Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.

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 (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.

Inhibitors of Cholesterol Biosynthesis. Part 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogues of the Tocotrienols.-In vitro activities toward cholesterol-biosynthesis-inhibition (CBI) and HMG-CoA reductase (HMGR) suppression of a series of title analogues and hypocholesterolemic activity of selected compounds are investigated. Compared with tocotrienols (Ia) and also (Ib), which express maximal activity toward CBI and HMGR suppression, mono-and diprenylated compounds (IIa) and (IIb) and OH-substitution lacking compounds (Ic) and (Id) show decreased CBI and (Ie) and (If), due to methyl substitution, show less HMGR suppression. Compound (III) has the best low-density lipoprotein (LDL) antioxidant properties in vitro, followed by (Ia). In vivo tests show compounds (Ig) and (IV) to exhibit greater cholesterollowering activities and (Va) and less (Vb) to be orally active. -(PEARCE, B. C.; PARKER, R. A.; DEASON, M. E.; DISCHINO, D. D.; GILLESPIE, E.; QURESHI, A. A.; VOLK, K.; WRIGHT, J. J. K.; J. Med. Chem. 37 (1994) 4, 526-541; Bristol-Myers Squibb Pharm. Res. Inst., Wallingford, CT 06492, USA; EN)