Pironetin structure

Identification of Molecular Target According to the structure-activity relationship analyses, it was speculated that pironetin binds to tubulin covalently by Michael addition via its a,P-unsaturated 8-lactone [6], The biotinylated pironetin... 

Y. (1994). Pironetin, a novel plant growth regulator produced by Streptomyces sp. NK10958 II. Structural elucidation. J. Antibiot, 47, 703-707. 

ABSTRACT Discodermolide and pironetin are two immunosuppressive agents with antitumor activity. The isolation, structure elucidation, biological activity are reported as well as the synthetic routes to these two compounds. Five syntheses of discodermolide and seven syntheses of pironetin are described. 

Recently, it has been noticed that natural products with polyketide units can be potent immunosuppressive agents as well as antitumor agents. Two structurally different polyketide lactones, discodermolide and pironetin belong to this group of compounds (Fig. 1). Due to the potential therapeutic applications and the extreme scarcity of discodermolide and pironetin, interest in the chemical synthesis of these two natural products and in their analogues continues unabated. 

The structure of pironetin was determined to be (5/ ,6/ )-5-ethyl-5,6-dihydro-6[(jE )-(2/ ,35,4/ ,55)-2-hydroxy-4-methoxy-3,5-dimethyl-7-nonenyl]-2H-pyran-2-one by FAB-MS, H and 13C NMR, COSY, COLOC, DEPT, IR, X-ray crystallographic analyses and adapted Mosher s method to determined the absolute configuration [74]. The biosynthesis of pironetin appeared to involve assembly of acetate, propionate and butyrate precursors. Four fermentation experiments were carried out in order to determine the biosynthetic origin of the carbon skeleton and oxygen atoms of pironetin. [1-13C] Acetate, [2-13C]acetate, [1,2-13C] acetate, [l-13C]propionate, [l-1 C]butyrate and L-[methyl-I3C]methionine were led separately to Streptomyces sp. culture and pironetin was isolated and purified. Analysis of pironetin by 13C NMR showed that pironetin was derived from four acetate units, two propionate units, one butyrate unit and one methyl unit of methionine [78] (Fig. 4). 

Not only the interesting activities but also the unique and simple structure make pironetin and its derivatives attractive synthetic targets and seven total synthesis of pironetin have been reported. 

Compound (80), a structural isomer of umuravarumbolide (55), is a minor constituent of Cryptocarya latifolia 89). The immunosuppressive agent, (—)-PA-48153 (81), has been isolated from Streptomyces prunicolor sp. PA 48153 (90). The same compound, obtained from Streptomyces sp. NK10958 and shown to be a plant growth regulator, has been named pironetin, and the structure based on spectral data, confirmed by X-ray analysis 91, 92) and synthesis 93). 

Kobayashi, S., K. Tsuchiya, T. Kurokawa, T. Nakagawa, andN. Shimada Pironetin, a Novel Plant Growth Regulator Produced by Streptomyces sp. NK 10958. II. Structural, Elucidation. J. Antibiot., 47, 703 (1994). 

A a,P-unsaturated 5-lactone library, inspired by bioactive natural products such as fostriecin and pironetin (Fig. 4), has been synthesized on a solid support in a highly enantioselective manner using the Lewis acid Ti-(il)-BINOL catalyst 15 (43). After subsequent transformations, a collection of 50 analogues containing structures 17, 18, and 19 were subjected to biological evaluation in phenotype-based screens. A few of them have been shown to be modulators of cell cycle progression and inhibitors of viral entry into cells. 

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