ABSTRACT
This work reports a method for the catalytic synthesis of C(3) SCF3-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF3 reagent. This method can drive the conversion of tryptamine to the C(3) SCF3-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF3 source by PIII/PV redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF3-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.
ABSTRACT
A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PVâO redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.
ABSTRACT
An efficient and environmentally friendly synthetic approach to prepare thiazolidine-2-imine and oxazolidine-2-one derivatives has been developed. Thiazolidine-2-imines are synthesized in good to excellent yields by [3 + 2] annulation of p-quinamines with isothiocyanates under catalyst- and solvent-free conditions. Oxazolidine-2-ones are produced in good to excellent yields via [3 + 2] annulation of p-quinamines with CO2 using triethylenediamine (DABCO) as an organocatalyst. Furthermore, this strategy can be performed on a gram scale and tolerate a wide range of functional groups.
ABSTRACT
A green method to construct C-S bonds using sulfonyl chlorides and alcohols/acids via a PIII/PVâO catalytic system is reported. The organophosphorus-catalyzed umpolung reaction promotes us to propose the "dual-substrate deoxygenation" strategy. Herein, we adopt the "dual-substrate deoxygenation" strategy, which achieves the deoxygenation of sulfonyl chlorides and alcohols/acids to synthesize thioethers/thioesters driven by PIII/PVâO redox cycling. The catalytic method represents an operationally simple approach using stable phosphine oxide as a precatalyst and shows broad functional group tolerance. The potential application of this protocol is demonstrated by the late-stage diversification of drug analogues.
Subject(s)
Organophosphorus Compounds , Catalysis , Oxygen/chemistry , Alcohols/chemistry , Acids/chemistry , Organophosphorus Compounds/chemistryABSTRACT
A series of indole-fused scaffolds and derivatives was synthesized via the cyclization reaction of 2-indolylmethanols with azonaphthalene. These reactions were realized under mild reaction conditions through catalyst control, providing structurally diverse indole derivatives with moderate to excellent yields. This protocol also shows good substrate adaptability, especially in six-membered ring products.
Subject(s)
Indoles , Catalysis , CyclizationABSTRACT
ATP citrate lyase (ACLY) is an important metabolic enzyme involved in the synthesis of fatty acid and cholesterol. The inhibition of ACLY is considered as a promising therapeutic strategy for various metabolic diseases and numerous malignancies. In this study, a novel macrocyclic compound 2 has been identified as a potent ACLY inhibitor with the "ring closing" strategy for conformational restriction based on NDI-091143. It showed potent ACLY inhibitory activity and binding affinity comparable to the positive control. Furthermore, compared with the positive control (T1/2 = 3.36 min), the metabolic stability of 2 in HLMs (T1/2 = 531.22 min) was significantly improved. All of these results characterized 2 as a promising lead compound worthy of further study.
Subject(s)
ATP Citrate (pro-S)-Lyase , Neoplasms , ATP Citrate (pro-S)-Lyase/chemistry , ATP Citrate (pro-S)-Lyase/metabolism , Enzyme Inhibitors/pharmacology , Humans , Neoplasms/metabolismABSTRACT
Extensive research effort has been put in pentacyclic triterpenoids due to their numerous biological activities. However, their poor water solubility and low oral bioavailability limit their antitumor effects in vivo. To address these issues, 37 triterpenoid acid derivatives linked to l-phenylalanine or l-proline were designed and synthesized in this study. Structure-activity relationship (SAR) studies found two promising glycyrrhetinic acid (GA) derivatives 11 and 16. Compound 11 was obtained by C3-OH esterification and C30-COOH modification with l-phenylalanine while 16 was obtained by attaching C3-OH with l-phenylalanine. Compounds 11 and 16 exhibit up to 48- and 120-fold improvement respectively compared with the IC50 values of naturally occurring GA in the cellular assay. Fluorescence microscope and flow cytometric analysis suggested that both compounds 11 and 16 increased the content of ROS and Ca2+ in cancer cells, decreased mitochondrial membrane potential (JC-1), and activated the regulator caspase-3/8/9 to trigger cell apoptosis. RNA-seq analysis and western blot analysis indicated that compounds 11 and 16 may promote apoptosis by upregulating the functions of pro-apoptotic factors while inhibiting the proteasome activity.
