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Estrane

Androstane

Pregnane

Pregnane

Pregnane

Cholestane

Cholane

' The parent ring structures and active steroid are given in Figure 2-3.

The parent ring structures are used as the stem term in constructing the formal nomenclature of any steroid (will be discussed later in the chapter).

The biosynthetic pathway of production of each of these general steroid classes will be presented separately later in this chapter. A discussion of their hormonal and biochemical aspects will appear later in individual chapters.

C. Structural Modification

The basic ring structures presented in Figure 2-3 can be subjected to a wide array of modifications by the introduction of hydroxyl or carbonyl substituents and unsaturation (double or triple bonds). In addition, heteroatoms such as nitrogen or sulfur can replace the ring carbons, and halogens and sulfhydryl or amino groups may replace steroid hydroxyl moieties. Furthermore, the ring size can be expanded or contracted by the addition or removal of carbon atoms. The consequences of these structural modifications are designated by application of the standard organic nomenclature conventions for steroids. The pertinent aspects of this system are summarized in Table 2-2. Prefixes and suffixes are used to indicate the type of structural modification. Any number of prefixes may be employed (each with its own appropriate carbon number and specified in the order of decreasing preference of acid, lactone, ester, aldehyde, ketone, alcohol, amine, and ether); however, only one suffix is permitted.

Table 2-3 tabulates the systematic and trivial names of many common steroids. All of these formal names are devised in accordance with the official nomenclature rules for steroids laid down by the International Union of Pure and Applied Chemistry (IUPAC).1

D. Asymmetric Carbons

An important structural feature of any steroid is recognition of the presence of asymmetric carbon atoms and designation in the formal nomenclature of

1 The IUPAC definitive rules of steroid nomenclature are presented in full in Pure & Applied Chemistry 31, 285-322 (1972) or Biochemistry 10, 4994-4995 (1971).

the structural isomer that is present. Thus, reduction of pregnan-3-one to the corresponding 3-alcohol will produce two epimeric steroids (see Figure 2-4). The resulting hydroxyl may be above the plane of the A ring and is so designated on the structure by a solid line; it is referred to as a 3/3-ol. The epimer, or 3a-ol, has the hydroxyl below the plane of the A ring and is so designated by a dotted line for the C • • • OH bond. If the a- or /3-orientation of a substituent group is not known, it is designated with a wavy line (C ~ OH).

Another locus where asymmetric carbon atoms play an important role in steroid structure determination is the junction between each of the A, B, C, and D rings. Figure 2-5 illustrates these relationships for cholestanol and coprostanol. Thus, in the 5a-form, the 19-methyl and a-hydrogen on carbon-5 are on opposite sides of the plane of the A: B ring; this is referred to as a trans fusion. When the 19-methyl and /3-hydrogen on carbon-5 are on the same side of the A: B ring fusion, this is denoted cis fusion. In the instance of cis fusion of the A: B rings, the steroid structure can no longer be drawn in one plane (as in 24). Thus, in all 5/3-steroid structures that have cis fusion between rings A and B, the A ring is bent into a second plane that is at approximately a right angle to the B: C: D rings (see 24 of Figure 2-5).

Thus, each of the ring junction carbons is potentially asymmetric, and the naturally occurring steroid will have only one of the two possible orientations at each ring junction. Although there are two families of naturally occurring steroids with either cis or trans fusion of the A:B rings, it is known that the ring fusions of B:C and C:D in virtually all naturally occurring steroids are trans.

In the estrogen steroid series in which the A ring is aromatic, there is no cis-trans isomerism possible at carbon-5 and -10. Also, as will become apparent upon consideration of the metabolism of many of the steroids that contain a 4-ene-3-one structure in ring A (see 1215, Figure 2-3), a family of structural isomers may be produced. Thus, when biological reduction of the 4-ene occurs, two dihydro products will arise, one with

Progestins

5a-Pregnane (C—21) (8)

Cholane iC-24) 111)

5a-Androstare (C-19) 5a-Estrane (C-18) Cholesterol iC-27) (3)

Cholane iC-24) 111)

Bile acids

5a-Androstare (C-19) 5a-Estrane (C-18) Cholesterol iC-27) (3)

Bile acids

Progestins

Structure 256 Isomers Cholesterol

FIGURE 2-3 Family tree of the seven principal classes of steroids (bottom row) that are structurally derived from the parent cholestane (top row).

