Squalestatins

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

The Chemistry of Fungi By James R. Hanson James R. Hanson, 2008 

Numerous quinones that are biosynthesized by the polyketide pathway have been isolated from fungi. The colour of the quinone that is isolated does not always reflect the colour of the fungus. This may be because the quinone is accompanied by its reduction products, forming a quinhydrone complex. 

Much of the early work on these substances was carried out before the advent of modern physical methods of structure determination. Typical experiments involved reduction and deoxygenation with zinc dust to form identifiable aromatic hydrocarbons, e.g. 2-methylanthracene from a C-2 substituted anthra-quinone. The oxygen functions were then placed on this carbon skeleton by unambiguous synthesis. 

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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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