Cholesterol biosynthesis inhibitor

Vinyloxiranes can also be converted into P-lactones (Scheme 9.30) [133, 134], Opening of 66 with Fe2(CO)9 resulted in the (7t-allyl)tricarbonyliron derivative 67 in good yield, together with a minor diastereomer (not shown). Oxidative cleavage of 67 then gave 3-lactone 68, which was used as a key intermediate in the preparation of the cholesterol biosynthesis inhibitor 1233A. 

For a synthesis of the anti-cancer drug taxol TPAP/NMO was used in three steps, two for oxidation of primary alcohols to aldehydes (by TPAP/NMO/PMS/ CHjClj) and one for a secondary alcohol to ketone (by TPAP/NMO/PMS/CHjClj-CHjCN) [66], cf. also [111] and for the SERCA inhibitor thapsigargin (two primary alcohol and one secondary alcohol oxidation steps) [112], This system was also used during synthesis of the cholesterol biosynthesis inhibitor 1233A [52], the antibiotic and anti-parasitic ionophore tetronasin [113, 114] and for the cytotoxic sponge alkaloids motopuramines A and B [115]. 

Korosec, T., Acimovic, J., Seliskar, M., Koqan, D., Tacer, K. F., Rozman, D., and Urleb, U. (2008). Novel cholesterol biosynthesis inhibitors targeting human lanosterol 14a-demethylase (CYP51). Bioorg. Med. Chem. 16, 209-221. 

An article on a promising cholesterol biosynthesis inhibitor appeared in The Journal of Organic Chemistry this month. 

Sebti, S.M., Tkalcevic, G.T., and Jani, J.P. (1991). Lovastatin, a cholesterol biosynthesis inhibitor, inhibits the growth of human H-ras oncogene transformed cells in nude mice. Cancer Commun 3 141-147. 

Bates, R. W., Fernandez-Megia, E., Ley, S. V., Ruck-Braun, K., Tilbrook, D. M. G. Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (jc-allyl)tricarbonyliron lactone complex. J. Chem. Soc., Perkin Trans. 11999,1917-1925. 

Gotteland, J.-R, Brunei, L, Gendre, F., Desire, J., Delhon, A., Junqudro, D., Oms, P, Halazy, S. (Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors synthesis and hypocho-lesterolemic activity of a new class of squalene epoxidase inhibitors. J. Med. Chem. 1995, 38, 3207-3216. 

Many attempts have been made to find cholesterol biosynthesis inhibitors for development as hypocholesterolemic agents. Microbial secondary metabolites have been used as valuable natural sources in the development of novel cholesterol biosynthesis inhibitors. Mevastatin and lovastatin were isolated from the fungi, Penicillium citrinum and Aspergillus terreus, respectively, as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the rate-limiting step of cholesterol synthesis in mammals. These findings have led to the development of statins , which are drugs of choice in the treatment of hypercholesterolemia. 

Inhibition of endogenous cholesterol biosynthesis has been known to be one of the most efficient approaches in the regulation of LDL cholesterol levels. Based on the several screening assay systems on enzymes, cell lines and laboratory animals, a number of cholesterol biosynthesis inhibitors have been isolated and identified from microorganisms as the lead compounds, some of which have been developed as therapeutic agents to regulate cholesterol metabolism. 

Cholesterol Biosynthesis Inhibitors Screened by Using Cell Lines... 

Inhibition of cholesterol biosynthesis constitutes an important strategy to the lowering of higher blood total and LDL cholesterol levels. Several in vitro assay systems have been used as screening methods for developing novel leads for cholesterol biosynthesis inhibitors. 

Aryloxy)methylsilane derivatives as new cholesterol biosynthesis inhibitors synthesis and hypocholesterolemic activity of a new class of squalene epoxidase inhibitors. J. Med. Chem. 38 3207-3216. 

Tacer KF, Rozman D, Urleb U (2008) Novel cholesterol biosynthesis inhibitors targeting human 2765. lanosterol 14a-demefhylase (CYP51). Biooig Med Chem 16 209-221... 

In an attempt to obtain compounds having hypocholesterolemic activity through inhibition of biosynthesis at a post-mevalonate stage, a number of substituted carboxyhc acids possessing an alicyclic ring were synthesized by Morand et al [249]. While some of the compounds in this series have been found to be active in vitro as cholesterol biosynthesis inhibitors, this activity was not achieved in vivo. The cyclic compounds, of which acid LXXXIII can be considered a prototype, were less active than 2-(4-biphenylyl)-4-hexenoic acid (LXXXI). 

Cholesterol biosynthesis inhibitors isolated from S. sp. A7361 have been shown to be analogues of chlorothricin, containing the disaccharide units 5 attached to the macrolide ring. ... 

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