Cholic acid (18)

Progesterone (12) Cortisol (13) Aldosterone (14) Testosterone (15) Estradiol (16) 1,25-Oihydroxyvitamin D3 ¡17)

FIGURE 2-3 Family tree of the seven principal classes of steroids (bottom row) that are structurally derived from the parent cholestane (top row).

Cholic acid (18)

TABLE 2-2 Steroid Nomenclature Conventions

Modification Prefix Suffix

Hydroxyl group (OH) Hydroxy- -ol

Hydroxyl above plane of ring ^-Hydroxy

Hydroxyl below plane of ring a-Hydroxy -

Carboxylic acid (COOH) Carboxy- -oic acid

Saturated ring system - -ane

One less carbon atom Nor-

One additional carbon atom Homo-

One additional oxygenation Oxo-

One less oxygen atom Deoxy-

Two additional hydrogen atoms Dihydro-

Two less hydrogen atoms Dehydro-

Two groups on same sides of plane cis-

Two groups on opposites sides of transplane

Other ring forms (rings A and B trans, Allo-as in allopregnane)

Opening of a ring (as in vitamin D) Seroconversion at a numbered carbon from Epi-conventional orientation (as in epicholesterol or 3a-cholesterol)

A:B cis fusion and one with A:B trans fusion. Two additional steroids will be generated by reduction of the 3-oxo group, giving rise to a total of four possible tetrahydro products of the 3-oxo-4-ene. Under normal biological circumstances, all four structural isomers can be detected. These relationships are summarized in Figure 2-6 for the male sex steroid androst-4-ene-3,17-dione.

The side chain is a third domain of the steroid structure where asymmetry considerations are important. Historically, interest first centered on carbon-20 of the cholesterol side chain, although side chain asymmetry is also now known to be crucial for the insect steroid hormone ecdysterone, for a number of vitamin D metabolites, and in the production of many bile acids. While the a-fi notation is satisfactory for the designation of substituents of the A, B, C, and D ring structures, this terminology is not applicable to the side chain. This is because there is free rotation of the side chain at the carbon-17-carbon-20 bond; thus, the side chain may assume a number of orientations in relation to the ring structure (see Figure 9-7A).

The chemical determination and designation of the absolute configuration of asymmetric carbon atoms on the side chain according to formal rules of nomenclature are complex. The "sequence rules" of Cahn2 must be applied. These rules describe operational procedures to generate unambiguous nomenclature specifications of the absolute configuration of all chemical compounds whether they be steroids, sugars, amino acids, thiopolymers, etc. A detailed consideration of these rules is beyond the scope of this book; however, a brief consideration applicable to the steroid side chain is given.

Asymmetric carbon atoms joined to four different substituents can be designated as Ca^cd. Application of the sequence rule requires determination of the a, b, c, and d groups joined to the carbon atom under consideration. The steps of application of the sequence rule are summarized in the following (see Figure 2-7):

1. The determination of priority is first based on the atomic weights of the four atoms attached to the asymmetric carbon, with higher atomic weights having priority over lower atomic weights (e.g., i60 > wc > i2C > H) Thus, for asymmetric carbon-20 on the cholesterol side chain, the three carbons, 17, 21, and 22, have priority over the hydrogen atom.

2. In instances where identical atoms are bonded to the asymmetric carbon atom (e.g., carbon-17, -21, and -22 bonded to the asymmetric carbon-20 of the steroid side chain), the determination of priority is made by reference to the next atom in each radical and evaluation of the total sum of the atomic weights directly bonded to it. Again, the carbon with higher atomic weight claims higher priority. In some instances it may be necessary to evaluate the substituents on a third atom distal to the asymmetric carbon. The sums of the directly bonded atomic weights are as follows: carbon-17, 12 + 12 + 1 ^ 25; carbon-22, 12 + 1 + 1 = 14; and carbon-21, 1 + 1 + 1=3. Thus, carbon-17 has priority over carbon-22, which has priority over carbon-21.

3. The chirality, or right- or left-handedness of the asymmetric carbon, is determined by visualizing the tetrahedron comprising the four substituent atoms bonded to the asymmetric carbon (see the example in Figure 2-7). The chirality is determined by looking at the atom with lowest priority (atom d) through the center of the opposite triangular face. Thus, the tetrahedron around the asymmetric carbon under

2 The sequence rule is described in detail by Cahn, Ingold, and Prelog (1960); a simplified description is given by Cahn (1964).

