ABSTRACT
A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.
Subject(s)
Antineoplastic Agents/chemical synthesis , Models, Molecular , NAD(P)H Dehydrogenase (Quinone)/chemistry , Streptonigrin/analogs & derivatives , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cytochromes c/chemistry , Drug Screening Assays, Antitumor , Humans , Protein Binding , Streptonigrin/chemical synthesis , Streptonigrin/chemistry , Streptonigrin/pharmacology , Structure-Activity RelationshipABSTRACT
A series of 6-bicycloaryloxynicotinamides were identified as opioid receptor antagonists at mu, kappa, and delta receptors. Compounds in the 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide scaffold exhibited potent in vitro functional antagonism at all three receptors.
Subject(s)
Amides/chemistry , Carboxylic Acids/chemistry , Ethers/chemistry , Ethers/pharmacology , Narcotic Antagonists , Acrylic Resins/chemistry , Ethers/chemical synthesis , Molecular Structure , Receptors, Opioid/metabolism , Structure-Activity RelationshipABSTRACT
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.
Subject(s)
Enzyme Inhibitors/pharmacology , Imidazoles/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Serine C-Palmitoyltransferase/antagonists & inhibitors , Administration, Oral , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , MCF-7 Cells , Male , Mice , Mice, Obese , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Serine C-Palmitoyltransferase/metabolism , Structure-Activity RelationshipABSTRACT
A structurally unique and new class of opioid receptor antagonists (OpRAs) that bear no structural resemblance with morphine or endogenous opioid peptides has been discovered. A series of carboxamido-biaryl ethers were identified as potent receptor antagonists against mu, kappa and delta opioid receptors. The structure-activity relationship indicated para-substituted aryloxyaryl primary carboxamide bearing an amine tether on the distal phenyl ring was optimal for potent in vitro functional antagonism against three opioid receptor subtypes.