Subject(s)
Antineoplastic Agents , Glycyrrhetinic Acid , Triterpenes , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Phenylalanine/pharmacology , Proline , Structure-Activity Relationship , Triterpenes/pharmacologyABSTRACT
A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.
Subject(s)
Copper , Indoles , Acetates , Catalysis , Cyclization , Dimerization , Molecular Structure , OximesABSTRACT
Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 µM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 µM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.
Subject(s)
Molecular Dynamics Simulation , Proprotein Convertase 9 , Hep G2 Cells , Humans , Proprotein Convertase 9/metabolismABSTRACT
Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3ß-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC50 value of 2.4⯵M in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic triterpenoid 3ß-ester derivatives and CETP protein for the further modification and optimization.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Esters/therapeutic use , Molecular Docking Simulation/methods , Cholesterol Ester Transfer Proteins/chemical synthesis , Esters/pharmacology , Humans , Structure-Activity Relationship , Triterpenes/chemical synthesis , Triterpenes/pharmacology , Triterpenes/therapeutic use , Ursolic AcidABSTRACT
Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.
Subject(s)
Non-alcoholic Fatty Liver Disease , PPAR alpha , Animals , Humans , Inflammation/metabolism , Lipid Metabolism , Liver/metabolism , Mice , Non-alcoholic Fatty Liver Disease/metabolism , PPAR alpha/genetics , PPAR alpha/metabolismABSTRACT
USP7 has been regarded as a potential therapeutic target for cancer. In this study, virtual screening, molecular dynamics (MD) simulation, and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. Among the obtained compounds, compound 12 with a novel scaffold structure exhibited certain USP7 inhibitory activity (Ub-AMC assay IC50 = 18.40 ± 1.75 µM, Ub-Rho assay IC50 = 7.75 µM). The binding affinity between USP7CD (USP7 catalytic domain) and this hit compound was confirmed with a KD value of 4.46 ± 0.86 µM. Preliminary in vitro studies disclosed its antiproliferative activity on human prostate cancer cell line LNCaP with an IC50 value of 15.43 ± 3.49 µM. MD simulation revealed the detailed differences of protein-ligand interactions between USP7CD and the ligands, including the reference compound ALM4 and compound 12, providing some important information for improving the bioactivity of 12. This hit compound will serve as a promising starting point for facilitating the further discovery of novel USP7 inhibitors.
Subject(s)
Molecular Dynamics Simulation , Neoplasms , Catalytic Domain , Humans , Molecular Docking Simulation , Ubiquitin-Specific Peptidase 7/metabolismABSTRACT
FFAR4 has been considered as a potential target for metabolic diseases, including diabetes. Some compounds with biphenyl scaffold, represented by compound SR13 reported by our group, showed significant FFAR4 selectivity. However, the molecular basis for their selectivity has not been definitely disclosed. This study provided insights into the protein-ligand interactions between agonists and FFAR4/FFAR1 by molecular modeling. The important residues identified were consistent with those found in experimental studies. Moreover, the results proposed that the selectivity of SR13 between FFAR4 and FFAR1 depended on whether it can enter the ligand-binding site through the entrance region by adopting its preferential conformation. The big difference between the preferential conformation of SR13 and the narrow entrance region determined its poor agonist activity against FFAR1. These findings will facilitate the further development of selective FFAR4 agonists.