TABLE 2-3 Trivial and Systematic Names of Some Common Steroids

Trivial name

Systematic name

Aldosterone

18,11-Hemiacetal of ll/3,21-dihydroxy-3,20-dioxopregn-4-en-18-al

Androstenedione

Androst-4-ene-3,17-dione

Androsterone

3a-Hydroxy-5a-androstan-17-one

Cholesterol

Cholest-5-en-3/3-ol

Cholic acid

3a, 7a, 12a-Trihydroxy-5/3-cholan-24-oic acid

Corticosterone

lljS,21-Dihydroxypregn-4-ene-3,20-dione

Cortisol

ll/3,17,21-Trihydroxypregn-4-ene-3,20-dione

Cortisone

17,21-Dihydroxypregn-4-ene-3,ll,20-trione

Dehydroepiandrosterone

3/3-Hydroxy-5-androsten-17-one

Deoxycorticosterone

21-Hydroxypregn-4-ene-3,20-dione

Ergosterol

5,7,22-Ergostatrien-3/3-ol

Estrone

3-Hydroxyestra-l,3,5(10)-trien-17-one

Estriol

Estra-l,3,5(10)-triene,3,16a,17/3-triol

Etiocholanolone

3a-Hy droxy-5j8-androstan-l 7-one

Lanosterol

8,24-Lanostadien-3/3-ol

Lithocholic acid

3a-Hydroxy-5jS-cholan-24-oic acid

Progesterone

Pregn-4-ene-3,20-dione

Testosterone

17/3-Hy droxyandrost-4-en-3-one

Vitamin D3 (cholecalciferol)

9,10-Seco-5,7,10(19)-cholesta-trien-3/3-ol

Vitamin D2 (ergocalciferol)

9,10-Seco-5,7,10(19),22-ergostatetraen-3j3-ol

consideration should be oriented so that the group of lowest priority (d) points away from the viewer. Then, if the other three atoms, a, b, and c, are arranged in clockwise order, the asymmetry is designated rectus (R) (right) or right-handed. Conversely, if the a, b, and c atoms are arranged in counterclockwise order, the asymmetry is designated sinister (S) (left) or left-handed. Two examples of the application of the sequence rule are provided in Figure 2-7.

Figure 2-8 identifies all of the asymmetric carbon atoms of cholesterol. In the parent sterane ring structure (6, Figure 2-2) there are six asymmetric carbons. Introduction of the A5,6-double bond deletes one asymmetric center, whereas addition of the eight-carbon side chain adds one asymmetric carbon at position 17. Carbon-20 of the side chain is also asymmetric. Finally, introduction of a hydroxyl group on carbon-3 creates still another asymmetric center. Thus, there are a total of eight asymmetric carbons or 28 = 256 possible structural isomers. Considering that cholesterol is the most prevalent naturally occurring steroid, it is an impressive testament to evolutionary events and to the specificity of the many enzymes involved in the biosynthesis of cholesterol that only one major sterol product is present in mammalian systems.

E. Conformation of Steroids

The steroid nucleus, sterane, is composed of three cyclohexane rings and one cyclopentane ring. The six carbon atoms of a cyclohexane ring are not fixed rigidly in space, but are capable of interchanging through turning and twisting between several structural arrangements in space called conformations. The two principal conformations of a cyclohexane ring are the chair (32) and boat (33) forms (see Figure 2-9).

Each of the two substituent groups on the six carbon atoms of the cyclohexane ring may exist in either the general plane of the ring and are designated as equatorial (e) or a plane perpendicular to the ring plane and are designated as axial (a). For the equatorial bonds, it is possible to superimpose on the equatorial notation an indication of whether they are below (a) or above (/3) the general plane of the ring. Cyclohexane is highly conformationally mobile, interchanging between the boat and chair forms many thousands of times per second. The most stable form of the cyclohexane ring is the chair form; in this conformer there is a greater interatomic distance between the equatorial and axial hydrogens than in the boat form. Figure 2-5 illustrates the nature of all of the equatorial (e) and axial (a) hydrogens on the cholestane and coprostane ring structures.

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