ABSTRACT
We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Guanosine Monophosphate/analogs & derivatives , Hepacivirus/drug effects , Prodrugs/chemistry , Prodrugs/pharmacology , AMP Deaminase/metabolism , Amides/chemistry , Amides/metabolism , Antiviral Agents/chemistry , Cell Line, Tumor , Drug Design , Drug Evaluation, Preclinical , Guanosine Monophosphate/chemistry , Guanosine Monophosphate/pharmacology , Hepacivirus/physiology , Hepatitis C/drug therapy , Humans , Hydrolysis , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/chemistry , Nucleosides/pharmacology , Phosphoric Acids/chemistry , Phosphoric Acids/metabolism , Phosphorylation , Prodrugs/chemical synthesis , Prodrugs/metabolism , Stereoisomerism , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
BACKGROUND: The reticulocyte maturation process is an ideal model for the study of biochemical alterations seen during final stage of erythropoiesis under disease conditions. In this study, determined whether type 2 diabetes has any effect on membrane lipids and protein-bound carbohydrates during the maturation of reticulocytes to erythrocytes. SUBJECTS AND METHODS: Lipids (cholesterol and phospholipids) and protein-bound carbohydrates (hexose, hexosamine and sialic acid) were extracted and estimated in plasma, membrane of reticulocytes and erythrocytes from 20 treated but uncontrolled type 2 diabetic volunteers and age matched controls. RESULTS: Plasma, membranes of reticulocytes and erythrocytes of diabetics showed increase in cholesterol (35.7%, 8.7% and 16.4%); phospholipids (43.4%, 18.8% and 8.2%); hexose (34.1%, 19.3% and 8.2%) and decrease in hexosamine (11.9%, 7.3% and 14.7%); and sialic acid (34.1%, 19.3% and 32.0%) compared to controls. As reticulocytes matured to erythrocytes, cholesterol, phospholipids, hexosamine and sialic acid levels were decreased; C/P ratio and hexose levels were increased in both controls and diabetics. However, these alterations were more intensified in diabetics. CONCLUSION: These alterations in diabetic patients may indicate the existence of one or both of the following conditions: acceleration of maturation processes and/or decreased red blood cell life span.