Subject(s)
Receptors, G-Protein-Coupled/agonists , Models, Molecular , Molecular Dynamics Simulation , Protein Conformation , Receptors, G-Protein-Coupled/chemistry , ThermodynamicsABSTRACT
Oleanolic acid (OA) is an active component of the traditional Chinese herb Olea europaea L. and has been found to exhibit a significant lipid-lowering effect; however, its direct molecular target is still unknown, which limits its clinical application and the possible structure modification to improve its beneficial functions. In this regard, we carried out the present study to identify potential hepatic targets of OA to mediate its lipid-lowering effect. We found that both acute and chronic OA treatments reduced serum levels of triglycerides, total cholesterol, and LDL cholesterol, and decreased hepatic expression levels of peroxisome proliferator-activated receptor-γ coactivator-1ß (PGC-1ß), which is an important regulator in maintaining hepatic lipid homeostasis, and its downstream target genes. Of note, liver-specific knockdown of PGC-1ß recapitulated the hypolipidemic effects of OA. At the molecular level, OA accelerated mRNA degradation of PGC-1ß. Microarray analysis revealed a host of microRNAs that potentially mediate OA-induced PGC-1ß mRNA degradation, among which, miR-98-5p significantly inhibited activity of Pgc-1ß 3' UTR as well as PGC-1ß expression and promoted its mRNA degradation. Conversely, miR-98-5p inhibitors blunted the inhibitory effects of OA on PGC-1ß expression. Collectively, our data demonstrated that OA ameliorated hyperlipidemia, likely via regulation of the miR-98-5p/PGC-1ß axis.-Chen, S., Wen, X., Zhang, W., Wang, C., Liu, J., Liu, C. Hypolipidemic effect of oleanolic acid is mediated by the miR-98-5p/PGC-1ß axis in high-fat diet-induced hyperlipidemic mice.
Subject(s)
Hyperlipidemias/metabolism , Hypolipidemic Agents/therapeutic use , MicroRNAs/genetics , Nuclear Proteins/metabolism , Oleanolic Acid/therapeutic use , Transcription Factors/metabolism , 3' Untranslated Regions , Animals , Cells, Cultured , Cholesterol/blood , Diet, High-Fat/adverse effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Hyperlipidemias/drug therapy , Hyperlipidemias/etiology , Hypolipidemic Agents/pharmacology , Male , Mice , Mice, Inbred C57BL , MicroRNAs/metabolism , Nuclear Proteins/genetics , Oleanolic Acid/pharmacology , RNA Stability , Transcription Factors/genetics , Triglycerides/bloodABSTRACT
In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC50â¯=â¯5.2⯱â¯0.9⯵M). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC50â¯=â¯2.8⯱â¯0.4⯵M). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I.
Subject(s)
Antineoplastic Agents/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Piperidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Electron Transport Complex I/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hep G2 Cells , Humans , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Structure-Activity RelationshipABSTRACT
GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50â¯=â¯93â¯nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure-activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications.
Subject(s)
Biphenyl Compounds/pharmacology , Drug Discovery , Hypoglycemic Agents/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Biphenyl Compounds/administration & dosage , Biphenyl Compounds/chemistry , Biphenyl Compounds/therapeutic use , Blood Glucose/analysis , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Dose-Response Relationship, Drug , Glucose Tolerance Test , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Male , Mice, Inbred ICR , Structure-Activity RelationshipABSTRACT
We disclosed a novel water-soluble photocatalyst that could promote aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent yields. This transformation uses visible-light irradiation under environmentally friendly conditions, that is, water-soluble catalyst, metal-free, green oxidant, room temperature.
ABSTRACT
Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors.
Subject(s)
Thiazoles/chemistry , Thiazoles/pharmacology , Ubiquitin Thiolesterase/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Binding Sites , Crystallography, X-Ray , Enzyme Activation/drug effects , HCT116 Cells , Humans , Inhibitory Concentration 50 , Molecular Conformation , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Thiazoles/chemical synthesis , Tumor Suppressor Protein p53/metabolism , Ubiquitin Thiolesterase/metabolism , Ubiquitin-Specific Peptidase 7ABSTRACT
A formal [4 + 2] cycloaddition reaction of 1,3-disubstituted indoles and alkylquinones was realized to furnish polycyclic indolines in good yields. This protocol proceeded smoothly under basic conditions, with high atom-economy and broad substrate scope.
ABSTRACT
A practical synthesis of α-amyrin (1), ß-amyrin (2), and lupeol (3) was accomplished in total yields of 32, 42, and 40% starting from easily available ursolic acid (4), oleanolic acid (5), and betulin (6), respectively. Remarkably, these three natural pentacyclic triterpenes exhibited potential inhibitory activity against human oxidosqualene cyclase.