ABSTRACT
A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aß antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aß antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aß peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC50 = 61 µM and self induced Aß 25-35 aggregation 45.45%), to increase its activity toward AD related targets. The most interesting multifunctional Aß antiaggregants were compounds 3a, 3h and 3i, highlighting 3h as potent Aß antiaggregant and good antiacetylholinesterase inhibitor (self induced Aß 25-35 aggregation 57.71% and hAChE IC50 = 21 µM), with good neuroprotective and antioxidant activity. In addition, these three most promising compounds prevent intracellular reactive oxygen species (ROS) formation and cell apoptosis induced by Aß25-35 peptides in SH-SY5Y cells. Molecular docking studies were also accomplished to understand the binding interaction of these compounds on Aß monomer, Aß fibril and AChE. Based on all data, compounds 3a, 3h and 3i were concluded as potent multifunctional Aß antiaggregant, useful candidate for the treatment of AD.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Benzofurans/pharmacology , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Piperidines/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Piperidines/chemical synthesis , Piperidines/chemistry , Protein Aggregates/drug effects , Protein Aggregation, Pathological/drug therapy , Protein Aggregation, Pathological/metabolism , Structure-Activity RelationshipABSTRACT
Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC50 = 79 nM) and d1 (IC50 = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC50 = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC50 = 4 nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Animals , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Drug Design , Hep G2 Cells , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/metabolism , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity RelationshipABSTRACT
Incretin pathway plays an important role in the development of diabetes medications. Interventions in DPP-4 and GLP-1 receptor have shown remarkable efficacy in experimental and clinical studies and imperatively become one of the most promising therapeutic approaches in the T2DM drug discovery pipeline. Herein, we analyzed the actionmechanismsof DPP-4 and GLP-1 receptor targeting the incretin pathway in T2DM treatment. We gave an insight into the structural requirements for the potent DPP-4 inhibitors and revealed a classification of DPP-4 inhibitors by stressing on the binding modes of these ligands to the enzyme. We then reviewed the drug discovery strategies for the development of peptide and non-peptide GLP-1 receptor agonists (GLP-1 RAs). Furthermore, the drug design strategies for DPP-4 inhibitors and GLP-1R agonists were detailed accurately. This review might provide an efficient evidence for the highly potent and selective DPP-4 inhibitors and the GLP-1 RAs, as novel medicines for patients suffering from T2DM.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Discovery , Hypoglycemic Agents/pharmacology , Incretins/antagonists & inhibitors , Peptides/pharmacology , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Hypoglycemic Agents/chemistry , Incretins/metabolism , Models, Molecular , Peptides/chemistryABSTRACT
Developing protein tyrosine phosphatase-1B (PTP1B) inhibitors is an important strategy to treat type 2 diabetes mellitus (T2DM). Most existing ionic PTP1B inhibitors aren't of clinical useful due to their low cell-permeability, however. Herein, we introduced a series of lipid-like acid-based (salicylic acid) modules to prepare PTP1B inhibitors, and demonstrated a marked improvement of cell-permeability while maintaining excellent PTP1B inhibitory activity (e.g. compound B12D, IC50â¯=â¯0.37⯵M against PTP1B and Pappâ¯=â¯1.5â¯×â¯10-6â¯cm/s). We believe that this strategy can be widely utilized to modify potent lead compounds with low cell-permeability.
Subject(s)
Enzyme Inhibitors/chemistry , Lipids/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Salicylic Acid/chemistry , Binding Sites , Catalytic Domain , Cell Membrane Permeability/drug effects , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Salicylic Acid/metabolism , Salicylic Acid/pharmacology , Structure-Activity RelationshipABSTRACT
Progranulin (PGRN) is a growth factor with significant biological effects in different types of cancer. However, its role in melanoma progression has not been explored. In this study, we first analyze clinical datasets and show that high PGRN expression levels are correlated with poor prognosis of melanoma patients. Further, we demonstrate in a transplanted murine melanoma model in which the endogenous Grn gene encoding PGRN has been deleted that tumor-derived, not host-derived PGRN, promotes melanoma growth and metastasis. Immunological analyses reveal an enhanced infiltration of natural killer cells, but not T lymphocytes, into PGRN-deficient tumors compared to the wild type control. Antibody-mediated depletion confirms the critical role of NK cells in controlling B16 tumor growth. RNA-seq analysis reveals that several chemokines including CCL5 are strongly upregulated in PGRN-deficient tumor. Silencing CCL5 expression in PGRN-deficient tumor reduces NK cell recruitment and restores tumor growth to the control level. Lastly, we show that PGRN inhibits Ccl5 gene expression at the transcriptional level. This study highlights a novel and critical role of PGRN in melanoma growth and metastasis and suggests that it may represent a potential therapeutic target.
Subject(s)
Chemokine CCL5/genetics , Killer Cells, Natural/metabolism , Melanoma/pathology , Progranulins/genetics , Progranulins/metabolism , Up-Regulation , Animals , Cell Line, Tumor , Cell Proliferation , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Melanoma/genetics , Melanoma/metabolism , Mice , Neoplasm Metastasis , Neoplasm Transplantation , Prognosis , Transcription, Genetic , Tumor MicroenvironmentABSTRACT
Type 2 diabetes mellitus is a fast-growing epidemic affecting people globally. We initiated the project by searching the possible target of the Pueraria lobata root extract (P. lobata). We conducted the IC50 assays of P. lobata on the four diabetes-related proteins: PTP1B, TCPTP, SHP-2 and DPP-4. Results indicated that P. lobata exhibited high PTP1B inhibitory activity with IC50 of 0.043â¯mg/ml. Treated insulin-resistant HepG2 cells with 0.0115â¯mg/ml of P. lobata increased the glucose uptake by two times compared with the negative control. Further, we performed OGTT test on the diabetic C57BL/6 male mice. 20% decreased blood glucose (AUC) was obtained with a dose of 1â¯g/kg P. lobata compared with the negative control. Herein, we were able to demonstrate the antidiabetic effects of P. lobata might be related to the inhibition of PTP1B and therefore, bettering the insulin signaling pathway.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Insulin/metabolism , Plant Extracts/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Pueraria/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/isolation & purification , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Roots/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Signal Transduction/drug effects , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80â¯nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49â¯nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10â¯mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.