Squalestatin

Medicinal chemistry has frequently drawn inspiration and important new leads from the examination of natural products, and this was proven to be the case once more. In 1992, researchers at Merck and Glaxo announced, almost simultaneously, the independent discovery of the same new class of natural products from two different fungi. As a consequence, the same family of natural products has two names - the zaragozic acids (Merck)4 or the squalestatins (Glaxo).5 A typical member of the family, zaragozic acid A (squa-lestatin SI) (1) was shown to have a tremendous affinity for squalene synthase (K, = 79 pM for rat microsomal squalene synthase) and could even lower serum cholesterol levels in vivo in a population of marmosets.6... 

Scheme 17. Retrosynthetic analysis of zaragozic acid A/squalestatin S1 (1).

Zaragozic Acid A/Squalestatin S1 35.3.4 Synthesis of the Side Chains... 

Coupling of Key Intermediates and Completion of the Total Synthesis of Zaragozic Acid A/Squalestatin SI... 

By using the Sharpless dihydroxylation, a variety of compounds have been transformed to diols with high enantiomeric excesses. The asymmetric dihydroxylation has a wide range of synthetic applications. As an illustration, the dihydroxylation was used as the key step in the synthesis of squalestatin 1 (3.8) (Scheme 3.2).74... 

Zaragozic acid A (which is also called squalestatin SI and has been shown to lower serum cholesterol levels in test animals by inhibition of squalene biosynthesis) by K. C. Nicolaou (University of California San Diego, Scripps Research Institute) ... 

However, the stability of the Ca2+ complex of the antibiotic squalestatin-1 is significantly greater than that of its citrate component (Bal, W. Drake, A. F. Jezowska-Bojczuk, M. Kozlowski, H. Pettit, L. D. Sadler, P. J. J. Chem. Soc. Chem. Commun. 1994, 555-556). 

Parra R, Aldred D, Magan N. (2005) Medium optimization for the production of the secondary metabolite squalestatin SI by a Phoma sp. combining orthogonal design and response surface methodology. Enzyme Microb Technol 37 704-711. 

Zaragozic Acids The zaragozic acids (squalestatins) are a class of competitive inhibitors of mouse, rat, and HepG2 squalene synthases, which also display antifungal activity [104]. The characteristic structural feature of this family of natural products is its highly oxygenated core. 

The zaragozic acids (squalestatins) are not macrolides, but they are primarily acetate derived, and the central ring system is suggested to be... 

Nadin A and Nicolaou KC (1996) Chemistry and biology of the zaragozic acids (squalestatins). Angew Chem Int Ed Engl 35, 1623-1656. 

MJ Dawson, JE Farthing, PS Marshall, RF Middleton, MJ O Neill, A Shuttleworth, C Stylli, RM Tait, PM Taylor, HG Wildman, AD Buss, D Langley, MV Hayes. The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity. J Antibiot 45 639-647, 1992. 

A Baxter, BJ Fitzgerald, JL Hutson, AD McCarthy, JM Motteram, BC Ross, M Sapra, MA Snowden, NS Watson, RJ Williams, C Wright. Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo. J Biol Chem 267 11705-11708, 1992. 

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