ABSTRACT
Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.
Subject(s)
Humans , Dipeptidyl-Peptidase IV Inhibitors , Chemistry , Drug Design , Drug Discovery , Methods , Hypoglycemic Agents , Chemistry , Linagliptin , Chemistry , Molecular Structure , Piperidines , Chemistry , Structure-Activity Relationship , Uracil , ChemistryABSTRACT
Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) belongs to peptidyl-prolyl cis-trans isomerase (PPIase) and is a novel promising anticancer target. Based on the lead structure of benzophenone, a series of novel diarylether derivatives containing a pyrimidine ring were designed and synthesized. The inhibitory activities on Pin1 of compounds 5a-5d and 6a-6i were evaluated by a protease-coupled enzyme assay. Of all the evaluated compounds, 6 compounds displayed inhibitory activities. Molecular docking was performed using FlexX algorithm to explore the binding mode of the active molecules.
Subject(s)
Humans , Drug Design , Enzyme Inhibitors , Chemistry , Pharmacology , Ethers , Chemistry , Pharmacology , Inhibitory Concentration 50 , Molecular Docking Simulation , Molecular Structure , NIMA-Interacting Peptidylprolyl Isomerase , Peptidylprolyl Isomerase , Metabolism , Pyrimidines , Chemistry , Structure-Activity RelationshipABSTRACT
Glucokinase (GK) is a new target for the treatment of type II diabetes mellitus (T2DM). In order to find a structure-simplified small molecule GK activator, 19 salicylic acid derivatives were designed and synthesized based on new lead compound (1). Experimental results showed that the potency of compound 8h is superior to control RO-28-0450 in GK activation.
Subject(s)
Drug Design , Enzyme Activation , Enzyme Activators , Chemistry , Pharmacology , Glucokinase , Metabolism , Hypoglycemic Agents , Chemistry , Pharmacology , Molecular Structure , Salicylates , Chemistry , Pharmacology , Thiazoles , PharmacologyABSTRACT
A novel series of sorafenib analogs containing 2-picolinyl hydrazide moiety were designed and synthesized. In vitro, most of synthesized compounds have antiproliferation activity on MDA-MB-231, ACHN, HepG2, Mia-PaCa-2 and SW1990 cell lines tested by MTT assay. It is worth noting that the antitumor activities of compounds 2c, 2d and 2f are more potent than that of sorafenib on pancreatic cancer cells Mia-PaCa-2 and SW1990, and the activities of compounds 3f and 3g are 2-3 times than that of sorafenib on human hepatocellular carcinoma HepG2 cell line.
Subject(s)
Humans , Antineoplastic Agents , Chemistry , Pharmacology , Cell Line, Tumor , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Molecular Structure , Niacinamide , Chemistry , Pharmacology , Phenylurea Compounds , Chemistry , Pharmacology , Structure-Activity RelationshipABSTRACT
Fructose-1, 6-bisphosphatase (FBPase), a rate-limiting enzyme involved in the pathway of gluconeogenesis, can catalyze the hydrolysis of fructose-1, 6-bisphosphate to fructose-6-phosphate. Upon inhibiting the activity of FBPase, the production of endogenous glucose can be decreased and the level of blood glucose lowered. Therefore, inhibitors of FBPase are expected to be novel potential therapeutics for the treatment of type II diabetes. Recent research efforts were reviewed in the field of developing allosteric inhibitors interacting with the AMP binding site of FBPase.
Subject(s)
Animals , Humans , Adenosine Monophosphate , Chemistry , Allosteric Site , Binding Sites , Blood Glucose , Metabolism , Diabetes Mellitus, Type 2 , Blood , Enzyme Inhibitors , Chemistry , Pharmacology , Fructose-Bisphosphatase , Chemistry , Metabolism , Fructosediphosphates , Metabolism , Fructosephosphates , MetabolismABSTRACT
The aim was to study the expression of VEGF-A, VEGF-C, angiopoietin-1, angiopoietin-2 and their receptors on development liver during gestation of weeks 3-12 of human embryo. Human embryo contingently aborted at 3-12 weeks of gestation were collected with signed agreements of the pregnant women suffered from accidental abortions. The specimens were fixed by 4% paraformaldehyde and embedded by paraffin. 5 microm serial sections were made. HE staining, immunohistochemistry method and light-microscope were employed. The results showed that at 4-5 weeks of development, liver was constituted by a few hepatic cords. Hematopoietic cell or blood cells were undetectable in the 4 week of gestation. A few cells which were larger, rounded and nucleared cells appeared and expressed VEGFA, flt-4 and Tie-2 proteins strongly in liver at 5 weeks of gestation. The number of these immuno-positive cells was highest in the 7th week and decreased at 11-12 weeks of gestation. These cells expressed flk-1 transiently in the 6th week. VEGF-C and flt-1 were expressed by hepatic cells from weeks 7 to 12 of gestation. The immuno-positive products were deposited in plasma of hepatic cells. Angiopoietin-1, angiopoietin-2 and Tie-2 were detectable on those cells which expressed VEGFA, flt-4 and Tie-2 from weeks 5 to 12 of gestation. The expression of angiopoietin-1 and angiopoietin-2 were weakly and Tie-2 was strongly. They were expressed weakly too by hepatic cells at 5 to 12 weeks of gestation. All factors and their receptors were undetectable on vascular endothelial cells at 4-12 weeks of gestation. It is concluded that the expression patterns of VEGF family on cells of liver are different before and after 7 weeks of gestation. The hematopoiesis in fetal liver may be related to development of hepatic cell.
Subject(s)
Female , Humans , Pregnancy , Angiopoietin-1 , Angiopoietin-2 , Extracellular Matrix Proteins , Gestational Age , Immunohistochemistry , Liver , Chemistry , Embryology , Receptor, TIE-2 , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor C , Vascular Endothelial Growth Factor Receptor-1 , Vascular Endothelial Growth Factor Receptor-3ABSTRACT
The study was to investigate the expression of VEGFA, VEGFC, angiopoietin-1, angiopoietin-2 and their receptors on yolk sac blood island, AGM region during gestation of 3th-12th weeks of human embryo. Human embryo contingently aborted at 3 - 12 weeks of gestation were collected with signed agreements of the pregnant women suffered from accidental abortions. The specimens were fixed by 4% paraformaldehyde and embedded by paraffin. 5 micro m serial sections were made. HE and immunohistochemistry method (SABC) and light-microscope were employed. The results showed that VEGFA and its receptors flt1/flk-1, VEGFC and its receptor flt-4, angiopoietin-2 and its receptor tie-2 proteins were expressed strongly and angiopoietin-1 was weakly expressed by hematopoietic cells and vascular endothelial cells of blood island at 21 and 25 days of gestation. In the 4th week of gestation, immuno-positive reaction of these factors and their receptors appeared in the aorta and mesonephros deposited in larger, rounded and nucleated cells which represented hematopoietic cells. Up to 7th week, positive hematopoietic cells in the regions were much abundant. The number of positive cells decreased at 8th week. Up to 12th week, almost all blood cells were immuno-negative. VEGFA, flt-1, flt-4, angiopoietin-1, angiopoietin-2 and Tie-2 protein were expressed mainly by gonad at 6 - 8 weeks, but it did not express VEGFC and flk-1. The immuno-reaction of the factors and their receptors could not detected in vascular endothelial cells during 3-12th weeks of gestation. It is concluded that hematopoietic cells and endothelial cells in blood island of yolk sac, mesonephros and dorsal aorta co-expressed some factors and their receptors in relation to vasculogenesis and hematopoiesis. Intraembryonic hematopoiesis began in the 4th week of gestation.