Biomedical subjects
Publications and source records attributed to Olov Sterner.
Extracts of submerged cultures of a Stereum species afforded four new pentasubstituted phenolic compounds, named hericenols A, B, C, and D (1-4), 6-hydroxymethyl-2,2-dimethylchroman-4-one (5) and the known erinapyrone C. Hericenol A (1) showed weak antimicrobial activity while hericenol C (3) was weakly cytotoxic. The structures of the metabolites were determined by spectroscopic techniques.
TWO CHROMONES: 5-hydroxy-2-(14'-(E)-nonadecenyl) chromone (1) and 5-hydroxy-2-[12'-(3",4"-methylenedioxyphenyl)dodecanyl] chromone (2), together with six known compounds have been isolated from Peperomia vulcanica Baker & C. H. Wright (Piperaceae). Their structures were determined by spectroscopic analysis including 2D NMR techniques.
A new furanosesquiterpene, (1E)-8,12-epoxygermacra-1,7,10,11-tetraen-6-one (3), was isolated from the resin of Commiphora sphaerocarpa together with the known compounds curzerenone (1), furanodienone (2), (1E)-3-methoxy-8,12-epoxygermacra-1,7,10,11-tetraen-6-one (4), (1(10)E,2R*,4R*)-2-methoxy-8,12-epoxygermacra- 1(10),7,11-trien-6-one (5), and dihydropyrocurzerenone (6). Hydrodistillates of the resins of C. sphaerocarpa, C. holtziana, C. kataf and C. myrrha were analysed. The identifications were aided by NMR, GC and GC-MS.
The dimeric nonprenylated acylphloroglucinol semimyrtucommulone (6) was obtained from the leaves of myrtle (Myrtus communis) as a 2:1 mixture of two rotamers. The known trimeric phloroglucinol myrtucommulone A (1) was also isolated and characterized spectroscopically as a silylated cyclized derivative (5). Myrtucommulone A showed significant antibacterial activity against multidrug-resistant (MDR) clinically relevant bacteria, while semimyrtucommulone was less active.
Modification of the St. John's wort acylphloroglucinol constituent, hyperforin (1), by acylation, alkylation, and oxidation resulted in detrimental effects on the inhibition of the synaptosomal accumulation of serotonin, showing the existence of definite structure-activity relationships in this in vitro test system and highlighting the role of the enolized cyclohexanedione moiety for activity on neurotransmitter reuptake.
The filamentous fungus Penicillium cyclopium conidiates in the presence of calcium ions in submerged culture without nutrient limitation according to a precisely timed program. Conidiation could be prematurely induced in a nutritionally sufficient medium which had previously supported growth, suggesting that a metabolite which influenced the process was produced. A diterpenoid with conidiation-inducing activity, conidiogenone, was purified from the culture medium, along with conidiogenol, a putative derivative with delayed activity. Contrary to previous thought, the presence of calcium was demonstrated to only decrease the threshold concentration of conidiogenone required for the induction to proceed. In light of these results, a mechanism of conidiation induction is presented according to which the mycelium produces a conidiation inducer (conidiogenone) that accumulates extracellularly. When a threshold concentration is reached, induction likely takes place by interaction with a specific cellular receptor. The results indicate that conidiogenone is both sufficient and necessary to induce conidiation.
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Eight secondary metabolites were isolated from submerged cultures of the ascomycete A111-95 during a search for new nematicidal metabolites. (-)-Galiellalactone (7) and compound 2 are metabolites previously obtained from cultures of Galiella rufa while the compounds 1, 3, 4, 5, 6 and 8 (3 and 4 were obtained as an unseparable mixture), were isolated as natural products for the first time. Compound 2, pregaliellalactone (5) and the mixture of 3 and 4 showed nematicidal activities towards Caenorhabditis elegans and Meloidogyne incognita. All compounds showed moderate or weak cytotoxic activities.
Two novel antifungal agents belonging to the sordarin family have been isolated from fermentations of Sordaria araneosa by bioassay-guided purification and their structures elucidated by NMR techniques. Neosordarin (1) is closely related to the recently discovered hypoxysordarin (2), with only small differences on the aliphatic side chain acylating the hydroxyl in the 3'-position of the sordarose moiety. Hydroxysordarin (3) closely resembles sordarin (4), the only slight difference being the replacement of sordarose with altrose as the sugar unit.
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5-(2'-oxoheptadecyl)-resorcinol [structure: see text] and 5-(2'-oxononadecyl)-resorcinol [structure: see text] were isolated from fermentations of an imperfect basidiomycete. The structures of the compounds were determined by spectroscopic techniques. Both compounds exhibit cytotoxic effects against the human colon tumor cell lines COLO-320, DLD-1 and HT-29 and the human promyeloid leukemia cell line HL-60, the human leukemia T cell JURKAT, the human hepatocellular carcinoma cell line HEP-G2 as well as the J774 mouse macrophage cell line. The compounds induce morphological and physiological differentiation of HL-60 cells into granulocytes, which subsequently die by apoptosis. Both compounds show no antibacterial and antifungal activity.
