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Statins: Powerful Inhibitors of Cholesterol Biosynthesis. H. O. Cholesterol: What is it? 1. Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans.
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OCholesterol: What is it?1
Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans.
Isolated cholesterol is a white, flaky solid that is insoluble in aqueous environments.
In order to transport the steroid through blood, cholesterol is attached to a set of proteins called lipoproteins. There are two types of lipoproteins: high density and low density lipoproteins.
HDL: High-density lipoproteins –collectcholesterol particles as they travel through blood vessels and deposits them in the liver where they are transferred to bile acids and disposed off.
LDL: Low-density lipoproteins –deposits on the walls of blood vessels, and over time, builds up into cholesterol plaque and blocks blood vessels, especially arteries that feed blood to the heart.
1. The liver manufactures, secretes and removes LDL cholesterol from the body. To remove LDL cholesterol from the blood, there are special LDL receptors on the surface of liver cells.
2. LDL receptors remove LDL cholesterol particles from the blood and transport them inside the liver. A high number of active LDL receptors on the liver surfaces is necessary for the rapid removal of LDL cholesterol from the blood and low blood LDL cholesterol levels.
A deficiency of LDL receptors is associated with high LDL cholesterol blood levels.
Diets that are high in cholesterol diminish the activity of LDL receptors!!!!
and regular exercise.
Exercise burns fat so it is not
coverted to cholesterol which the
Body will have to dispose off.
Preliminary experiments showed that these fungal metabolites had no effect on mevanolate or other steps in the biosynthetic pathway.
This led to the speculation that their action was somewhere between the mevanolate and the HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)
Amounts required for 50% inhibition
ML-236A 0.18 µg/mL
ML-236B 0.01 µg/mL
ML-236C 0.08 µg/mL
Today, there are two classes of statins:
Natural Statins: Lovastatin(mevacor),
Compactin, Pravastatin (pravachol), Simvastatin (Zocor).
Synthetic Statins: Atorvastatin (Lipitor),
Statins are competitive inhibitors of
HMG-CoA reductase. They are bulky and
literally get “stuck” in the active site.
This prevents the enzyme from binding
with its substrate, HMG-CoA.
Lovastatin and compactin can be made in the lab in multistep syntheses.
This allowed scientists to study the structural-activity relationship of statins. The lactone was found to be the business end of the drugs.4
(Lee, et. al. 1982) ii. homologation of the lactone ring
iii. converting lovastatin to mevanolate analog (changing stereochemistry at the hydroxy- bearing carbon in the lactone)
iii. converting lovastatin to mevanolate analog (placing a methyl group at the hydroxy-bearing carbon in the lactone)6
i. The ethers were tested against their ester analogs
ii. Compactin was used as standard and assigned a relative potency of 100
In vitro HMG-CoA reductase inhibitory activity
showed that absence of the carbonyl has
detrimental effect on the inhibitory strength.
General conclusion: side-chain ether analogs are
weaker inhibitors of HMGR than their
Corresponding ether analog.
The role of the ester group in the synthetic
pathway is still under investigation.
3.Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibio. (Tokyo) 1976, 29, 1346-1348.
4.Istvan, E. S. American Heart Journal 2002, 144, S27-32.
5.Lee, T. J.; Holtz, W. J.; Smith, R. L.; Alberts, A. W.; Gilfillan, J. L. J Med Chem 1991, 34, (8), 2474-7.
6. Lee, T. J. H., W. J.; Smith, R. L. Journal of Organic Chemistry 1982, 47, (24), 4750.