Compounds Derived from Cholesterol

Vitamin D plays a very central role in maintaining the integrity of bone structure. The vitamin actually comprises a set of closely related derivatives of cholesterol that incorporate a 5,7 diene in ring B. The compounds are not actually active per se, requiring activation by ultraviolet light. In a typical example the action of light on 

The presence of a hydroxyl group at the 1 position (steroid numbering), which also occurs in a vitamin D metabolite, also enhances potency. The synthesis in this case starts with an advanced ring opened intermediate (36-5) already provided with that extra hydroxyl group [30]. Constmction of the side chain begins with condensation of the ylide from phosphonium salt (36-1) with pivalaldehyde. The ketone in the product (36-2) is then reduced to the alcohol (36-3). The olefin is then epoxidized 

Horvath, J. Vincze, J. Chem. Phys. Lipids 1992, 63, 23. 

Nakagawa, S. Ando, Y. Sakane, S. Shiono, M. 1993, Japanese Patent Appl. 04273894. 

See Lednicer, D. Mitscher, L. A. The Organic Chemistry of Drug Synthesis, Vol. 3, Wiley, New York, 1984, 03 for closely related compounds. 

---

Steroids Compounds derived from cholesterol (itself also a steroid), most of which are hormones. 

Although it can be produced by many cells in the body, including fat cells, in the brain and in artery walls (in males as well as females), most estradiol is synthesized in the ovaries from compounds derived from cholesterol (see p91). 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Studies using animals suggest that regular consumption of flaxseed can protect against certain types of tumors and reduce the risk of colon cancer. Flaxseed, also called linseed, has been shown in some studies to improve kidney function, lower LDL cholesterol levels, and increase bowel movements. A compound derived from flax is being investigated as a possible treatment for lupus. 

The class of lipids includes cholesterol, the bile salts and steroid hormones (which are derived from cholesterol), the fat-soluble vitamins, and compounds such as the prostaglandins. 

Cholesterol (3-hydroxy-5,6-cholestene) belongs to a family of compounds derived from a fused, reduced, nonlinear four-ring system of cyclopenta(a -phenanthrene. Bile adds, steroid hormones, and vitamin D metabolites are derivisd from diolesterol. 

On the other hand, HMG-CoA reductase inhibitors have also been shown to decrease the biosynthesis of other biologically important isoprenoid compounds derived from mevalonate. Thus, there has been continued interest in developing hypolipidemic agents that inhibit the enzymes involved specifically in the later stages of cholesterol biosynthesis. Zaragozic acid derivatives were isolated from several microbial species and they exhibited dose-dependent inhibition of cholesterol biosynthesis as potent squalene synthase inhibitors. Viridiofungins, bisabosquals, macrolactins, CJ-15,183, CJ-13,981 and CJ-13,982 were also isolated as mammalian squalene synthase inhibitors of microbial origin. 

Among the diverse reactions carried out by mammalian CYPs are iV-dealkylation, O-deaUcylation, aromatic hydroxylation, A-oxidation, -oxidation, deamination, and dehalogenation (Table 3-2). CYPs are involved in the metabolism of dietary and xenobiotic agents, as well as the synthesis of endogenous compounds that are derived from cholesterol e.g., steroid hormones and bile adds). 

Endocrine hormones are defined as compounds, secreted from specific endocrine cells in endocrine glands, that reach their target cells by transport through the blood. Insulin, for example, is an endocrine hormone secreted from the p cells of the pancreas. Classic hormones are generally divided into the structural categories of polypeptide hormones (e.g., insulin -see Chapter 6, Fig. 6.15 for the structnre of insnlin ), catecholamines such as epinephrine (which is also a nen-rotransmitter), steroid hormones (which are derived from cholesterol), and thyroid hormone (which is derived from tyrosine). Many of these endocrine hormones also exert paracrine or autocrine actions. The hormones that regnlate metabolism are discussed throughout this chapter and in snbseqnent chapters of this text. 

Some compounds normally considered hormones are more difficnlt to categorize. For example, retinoids, which are derivatives of vitamin A (also called retinol) and vitamin D (which is also derived from cholesterol) are nsnally classified as hormones, although they are not synthesized in endocrine cells. 

The ultimate precursor of all the carbon atoms in cholesterol and in the other steroids that are derived from cholesterol is the acetyl group of acetyl-GoA. There are many steps in the biosynthesis of steroids. The condensation of three acetyl groups produces mevalonate, which contains six carbons. Decarboxylation of mevalonate produces the five-carbon isoprene unit frequently encountered in the structure of lipids. The involvement of isoprene imits is a key point in the biosynthesis of steroids and of many other compounds that have the generic name terpenes. Vitamins A, E, and K come from reactions involving terpenes that humans cannot carry out. That is why we must consume these vitamins in our diets vitamin D, the remaining lipid-soluble vitamin, is derived from cholesterol (Section 8.8). Isoprene units are involved in the biosynthesis of ubiquinone (coenzyme Q) and of derivatives of proteins and tRNA with specific five-carbon units attached. Isoprene units are often added to proteins to act as anchors when the protein is attached to a membrane. 

Fig. (1). The mevalonate pathway in animal and numan cells. The pathway describes the role of HMGR in biosynthesis of cholesterol and derivatives, as well as other compounds derived from isoprenylated intermediates.

Oxidation products derived from cholesterol appear to have the greatest potential for health impairment of all classes of compounds isolated from rancid foods up to the present time. Potent angiotoxic effects have been noted (40-44) for several of these compounds leading researchers to hypothesize a likely role... 

The synthesis of mevalonate is required not only for the synthesis of cholesterol but also for the synthesis of a number of other important compounds derived from isopentenyl pyrophosphate, including ubiquinone (CoQ), an important component of the electron transport chain. Therefore, the complete blockage of mevalonate synthesis, even if adequate cholesterol is available in the diet, would be ill-advised. 

Heinrich Otto Wieland (Germany) for his investigations of the constitution of the bile acids and related substances. The bile acids are a set of steroid acids whose synthesis begins in the liver with the production of chloic acid chenodeoxycholic acid (all of which derive from cholesterol). Wieland isolated and determined the structure of a number of these biochemically significant compounds. During his career he also isolated toxins from poisonous frogs and mushrooms. 

The steroids are another group of compounds derived from mevalonic acid. They inciude i synthesis of the steroids is sex hormones such as testosterone and progesterone, and the cholesterol needed to build cell discussed in the online chapter membranes but also implicated in the damage to arteries caused by atherosclerosis. Natural products. ... 

A number of basic ethers of steroids have been prepared by Cantrall et al. [373]. The oxime of CLVIII and compound CLIX appeared to be 20 times more potent than triparanol. However, these substances caused accumulation of desmosterol. Essentially similar results were reported for the diethylamino analog of CLVIII, (U-18,666A), by Phillips and Avigan [374]. Surprisingly, the basic ether derived from cholesterol (CLX) was reported to be inactive [373]. 

Figure 7.42 Steroids are biologically derived from cholesterol, and the ring-numbering scheme used to describe these compounds is shown. Androstane is an example of a steroid molecule with a methyl group at the Cl9 position, an important position for classification. 

---