ABSTRACT
A novel compound, nafuredin, was isolated as an inhibitor of anaerobic electron transport (NADH-fumarate reductase). It was obtained from culture broth of Aspergillus niger FT-0554 isolated from a marine sponge. The structure was elucidated as an epoxy-delta-lactone with an attached methylated olefinic side chain on the basis of spectral analysis.
Subject(s)
Aspergillus niger/metabolism , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/antagonists & inhibitors , Pyrones/metabolism , Pyrones/pharmacology , Aspergillus niger/classification , Aspergillus niger/ultrastructure , Chemical Phenomena , Chemistry, Physical , Enzyme Inhibitors/chemistry , Fermentation , Magnetic Resonance Spectroscopy , Microscopy, Electron, Scanning , Molecular Structure , Pyrones/chemistryABSTRACT
Infections with parasitic helminths are important causes of morbidity and mortality worldwide. New drugs that are parasite specific and minimally toxic to the host are needed to counter these infections effectively. Here we report the finding of a previously unidentified compound, nafuredin, from Aspergillus niger. Nafuredin inhibits NADH-fumarate reductase (complexes I + II) activity, a unique anaerobic electron transport system in helminth mitochondria, at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep. Thus, our study indicates that mitochondrial complex I is a promising target for chemotherapy, and nafuredin is a potential lead compound as an anthelmintic isolated from microorganisms.
Subject(s)
Anthelmintics/pharmacology , Aspergillus niger/chemistry , Haemonchus/drug effects , Haemonchus/enzymology , Mitochondria/enzymology , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/antagonists & inhibitors , Pyrones/pharmacology , Administration, Oral , Animals , Anthelmintics/administration & dosage , Anthelmintics/chemistry , Anthelmintics/therapeutic use , Ascaris suum/drug effects , Ascaris suum/enzymology , Electron Transport/drug effects , Feces/parasitology , Haemonchiasis/drug therapy , Inhibitory Concentration 50 , Kinetics , Mitochondria/drug effects , Molecular Structure , Oxidoreductases/metabolism , Pyrones/administration & dosage , Pyrones/chemistry , Pyrones/therapeutic use , Sheep/parasitology , Time Factors , Ubiquinone/analogs & derivatives , Ubiquinone/metabolismABSTRACT
Motilide, an erythromycin derivative, has been shown to equal activity to that of motilin as an agonist at the motilin receptor. However, there is little information on the three-dimensional (3D) structure-activity relationship between these two molecules, largely because they have quite different structures. In this study, we applied a rational computational procedure consisting of conformational analysis and a novel superposing method to investigate the 3D structure-activity relationship between motilide and motilin. We propose common 3D structural features between these molecules, which may be important for their similar activity.
Subject(s)
Erythromycin/analogs & derivatives , Motilin/analogs & derivatives , Motilin/chemistry , Erythromycin/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
Natural product acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor pyripyropene A was synthetically converted to acetylcholinesterase (AChE) inhibitor via heterolitic cleavage of the 2-pyrone ring, followed by gamma-acylation/cyclization with several aroyl chlorides. The 4-pyridyl analogue selectively showed AChE inhibitory activity (IC50 7.9 microM) and no ACAT inhibitory activity IC50 = >1000 microM.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Enzyme Inhibitors/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , HumansSubject(s)
Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Sesquiterpenes/chemistry , Antineoplastic Agents/pharmacology , Drug Resistance, Multiple , Enzyme Inhibitors/pharmacology , Sesquiterpenes/pharmacology , Sterol O-Acyltransferase/antagonists & inhibitors , Structure-Activity Relationship , Tumor Cells, Cultured/drug effectsSubject(s)
Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Staurosporine/analogs & derivatives , Angiogenesis Inhibitors/pharmacology , Animals , Cattle , Enzyme Inhibitors/pharmacology , Molecular Structure , Muscle, Smooth, Vascular/drug effects , Structure-Activity RelationshipABSTRACT
The mutant of Penicillium sp. FO-4259, an arisugacins A and B producing strain, was found to produce a series of metabolites, designated arisugacins C, D, E, F, G and H, which were structurally related to arisugacins A and B. These compounds were isolated from the culture broth and the physico-chemical and biological properties were examined. The IC50 values of arisugacins C and D against acetylcholinesterase (AChE) were 2.5 microM and 3.5 microM, respectively. However arisugacins E, F, G and H did not inhibit AChE at 100 microM. Though they showed only weak or no activity against AChE compared with arisugacins A and B, they may be useful for the study of the structure-activity relationship.
