ABSTRACT
Mellamide, a novel indole amide, was isolated from a fermentation of Aspergillus melleus using silica gel and high-performance liquid chromatographic methods. This allowed its separation from three known antiparasitic compounds (ochratoxin A, viomellin and xanthomegnin) also present in the potent extract. The structure was elucidated by (1)H, (13)C, COSY, DEPT, HMQC and HMBC NMR experiments. HR-FTMS aided in the molecular weight and formula determination. Mellamide showed in vitro insecticidal activity in bioassays against larvae of Lucilia sericata and Aedes egypti with LD(90) of 1,000 and 50 micro g/ml, respectively.
Subject(s)
Amides/isolation & purification , Aspergillus/chemistry , Indoles/isolation & purification , Insecticides/isolation & purification , Amides/chemistry , Animals , Biological Assay , Culicidae/drug effects , Culicidae/growth & development , Diptera/drug effects , Diptera/growth & development , Indoles/chemistry , Industrial Microbiology , Insecticides/chemistry , Larva/drug effectsABSTRACT
[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.
Subject(s)
Antiprotozoal Agents/chemistry , Histone Deacetylases/metabolism , Peptides, Cyclic/chemistry , Amino Acid Substitution , Animals , Antiprotozoal Agents/pharmacology , Eimeria tenella/drug effects , Histone Deacetylase Inhibitors , Magnetic Resonance Spectroscopy , Molecular Conformation , Parasitic Sensitivity Tests , Peptides, Cyclic/pharmacology , Proline/chemistry , Sarcocystidae/drug effects , Valine/chemistryABSTRACT
[figure: see text] Blockers of the voltage-gated potassium channel Kv1.3 are potential immunosuppressants. Candelalides A-C are three novel diterpenoid pyrones that block this channel. The structure, stereochemistry, and activity against Kv1.3 are described.
Subject(s)
Diterpenes/chemical synthesis , Potassium Channel Blockers , Potassium Channels, Voltage-Gated , Potassium Channels , Pyrones/chemical synthesis , Animals , CHO Cells , Cricetinae , Diterpenes/chemistry , Diterpenes/pharmacology , Fermentation , Hypocreales/growth & development , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Kv1.1 Potassium Channel , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Pyrones/chemistry , Pyrones/pharmacology , Recombinant Proteins/antagonists & inhibitorsABSTRACT
Investigation of the fungus Aspergillus tubingensis has led to the isolation and identification of two dihydrocarbazole-containing compounds (1 and 2). Details of the purification and structure elucidation of 1 and 2 are described. This is the first known report of dihydrocarbazole-containing compounds to be isolated from a living system.
Subject(s)
Alkaloids/chemistry , Aspergillus/chemistry , Carbazoles/chemistry , Alkaloids/isolation & purification , Carbazoles/isolation & purification , Fermentation , Magnetic Resonance Spectroscopy , Mass Spectrometry , Oxidation-Reduction , Spectrophotometry, UltravioletABSTRACT
A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.
Subject(s)
Enzyme Inhibitors/pharmacology , Lactones/pharmacology , MAP Kinase Kinase Kinase 1 , Protein Serine-Threonine Kinases/antagonists & inhibitors , Resorcinols/pharmacology , Adenosine Triphosphate/pharmacology , Humans , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitorsABSTRACT
A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.
Subject(s)
Antiprotozoal Agents/pharmacology , Enzyme Inhibitors/pharmacology , Eukaryota/drug effects , Histone Deacetylase Inhibitors , Malaria/drug therapy , Peptides, Cyclic/pharmacology , Plasmodium berghei , Animals , Eimeria tenella/drug effects , Female , Humans , Kinetics , Mice , Mice, Inbred BALB C , Neospora/drug effects , Peptides, Cyclic/therapeutic use , Plasmodium falciparum/drug effects , Protein Binding , Protozoan Infections/drug therapy , Structure-Activity Relationship , Toxoplasma/drug effectsABSTRACT
A novel cytochalasin, L-696,474, (18-dehydroxy cytochalasin H) that inhibits HIV-1 protease was discovered in fermentations of a bark-inhabiting Ascomycete, Hypoxylon fragiforme. The product was first identified from extracts of an agar medium. Fermentation studies on a number of media indicated that the product can be made on several solid and liquid media. Optimum production was obtained from growth in a complex medium composed of glycerol, glucose, citrate, Ardamine, soybean meal, tomato paste, and inorganic salts. Other Hypoxylon spp., related species of Xylariales, and other fungi known to produce cytochalasins, were also surveyed for their ability to make L-696,474. Only one other Hypoxylon fragiforme isolate was found to make this novel cytochalasin; none of the other cultures surveyed made L-696,474 or any other compounds which inhibit HIV-1 protease.
