Three new N-methyl-4-hydroxy-2-pyridinone analogs, 6-epi-oxysporidinone (3), the dimethyl ketal of oxysporidinone (4), and N-demethylsambutoxin (5), along with the known compounds, (−)-oxysporidinone (1), (−)-sambutoxin (2), wortmannin (6), enniatin A (7), enniatin A1 (8), and enniatin B1 (9) were isolated from Fusarium oxysporum (N17B) by bioassay-guided fractionation. Compounds 1 and 3 showed selective fungistatic activity against Aspergillus fumigatus and wortmannin had selective potent activity against Candida albicans. Moderate activity was observed with the enniatins 7-9 against C. albicans, Cryptococcus neoformans, and Mycobacterium intracellulare. Compounds 1-5 had no activity against the agriculturally important fungi Fusarium verticillioides (syn. F. moniliforme) and Aspergillus flavus.Opportunistic fungal infections constitute a major cause of morbidity and mortality in AIDS patients. 1 The drugs available for the treatment of these infections are of limited utility due to their toxicity, adverse side reactions, and the frequent emergence of resistant strains. 2 As a part of a program to identify new drug candidates for the treatment of opportunistic fungal infections, we have screened a number of extracts from various natural sources against the following common opportunistic fungal pathogens: Candida albicans, Cryptococcus neoformans, Mycobacterium intracellulare, and Aspergillus fumigatus. The ethyl acetate extract of the fungus Fusarium oxysporum (N17B) showed broad-spectrum antifungal activity. Previous studies on F. oxysporum (N17B) have shown that it produces a toxin which causes hemorrhaging and death in mice, 3 and wortmannin has been identified as the compound responsible for this toxicity. 4,5 Wortmannin, a powerful inhibitor of phosphatidylinositide 3-kinase, 6 was shown to have antifungal properties. 7Bioassay-guided fractionation of the ethyl acetate extract of F. oxysporum (N17B) grown on rice medium gave two fractions with selective activity against A. fumigatus and C. albicans respectively, and another with broad activity against C. albicans, C. neoformans, and M. intracellulare. Further purification of the fraction with selective activity against A. fumigatus led to the isolation of compounds 1 and 3 as the constituents responsible for the activity. Compound 1 had identical spectroscopic data including 1 H-13 C NMR correlations as those reported for oxysporidinone, which was previously isolated from a different strain of F.⊥ Dedicated to Dr. Norman R. Farnsworth of the University of Illinois at Chicago for his pioneering work on bioactive natural products. * To whom correspondence should be addressed. From the inactive fractions, (−)-sambutoxin (2) and two further 4-hydroxy-2-pyridinone analogs (4 and 5) were isolated. Sambutoxin, a hemorrhagic mycotoxin, has been isolated from F. sambucinum. 9 This is the first report of compounds 3-5 in nature. From the fraction with selective activity against C. albicans, wortmannin (6) was isolated as the active constituent. Separation of...

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Nine new tetranorditerpenoid dilactones (2-10), together with two previously reported norditerpenoids dilactones (1, 11), and two known putative biosynthetic intermediates oidiolactone-E (12) and 13 were isolated from an ethyl acetate extract of a culture medium of Sclerotinia homoeocarpa. Structures and absolute configuration of these compounds were determined by spectroscopic methods and confirmed by X-ray crystallographic analysis of representative compounds. Compounds were evaluated for herbicidal, antiplasmodial and cytotoxic activities. Compounds 1, 2, 6, 7, 11 were more active as growth inhibitors in a duckweed bioassay (I 50 values of 0.39 -0.95 µM) than more than half of 26 commercial herbicides previously evaluated using the same bioassay. Some of these compounds exhibited strong antiplasmodial activities as well, but they also had cytotoxic activity thus precluding them as potential antimalarial agents.Malaria continues to be a major cause of morbidity and mortality in many parts of the tropics and subtropics. Every year about 500 million people become ill with malaria and over a million people, most of them young children, die of this disease. 1 Wide-spread resistance to first-line antimalarial drugs has hampered the effective control of this disease. Many efforts are underway to develop new classes of antimalarials to counter this trend. 2 One of these involves searching for compounds to inhibit unique metabolic pathways in the apicoplast. 2,3 Plasmodium parasites, which cause malaria in humans, contain an organelle called the apicoplast. 4 The apicoplast is very similar to plastids (chloroplasts are one of several plastid forms) of plants and is believed to have been acquired by the engulfment of an ancestral alga and retention of the algal plastid. The apicoplast is essential for the survival of parasites, and it contains many plant-like metabolic pathways such as essential amino acid, heme, and type *To whom correspondence should be addressed. Tel.: 1-662-915-1019. Fax: 1-662-915-1006. dhammika@olemiss.edu . NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2010 December 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptII fatty acid biosynthesis not present in the vertebrate hosts of malaria parasites. 4 Several studies have been initiated to evaluate antimalarial activity of herbicides and natural phytotoxins which are known to inhibit metabolic pathways of the plastid in plants. 5 -7 A number of plant pathogenic fungi are known to release phytotoxins that disrupt biological processes in plants. [8][9][10] Some of these have also been shown to inhibit metabolic pathways in the plastid; 11 thus, plant pathogens could be a potential source of antimalarial compounds.As part of a program to search for antimalarial compounds from natural sources, we initiated a project to screen phytopathogenic fungi for antimalarial activity. Sclerotinia homoeocarpa is the causal agent of "dollar spot," the most prevalent disease of turfgrass in...

