Squalestatins acids

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... 

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) ... 

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. 

Stoermer, D, Caron, S, Heathcock, C H, Total synthesis of zaragozic acid A (squalestatin SI). Degradation to a relay compound and reassembly of the natural product, J. Org. Chem., 61, 9115-9125, 1996. 

Mann, R K, Parsons, J G, Rizzacasa, M A, Towards the synthesis of the squalestatins/zaragozic acids synthesis of an advanced intermediate and introduction of the C-1 sidechain, J. Chem. Soc., Perkin. Trans. 1, 1283-1293, 1998. 

The squalestatins (also known as zaragozic acids) are a family of potent squalene synthase inhibitors with potential use as anticholesterol compounds. 

The pTAex3 expression system utilises the awyB promoter which is repressed by glucose and induced by starch. A. oryzae transformants were grown in the presence of starch. Organic extracts of the medium from the WT and transformant strains were then analysed by RP-HPLC. Of five transformants shown to have integrated the Phoma PKSl, one strain showed the presence of a new compound in the HPLC trace. This compound was isolated and purified by repeated RP-HPLC. Full structural characterisation revealed the new compound to be the doubly methylated unsaturated acid 14 (Figure 5). Comparison of optical rotation data with synthetic material proved it to be the 45,6.S enantiomer, and thus chain B of squalestatin. We thus named this PKS SQTKS (squalestatin tetraketide synthase). 

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. 

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