirrolidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/efectos de los fármacos , Células CHO , Cricetulus , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).
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Hipoglucemiantes/farmacología , Oxazinas/farmacología , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Oxazinas/síntesis química , Oxazinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) have been regarded as promising targets for the treatment of cancer. Herein, we synthesized a new series of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as novel PI3Kα/mTOR dual inhibitors for cancer therapy. All compounds were evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and Hela). Most of the target compounds exhibited moderate to excellent anti-tumor activities against these three tested cancer cell lines especially against A549 and Hela cancer cell lines. Among them, the most promising compound 13g showed excellent anti-tumor potency for A549, MCF-7 and Hela cell lines with IC50 values of 0.20 ± 0.05 µM, 1.25 ± 0.11 µM and 1.03 ± 0.24 µM, respectively. Notably, according to the result of enzymatic activity assay, compound 13g was identified as a novel PI3Kα/mTOR dual inhibitor, which had an approximately 10-fold improvement in mTOR inhibition, compared to the class I PI3K inhibitor 1 (pictilisib, GDC-0941), with IC50 values of 525 nM to 48 nM. And western blot analysis indicated compound 13g could efficiently suppress the phosphorylation of AKT at the dose of 0.1 µM, which further demonstrated compound 13g had significant inhibitory effect on the PI3K/Akt/mTOR pathway. Furthermore, compound 13g could stimulate A549 cells arrest at G0/G1 phase in a dose-dependent manner, and induced apoptosis at a low concentration.
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Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Tiofenos/química , Triazinas/química , Triazinas/farmacología , Células A549 , Células HeLa , Humanos , Triazinas/síntesis químicaRESUMEN
A series of ester and amide derivatives of triterpenoid saponin Pulsatilla saponin D (PSD) were designed, synthesized, and evaluated for their antiproliferative activity. Compounds 1 and 6 displayed 1.7-8.3 times more potent cytotoxicity (IC50 = 1.2-4.7 and 1.7-4.5 µM, respectively) against five human tumor cell lines (SMMC-7721, MCF-7, NCI-H460, A549, and HCT-116) in vitro and lower acute toxicity to mice in vivo than did PSD. Furthermore, compound 6 was observed to show potent tumor growth inhibition against mice H22 hepatocellular cells (49.8% at 20 mg/kg) and induce cell cycle at G1 phase and apoptosis in HCT-116 cells.
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Three series of novel thienopyrimidine derivatives 9a-l, 15a-l, and 18a-h were designed and synthesized, and their IC50 values against four cancer cell lines HepG-2, A549, PC-3, and MCF-7 were evaluated. Most compounds show moderate cytotoxicity against the tested cancer cell lines. The most promising compound 9a showed moderate activity with IC50 values of 12.32 ± 0.96, 11.30 ± 1.19, 14.69 ± 1.32, and 9.80 ± 0.93 µM, respectively. The inhibitory activities of compounds 9a and 15a against PI3Kα and mTOR kinase were further evaluated. Compound 9a exhibited PI3Kα kinase inhibitory activity with IC50 of 9.47 ± 0.63 µM. In addition, docking studies of compounds 9a and 15a were also investigated.