Flavonoids and their glycosides form a large group of polyphenolic compounds which are widely distributed in plants. 2,3) Animals depend on plants for flavonoids as they are unable to biosynthesize them.4) The exception was the detection of flavonoids in butterfly wings with the likely source being the plant food of the larva.5) Flavonoids add colour, 6) flavour and processing characteristics to many foods (fruits and vegetables) and drinks (tea, wine). 7) So far, over 4000 flavonoid derivatives have been identified and numerous beneficial health effects including, anti-inflammatory, [8][9][10] antiviral 11) and anti-cancer 8,12,13) properties have been reported. Some epidemiological studies have also demonstrated that the intake of flavonoids reduced the risk of cardiovascular diseases. 8,[14][15][16] Most of the pharmacological activities could be attributed to their ability to inhibit certain enzymes and to their oxygen free radical scavenging and iron chelating capabilities.17) The antioxidant properties are suggested to be due to the number and arrangement of their phenolic hydroxyl groups.18) It has been shown that 3-hydroxy-, 7-hydroxy-and 5-hydroxyflavones have hypochlorite scavenging activity with 3-hydroxyflavone showing the greatest effect.19) Depending on the concentration and the reaction conditions, flavonoids could act as antioxidants as well as prooxidants. 17)Toxicity of some flavonoids has been attributed to their prooxidant behavior. Hence, careful examination of flavonoids for their behavior in varying reaction conditions has to be carried out before being considered for therapeutic uses. 17)Although in vitro experiments have shown that flavonoids possess a wide range of biological activities, their overall function in vivo has to be clarified. It has been observed that only aglycones and flavonoid glucosides are absorbed in the small intestine.18) They are then metabolized rapidly to methylated, glucuronidated or sulphated metabolites in the jejunal and ileal parts of the small intestine. After metabolism in the intestine, the flavonoids are further metabolized in the liver to yield various conjugated forms. The reactions include methylation, sulphation and glucuronidation. Conjugation is essentially a detoxification process in which the compounds are made to eliminate by way of bile and urine by increasing their hydrophilic character.20) The unabsorbed flavonoids undergo further metabolism by the bacterial enzymes in the colon.21) Using animal models, human trials and in vitro fermentation experiments, it was shown that the intestinal microorganisms are greatly responsible for catabolism and scission of the flavonoid. Scission of the flavonoid structure depends on their hydroxylation pattern.21) Absence of hydroxyl groups in the B-ring for example, prevents ring scission. In vitro metabolism studies of flavonoids using rat liver microsomes showed that the B-ring is the main structural moiety that undergoes biotransformation. B-rings with a single hydroxyl group at C-4Ј or none at all get hy...

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The fungi, Beauveria bassiana (ATCC 13144) and Penicillium chrysogenium (ATCC 9480) transformed resveratrol to resveratrol-3-O-sulphate. The former, in addition, gave 5-methoxyresveratrol-3-O-β-glucoside with the latter yielding 5-methoxyresveratrol-3-O-sulphate. The structures were established by spectroscopic methods. Evaluation of biological activity of metabolites through a series of mammalian cell based assays indicated that resveratrol tends to lose its anti-inflammatory, cytotoxic and anti-oxidant activities with the substitution of its hydroxyl groups.

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