Polyoxins structures

The discovery of the polyoxin group (1) of antifungal nucleoside antibiotics (2) spurred the attention of synthetic chemists as well as biologists for a number of reasons. Their unusual structural features combined with unique biological activity fostered studies on many fronts (3). During their studies on the biosynthesis of the polyoxins, Isono, Crain and McCloskey (4) discovered three novel acidic nucleosides which they called octosyl acid A, B and C,... 

Difficulty for analysis in micro-scale Antibiotics are generally mixtures of various structurally related components like polyoxins. This complexity is a difficulty for analysis in microscale and safety evaluation of compounds. 

Isono K, Asahi K, Suzuki S (1969) Studies onpolyoxins, antifungal antibiotics. 13. The structure of polyoxins. J Am Chem Soc 91 7490-7505... 

In the synthesis of ( + )-polyoxamic acid36, representing a common structural feature of the polyoxin-type antifungal antibiotics, rearrangement of a trichloroacetimidate 1, derived from L-tartrate, gives a 1 1 mixture of diastereomers 2 and 3, showing no induction by the stereogenic centers outside the electrocyclic arena. 

We gratefully acknowledge the excellent technical assistance of Mr. George Udowenko and the support of other members of the SK F Department of Natural Products Pharmacology for supplies of fermentation products. We thank Dr. James Chan for data on the structure of the purified polyoxins. 

As mentioned, the insecticides inhibit chitin synthesis indirectly and they are not useful as fungicides. Polyoxins, however, are structural analogues to uridine diphospate-2-acetamido-2-deoxy-D-glucose, which is the substrate for chitin synthetase, and inhibit the incorporation of 2-aceta-mido-2-deoxy-D-glucose into chitin. It is produced by fermentation of Strep-tori n/ces cacaoi var. asoensis. It is used as a fungicide against powdery mildews in apples and pears, and for many other purposes. Its mammalian toxicity is very low, and it has a no-observed-effect level (NOEL) in rats of 44,000 mg/kg in diet in 2-year studies. The compounds inhibit chitin synthetase from insects, but are not toxic to insects in vivo. 

Polyoxin antibiotics were discovered in Japan in cultures of Streptomyces cacaoi var. asoensis (Suzuki et al., 1965). They are a mixture of related components with similar physical and chemical properties. The structure of polyoxins (15, 16) was elucidated by Isono et al. (1969). That, for example, of polyoxin B was found to be... 

Polyoxins constitute a group of antifungal metabolites produced by Streptomyces cacaoi var. asoensis, the gross structure of which is divisible into a nucleoside moiety and a dipeptide comprised of a unique functionalized polyhydroxynorvaline known commonly as 5-(9- or d-... 

A group of aminoacylamino- nucleoside antibiotics (more than 25 components) from cultures of Streptomyces tendae, see also polyoxins. The N. exhibit acar-icidal, insecticidal, and antifungal activities. The activity is based on an inhibition of chitin biosynthesis as a result of the structural analogy to UDP-Al-acetyl-... 

Polyoxin D and nikkomycin Z are Streptomyces derived peptidyl nucleoside antibiotics that have been shown to be competitive inhibitors of chitin synthetase in both fungal and insect in vitro systems [39-44]. Both polyoxin D and nikkomycin Z have structural similarities to the substrate UDP-N-acetylglucosamine, which most likely accounts for the competitive nature of their ability to inhibit chitin... 

The chemistry and biochemistry of polyoxins has been discussed. The structure of the neopolyoxins A, B, and C, which are potent inhibitors of fungal cell-wall chitin synthetase, has been established neopolyoxins A and B are the imidazole nucleosides (18) and (19), respectively, whereas neopolyoxin C is the corresponding uracil-1-yl nucleoside the structure of polyoxin N was also revised, the amino-acid side-chain of (18) being replaced by 2-amino-5-(9-carbamoyl-2-deoxy-L-xyIonic acid. The new antibiotic nikkomycin B also has the structure of (18), although its stereochemistry has not been fully established. Adenomycin has... 

Total syntheses of thymine polyoxin C and polyoxin have been reported. Syntheses have also been reported for neosidomycin 8 and the related antibiotic SF-2140 9, thereby confirming their structures. ... 

The biosynthesis of the nucleoside skeleton of polyoxins has been studied using C- and C-labelled glucose, glycerate, and uridine substrates it was suggested that condensation of uridine as its 5 -aldehyde with phosphoenol pyruvate gives an octofuranuloseuronic acid nucleoside, which loses the two terminal carbon atoms by oxidative elimination followed by transamination to give the required uridyl-5-amino-5-deoxy-D-allofuranosyluronic acid structure. ... 

Our interest in the polyoxin group of antibiotics [50] was focused on the nature of polyoximic acid [51], a deceptively simple azetidine carboxylic acid derivative which had eluded the efforts of synthetic chemists [52] since the original publication of the structure. Only recently was a synthesis reported for /rnatural product based on low field NMR stupes [51]. A total synthesis of this acid in our laboratory [54,55], and comparison of NMR spectra with a sample kindly provided by Professor Isono showed that they were different. The sample of the naturally-derived amino acid was suitable for X-ray analysis (even after 20 years of isolation and storage ), and it proved to be ci5-polyoximic acid [54]. A new synthesis of this isomer was undertaken and confirmed its structural as well as stereochemical identity (Scheme 9) [55]. TTie stereochemical revision of polyoximic acid could... 

Polyoxln - Hine componenta of the polyoxin complex have been separated and characterized. The structures shown below have been determined for three (a, B, and c) of these glycosidic 5-hydroxymethyluracil (ix) derivatives, which are inhibitory only to phytopathogenic fungi.139-1 2 polyoxins show a chemical relationship to gougerotin (x).1 3 The latter substance... 

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