Methyl mevinolin

Sample preparation Prepare a 1 mL Bond-Elut C2 SPE cartridge by washing with 1 mL MeOH and 1 mL buffer. Plasma. 500 xL Plasma -i- 500 p,L buffer, keep in an ice water mixture, add 100 p,L MeCN water 60 40, add 50 pL 5 pg/mL methyl mevinolinic acid in MeCN water 60 40, mix, add to the SPE cartridge, wash twice with 1 mL huffer, wash twice with 1 mL MeCN buffer 20 80, elute with 400 pL MeCN water 75 25, inject a 30 pL ahquot of eluant. Bile. Inject a 10 pL aliquot directly. (Buffer was 100 mM pH 7.2 potassium phosphate buffer.)... 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

An example of reversible ring closure is found with mevinolin and compactin that are both potent inhibitors of hydroxy-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-determining enzyme in the de novo biosynthesis of cholesterol. 

Araki, Y, and Konoike, T, Enantioselective total synthesis of (+)-6- 77i-mevinolin and its analogs. Efficient construction of the hexahydronaphthalene moiety by high pressure-promoted intramolecular Diels-Alder reaction of (7 ,2Z,8 , 10 )-l-[(fert-butyldimethylsilyl)oxy]-6-methyl-2,8,10-dodecatrien-4-one, 7. Org. Chem., 62, 5299, 1997. 

Biosynthetic experiments with variously labelled acetate units and [methyl- C] methionine established that the carbon skeleton of mevinolin was formed from nine acetate units, with the extra methyl group arising from methionine. The ester arose from two acetate units and a methionine. The oxygen atoms of the side chain at C-11, C-13 and C-15 were derived from the original acetate units whilst that at C-8 came from oxygen of the air. The cyclization reaction to form the bicyclic carbon skeleton may be a Diels-Alder cyclization (4.93 4.94). These are biosynthetically rather unusual. In the late stages of the biosynthesis, 4ot,5-dihydromonacolin L (4.95) is hydroxylated and dehydrogenated to form mevinolin. 

The Diels-Alder was successful20 129 but now the methyl group in the SW comer needs to be added by conjugate addition and that requires an enone. Oxidation of the silyl enol ether 130, prepared by kinetic enolate formation with LDA, with catalytic Pd(OAc)2 and benzoquinone as the stoichiometric oxidant gave the required enone 131 in 57% yield. Addition of Me2CuLi was stereoselective to give 132 and the synthesis of mevinolin completed. 

Mevinolin 13.6,7,8,8a-hexahydro-p,6-dihydroxy-2,6-dimethyl-8-(2-methyl-l-oxobutoxy)-l-naphtha-lene-heptanoic acid 6-lactone (Fig.), a fungal metabolite from the culture medium of Aspergillus terreus The parent hydroxyadd (mevolinic acid) is a potent competitive i bitor K 0.6 nM) of 3-hydroxy-3-me-thyl utaryl-CoA reductase (EC 1.1.134). Chal administration of M. produces a 30% decrease of plasma LDL cholesterol and a moderate increase in the number of LDL receptors in human heterozygotes for familial hypercholesterolemia (see Lipoproteins). When M. is administered with Cholestyramine (see). 

Fig. 117.9 An overview of the cytosolic mevalonate pathway and plastidial mevalonate-independent pathway for the biosynthesis of terpenoids (isoprenoids) in plant cells [99] (DMAPP, dimethylallyl diphosphate DXP, l-deoxy-D-xylulose-5-phosphate DXS, DXP synthase DXR, DXP reductoisomerase MEP, 2-C-methyl-D-erythritol 4-phosphate GASP, gfyc-eraldehyde-3-phosphate HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA HMGR, HMGR-CoA reductase IPP, isopentenyl diphosphate. Mevinolin and fosmidomycin are inhibitors of HMGR and DXR, respectively)...

Safety aspects and experimental scale apart, there are no fundamental differences in the reaction of aliphatic C—H acidic compounds with labeled or unlabeled methyl iodide. For example (Figure 5.56), the alkylation of deprotonated 2,6-dimethylcyclohexanone (202), key step in the synthesis of [ CJvitamin A , of the A,A-dimethyUiydrazone of dihydrotestosterone of mevinolin (20 and tricarbethoxymethane (208) , furnishing... 

Type-II intramolecular ene reactions of aldehydes and ketones proceed readily with Me2AICl as the Lewis acid. " Unsaturated aldehydes and ketones can be generated in situ by Mc2 AlCl-catalyzed reaction of Acrolein and Methyl Vinyl Ketone with alkylidenecycloalkanes at low temperatures (eq 12). The mono-cyclic aldehyde reacts further under these conditions. The mono-cyclic ketone can be isolated at low temperature but undergoes a second ene reaction at rt to give the bicyclic alcohol. p-Keto esters form tertiary alcohols in intramolecular ene reactions. The products are stable because they are converted to the aluminum alkoxide (eq 13). Intramolecular Me2AlCl-catalyzed ene reactions have been used for the preparation of the bicyclic mevinolin ring system (eq 14). ... 

Lovastatin is rapidly metabolised, which is undesirable for any dmg likely to be chronically administered. In order to achieve once-daily dosing, steric hindrance around the ester carbonyl was increased by the introduction of an extra methyl group close to the ester bond in order to reduce the rate of esterase hydrolysis. This resulted in formation of simvastatin, a highly successful lipid-lowering agent. Simvastatin (like lovastatin) is inactive until metabolised in the liver to form its active metabolite mevinolinic acid (Fig. 8.48). Part of mevino-linic acid is stmcturally similar to the HMG portion of HMG-GoA, the substrate for HMG-CoA reductase, and hence competes with it for the active site of the enzyme. This reduces the amount of mevalonic acid which is produced. Mevalonic acid is a precursor of cholesterol. 

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