In a screening of basidiomycete cultures from Chile for the production of antibiotics we identified a Serpula himantoides strain as a producer of metabolites inhibiting the growth of bacteria and fungi. Bioactivity guided purification resulted in the isolation of four new antibiotics. Their structures were elucidated by spectroscopic methods. All four compounds are succinimide and maleimide derivatives, of which two are N-hydroxylated.
The HL-60 cell line, derived from a patient with acute promyelocytic leukemia, is a widely used model system to study the cellular and molecular events involved in differentiation of leukemic cells. In a screening for inducers of differentiation of HL-60 cells, cultures of Gliocladium strain 4-93 were found to produce Sch 52900, a previously isolated diketopiperazine (Chu et al,. J Antibiotics 48, 1440-1445). Sch 52900 induced the differentation of 50-69% of HL-60 cells at concentrations of 6.8-13.6 nM as measured by nitro-blue tetrazolium chloride (NBT) reduction which was followed by apoptosis as shown by DNA fragmentation. Our results demonstrate that growth arrest and the induction of differentiation by Sch 52900 is due to the induction of the cell cycle inhibitor p21WAF and an inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway which leads to the activation of the transcription factor AP-1.
Two new antibiotic metabolites, dacrymenone (1) and VM 3298-2 (2), were isolated from fermentations of a Dacrymyces sp., and their structures were determined by spectroscopic techniques. Dacrymenone (1) is a new eremophilane sesquiterpenoid while VM 3298-2 (2) is a bis-enol ether between methyl pyruvate and 4,6-dihydroxycyclohexan-1,3-dione. Dacrymenone (1) shows weak antibacterial and antifungal activity while VM 3298-2 (2) exhibits cytotoxic and antifungal activities.
In a search for new fungal compounds inducing apoptosis of the colon cancer derived cell line COLO-320, hormonemate (1) was purified from fermentations of an endophytic fungus isolated from living needles of a Pinus species. The producing strain was identified as Hormonema dematioides by microscopy and ITS rDNA sequence analysis. The structure of hormonemate was determined by spectroscopic methods. The compound exhibited cytotoxic effects against the human colon tumor cell lines COLO-320, DLD-1 and HT-29 as well as five other human cell lines (HL-60, JURKAT, HEP-G2, MCF-7, HeLa S3). It also induced apoptosis in COLO-320 cells as detected by a caspase-activity assay and morphological changes, and it triggered morphological and physiological differentiation of HL-60 cells into granulocytes, which subsequently died by apoptosis.
In dual cultures Oudemansiella mucida and Xerula melanotricha (basidiomycetes) react to the presence of living Penicillium notatum or P. turbatum with an increased production of strobilurin A (1) or X (2). P. notatum in turn reacts to the two basidiomycetes or their antibiotic strobilurin A alone with the production of N-(2-hydroxypropanoyl)-2-aminobenzoic acid amide (3) or chrysogine (4). P. melinii and P. urticae overgrow O. mucida due to complete resistance to strobilurin A. P. brevicompactum, P. citrinum, P. janczewskii and the other Penicillium strains are all sensitive but apparently do not induce O. mucida to produce the amounts of strobilurin A needed to inhibit their growth.
Erythrina crista-galli (Fabaceae) is used in Argentinean ethnopharmacology as anti-inflammatory medication, narcotic, desinfectant, and for the treatment of wounds. The common name of the tree is "ceibo" or coral tree. The dominating endophytes in E. crista-galli all belong to the genus Phomopsis as identified by microscopic features and the analysis of their ITS sequences. To investigate a possible contribution of Phomopsis spp. to the metabolites found in the plant, twelve different isolates were cultivated in different media. Besides several new metabolites a number of known compounds were detected: mellein, nectriapyrone, 4-hydroxymellein, scytalone, tyrosol, clavatol, mevinic acid, and mevalonolactone.
In a search for inhibitors of the inducible tumor necrosis factor-a (TNF-a) promoter activity and synthesis, a new chlorinated cyclopentenone was isolated from fermentations of the ascomycete Mollisia melaleuca. The structure was determined by a combination of spectroscopic techniques The compound blocked the inducible human TNF-alpha promoter activity and synthesis with IC50-values of 2.5-5 microg/ml (8.1-16.1 microM). Studies on the mode of action of the compound revealed that the inhibition of TNF-a promoter activity is caused by an inhibition of the phosphorylation of the IkappaB protein which prevents the activation of the transcription factor NF-xB. No cytotoxic, antibacterial and antifungal activities could be observed up to 100 microg/ml (323 microM) of the compound.