Steroid molecules

The vitamins D ate 9,10-secosteroids, that is, steroid molecules with an opened 9,10 bond of the B-ring. The relationship between the provitamin steroid (pethydto-l,2-cyclopentanophenanthrene ring system) and the 9,10-secosteroid nucleus is shown in stmctures (5) and (6), cholestane and 9,10-secocholestane (calcitane), respectively. 

Although lead tetraacetate can attack many polar and nonpolar functions in the steroid molecule, its greatest reactivity is towards vicinal diols. These diols are generally cleaved so rapidly under stoichiometric conditions that other alcohol functions in the molecule need not be protected. Thus lead tetraacetate in acetic acid at room temperature splits the 17a,20-diol group in (9) to yield the 17-ketone (10), the allylic A -3jS-alcohol remaining intact during this oxidation. Since lead tetraacetate is solublein many anhydrous... 

A -dien-3-ol ethers gives rise to 6-substituted A" -3-ketones. 6-Hydroxy-A" -3-ketones can be obtained also by autooxidation.Structural changes in the steroid molecule may strongly affect the stability of 3-alkyl-A -ethers. Thus 11 j5-hydroxyl and 9a-fluorine substituents greatly increase the lability of the enol ether/ while halogens at C-6 stabilize this system to autooxidation and acid hydrolysis. 

Because of Asymmetry in the Steroid Molecule, Many Stereoisomers Are Possible... 

Some steroid molecules (estrone, estradiol, and estriol) have phenolic hydroxyl in the ring A (Figure 29.12) and therefore, are able to react as free radical scavengers. In 1987, Japanese authors [264,265] showed that all these compounds inhibited iron adriamycin- or iron ADP-ascorbate-dependent phospholipid and liposomal lipid peroxidation. Later on, most attention was drawn to the study of antioxidative properties of estradiol-17(3 (estrogen E2) it has been proposed that E2 antioxidant activity may contribute to cardioprotection observed after estrogen therapy in postmenopausal women. The necessity for the phenolic hydroxyl has been shown by studying the effects of several estrogens on LDL oxidation. It was found [266]... 

Steroid molecules can be constructed by applying the benzocyclobutene-o-xylylene method. When the compound (329) was heated in o-dichlorobenzene at 180 °C for 14 hours, the compound (330) was isolated, which could be converted by a number of steps to the steroid acetate (331) u4). 

The fact that the dendritic shell can produce localized microenvironments has been used by Diederich et al. who developed water-soluble dendritic cyclophanes (dendrophanes) as models for globular proteins (Figure 16.13) [5, 170, 171], These dendrimers contain well-defined cyclophane recognition sites as initiator cores for the complexation of small aromatic guests [172-174] and steroids [174-176], Enlargement of the cyclophane core could be used as a tool to complex larger steroid molecules. 

Astatosteroids. Several complex steroid molecules have been astatinated via their chloromercuriderivatives a mixture of 2-as-tatoestradiol (I), 4-astatoestradiol (II), and 2-astato-4-iodoestradiol (III) was obtained with yields of 55, 19, and 18%, respectively (170). Estradiol was mercurated by Hg(CH3COO)2 in a C2H50H-water solution for 16 hours at room temperature, and then allowed to react with At in H2SO4 in the presence of KI3 for 1 hour. The products were separated and identified by TLC (170). 

Gels are obtained for concentrations shown in the temperature-concentration phase diagram (Figure 1). Electron spin resonance (ESR) shows (10) that for a given temperature only a fraction (p) of the initial steroid concentration is transferred from the solution to the gel network. The picture of this gel is thus of a supersaturation gel there is a dynamic equilibrium between free molecules in solution and aggregated steroid molecules included in the long objects which constitute the gel network. The free steroid molecules concentration at a temperature where the gel state is stable is (1-p), while C p is the steroid concentration within the solid-iike gel aggregates. 

Within the basic structure of the steroid molecule (Fig. 60.4), a 4,5 double bond and a 3-ketone group are needed for typical steroid activity. A hydroxyl group on Cll is needed for glucocorticoid activity (corticosterone) but is not required for sodium-retaining activity (desoxycorticosterone). The addition of a hydroxyl group on C17, which converts corticosterone to cortisol, also increases glucocorticoid activity. 

The ultimate aim in altering the steroid molecule is to decrease sodium-retaining activity and to increase antiinflammatory glucocorticoid activity. 

Testosterone synthesis from pregnenolone can occur along two distinct metabolic pathways (Fig. 63.1). The names given to these two routes of metabolism refer to the position in the steroid molecule where an unsaturated bond is maintained. Thus, in the delta-4 pathway an unsaturated position is between C4 and C5 of ring A, whereas in the delta-5 pathway, the unsaturated position is between C5 and C6 of ring B. In the human testis, the delta-5 pathway is the predominant (but not exclusive) one used for the biosynthesis of testosterone. 

As is the case for steroid molecules of natural origin, cortisone is optically active and exhibits optical rotation. The following specific rotation results have been measured at the sodium-D line (546 nm) at 25C ... 

Upon entering the cell, the steroid molecule initially binds to the steroid receptor protein (E domain) to form the steroid-hormone-receptor complex. This complex concomitantly binds to an additional eight or more other peptides (also via the E domain) these peptides are termed chaperone peptides and consist of macromolecules such as heat shock proteins (e.g., hsp70, hsp90). The chaperone peptides help to twist and turn the steroid receptor protein into an improved three-dimensional shape for final and optimal binding of the steroid molecule. Following binding of the chaperone peptides, the steroid-hormone-receptor complex becomes a mature steroid-hormone-receptor... 

Conformational isomerism in cyclohexane Cyclohexane (C6H12) is a six-carbon cyclic alkane that occurs extensively in nature. Many pharmaceutically important compounds possess cyclohexane rings, e.g. steroidal molecules. If we consider cyclohexane as a planar and regular hexagon, the angles are 120° (cf. 109.5° for sp hybrids). 

Synergy with catecholamines. The lipid soluble steroid molecules enter cells and bind the intracellular receptors. This results in up-regulation of specific genes, changes in RNA production, and protein synthesis. 

The natural adrenocortical hormones are steroid molecules produced and released by the adrenal cortex. Both natural and synthetic corticosteroids are used for the diagnosis and treatment of disorders of adrenal function. They are also used—more often and in much larger doses—for treatment of a variety of inflammatory and immunologic disorders. 

Anastrozole, a selective nonsteroidal inhibitor of aromatase (the enzyme required for estrogen synthesis. Figures 40-2 and 40-5), is effective in some women whose breast tumors have become resistant to tamoxifen (see Chapter 54). Letrozole is similar. Exemestane, a steroid molecule, is an irreversible inhibitor of aromatase. Like anastrozole and letrozole, it is approved for use in women with advanced breast cancer (see Chapter 54). 

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