Subject(s)
Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/isolation & purification , Pyrans/pharmacology , Cholinesterase Inhibitors/metabolism , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Penicillium , Pyrans/chemistry , Pyrans/isolation & purification , Structure-Activity RelationshipABSTRACT
Erythromycin (EM), and related 14-member macrolide antibiotics, has attracted attention for its effectiveness in airway diseases including diffuse panbronchiolitis and sinobronchial syndrome. However, its molecular mechanisms remain unknown. We evaluated the effects of EM on activation of several transcription factors, including nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in human bronchial epithelial cell line BET-1A, which are known to regulate the expression of many proinflammatory cytokines and chemokines such as interleukin-8 (IL-8). BET-1A cells were cultured with hormonally defined Ham's F12 medium, and were stimulated by phorbol myristate acetate (PMA). EM suppressed mRNA expression as well as the release of IL-8 at therapeutic and noncytotoxic concentrations (% inhibition of IL-8 protein release: 42.2 +/- 5.5%, at 10(-6) M). Furthermore, electrophoretic mobility shift assays revealed that EM inhibited the activations of NF-kappaB and AP-1 induced by PMA in BET-1A cells. These data indicate that EM has inhibitory effects not only on the mRNA expression and release of IL-8, but also on the activation of transcription factors NF-kappaB and AP-1. Our findings support the concept that the recruitment of neutrophils in airway diseases may be regulated by NF-kappaB and AP-1.
Subject(s)
Erythromycin/pharmacology , Gene Expression Regulation/drug effects , Interleukin-8/genetics , NF-kappa B/metabolism , Respiratory Mucosa/physiology , Transcription Factor AP-1/metabolism , Bronchi , Cell Line , Humans , NF-kappa B/antagonists & inhibitors , RNA, Messenger/genetics , Respiratory Mucosa/drug effects , Tetradecanoylphorbol Acetate/pharmacology , Transcription Factor AP-1/antagonists & inhibitors , Transcription, Genetic/drug effectsABSTRACT
7-O-Benzoylpyripyropene A (7-O-BzP), a semi-synthetic analog of pyripyropene, was investigated for its reversing effect on multidrug-resistant (MDR) tumor cells. 7-O-BzP (6.25 microg/ml) completely reversed resistance against vincristine and adriamycin in vincristine-resistant KB cells (VJ-300) and adriamycin-resistant P388 cells (P388/ADR), respectively. 7-O-BzP alone had no effect on the growth of drug sensitive and drug-resistant cells. 7-O-BzP (6.25 microg/ml) significantly enhanced accumulation of [3H]vincristine in VJ-300 cells and completely inhibited the binding of [3H]azidopine to the P-glycoprotein in VJ-300 cells and P388/ADR cells. The result suggests that 7-O-BzP effectively reverses P-glycoprotein-related MDR by interacting directly with P-glycoprotein in drug resistant VJ-300 and P388/ADR cells.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Pyridones/pharmacology , Sesquiterpenes/pharmacology , Vincristine/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Azides/metabolism , Carcinoma, Squamous Cell , Dihydropyridines/metabolism , Humans , KB Cells , Tumor Cells, Cultured , Vincristine/metabolismABSTRACT
A synthetic beta-lactone trans-DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methylcarbonyl)-naphthalen++ +-1-yl]pentanoic acid 1,3-lactone, a mixture of (2R, 3R)- and (2S, 3S)-beta-lactones) was found to inhibit HMG-CoA synthase (IC(50): 0. 15 microM) and pancreatic lipase (IC(50): 120 microM). The effects of the optically pure DU-6622 isomers on the two enzymes were compared. The (2R, 3R)-isomer was shown to be a highly specific inhibitor of HMG-CoA synthase (IC(50): 0.098 microM vs 270 microM for pancreatic lipase), while the (2S, 3S)-isomer markedly increased the specificity of lipase inhibition (IC(50): 27 microM vs 31 microM for HMG-CoA synthase). Furthermore, the (2R, 3R)-isomer strongly inhibited the binding of [(14)C]hymeglusin to HMG-CoA synthase, indicating that the isomer was bound to the same site of the synthase as hymeglusin. The (2R, 3R)-beta-lactone is responsible for the specific inhibition of HMG-CoA synthase, while the (2S, 3S)-beta-lactone is responsible for the inhibition of pancreatic lipase.
Subject(s)
Enzyme Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Synthase/antagonists & inhibitors , Lactones/pharmacology , Lipase/antagonists & inhibitors , Naphthalenes/pharmacology , Animals , Binding Sites , Enzyme Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Synthase/metabolism , In Vitro Techniques , Lactones/chemistry , Naphthalenes/chemistry , Pancreas/enzymology , Rats , Stereoisomerism , Structure-Activity Relationship , SwineSubject(s)
Anti-Bacterial Agents/pharmacology , Bronchi/drug effects , Epithelial Cells/drug effects , Erythromycin/analogs & derivatives , Erythromycin/pharmacology , Interleukin-8/biosynthesis , Bronchi/cytology , Bronchi/metabolism , Cell Line , Clarithromycin/pharmacology , Colony Count, Microbial , Epithelial Cells/metabolism , Gastrointestinal Motility/drug effects , Humans , Stimulation, Chemical , Structure-Activity RelationshipSubject(s)
Alkyl and Aryl Transferases , Enzyme Inhibitors/chemical synthesis , Indoles/chemical synthesis , Phenols/chemical synthesis , Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Phenols/chemistry , Phenols/pharmacologyABSTRACT
Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA : cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition.
ABSTRACT
Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition.