Zaragozic acid cholesterol biosynthesis

Scheme 1. Sites of inhibition of cholesterol biosynthesis by Mevacor and zaragozic acid A.

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) ... 

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. 

On the other hand, HMG-CoA reductase inhibitors have also been shown to decrease the biosynthesis of other biologically important isoprenoid compounds derived from mevalonate. Thus, there has been continued interest in developing hypolipidemic agents that inhibit the enzymes involved specifically in the later stages of cholesterol biosynthesis. Zaragozic acid derivatives were isolated from several microbial species and they exhibited dose-dependent inhibition of cholesterol biosynthesis as potent squalene synthase inhibitors. Viridiofungins, bisabosquals, macrolactins, CJ-15,183, CJ-13,981 and CJ-13,982 were also isolated as mammalian squalene synthase inhibitors of microbial origin. 

Zaragozic acids (squalestatins). Highly active, competitive inhibitors of squalene synthase (SQS) and thus of cholesterol biosynthesis. The different names are a result of the independent, simultaneous discovery of this class of natural products in various ascomycete strains (e. g., Phoma sp., Setosphaeria khartoumensis) by three research groups. All Z. possess a 4,6,7-tri-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarbox-ylic acid skeleton carrying acyl groups on the C-6 oxygen atom as lipophilic side chains and alkyl groups on the C-1 carbon atom. 

In comparison with ketone-based SAMP/RAMP hydrazones, the use of aldehyde-derived SAMP/RAMP hydrazones in natural product syntheses is much more prevalent. For instance, Nicolaou et al. synthesized the side chain of zaragozic acid A 49 using two successive SAMP hydrazone alkylations (Scheme 1.1) The zaragozic acid class of natural products inhibits squalene synthase, the enzyme responsible for the biosynthesis of cholesterol. Inhibition of this enzyme has implications in the treatment of coronary artery disease. The synthesis of the side chain of zaragozic acid began with the formation of 42, which... 

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