Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogs of the Tocotrienols

• Published in: Journal of medicinal chemistry Vol. 37; no. 4; pp. 526 - 541
• Main Authors: Pearce, Bradley C, Parker, Rex A, Deason, Michael E, Dischino, Douglas D, Gillespie, Elizabeth, Qureshi, Asaf A, Wright, J. J. Kim, Volk, Kevin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.02.1994; Amer Chemical Soc
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Antioxidants - chemical synthesis; Antioxidants - pharmacology; Benzopyrans - chemical synthesis; Benzopyrans - pharmacology; Cells, Cultured; Chemistry, Medicinal; Chickens; Cholesterol - biosynthesis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Sciences & Biomedicine; Lipid Metabolism; Liver - drug effects; Liver - metabolism; Male; Pharmacology & Pharmacy; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - pharmacology; Vitamin E - analogs & derivatives; SUPPLEMENTATION; ATHEROGENESIS; OXIDATIVE MODIFICATION; LIPID-PEROXIDATION; LOW-DENSITY-LIPOPROTEIN; ARTERIAL-WALL; ATHEROSCLEROSIS; D-ALPHA-TOCOPHEROL; VITAMIN-E DERIVATIVES; RESONANCE SPECTRA
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00030a012

Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves; posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the; action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity:of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced:LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR Suppression, unsurpassed by synthetic analogues of the present study. In orally dosed; chickens, 8-bromotocotrienol (40), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.