Statine synthesis

In addition to the enzyme s amino acid sequence, other parameters can affect the outcome of a biocatalytic process. For instance, a similar outcome in the aforementioned DERA-catalyzed statin synthesis was achieved by process improvements [21]. Using a thermostable variant of DERA (thermostability generally correlates well with tolerance to high concentrations of organic reagents or cosolvents), and fed-batch conditions, an efficient process that overcame sensitivity to high concentrations of chloroacetaldehyde was developed. 

Konno, H. Toshiro, E. Hinoda, N. An epoxide ring-opening reaction via a hyperva-lent silicate intermediate synthesis of statine. Synthesis 2003, 2161-2164. 

Silyl ketene acetal adds photolytically to C50 give a-fullerene-substituted carboxylic esters and are used in L-quebrachitol and statine synthesis They induce the first highly asymmetric Pummerer-type reaction of acyclic sulphoxides, giving siloxy(arylthio)alkanes with >99% ee541. 

The phenyl group became a practical protective group for carboxylic acids when Sharpless published a mild, effective one-step method for its conversion to a carboxylic acid. It has recently been used in a synthesis of the amino acid statine, where it served as a masked or carboxylic acid equivalent. ... 

Mechanism of action of statins cholesterol synthesis pathway... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

Greenberg, W.A., Varvak, A., Hanson, S.R. el ai (2005) Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proceedings of the National Academy of Sciences of the United States of America, 101, 5788-5793. 

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

Combination therapy with a statin and BAR is rational because numbers of LDL-Rs are increased, leadingto greater degradation of LDL cholesterol intracellular synthesis of cholesterol is inhibited and enterohepatic recycling of bile acids is interrupted. 

Scheme 11. Aldolase-catalyzed synthesis of statin drugs via the megagenonuc approach...

Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates. Proc Natl Acad Sci USA 101 5788-5793... 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Activators and inhibitors regulate not the amount of enzyme protein but the activity ( efficiency ) of that which is present. Two principal mechanisms of control are (i) competitive and (ii) allosteric. Competitive control (inhibition) occurs when a compound which is structurally similar to the true substrate binds to the active site of the enzyme. This is how a number of drugs and poisons bring about their effect. For example, a group of therapeutic drugs called statins are used to treat heart disease because by inhibiting a key enzyme called HMGCoA reductase, they reduce the hepatic synthesis of cholesterol and therefore the plasma concentration of that lipid. 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

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