Active steroids

The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

It is also used ia the preparation of biologically active steroids where the fluorine is added in a cis configuration to the double bond (13,14). 

The stereocontroUed syntheses of steroid side chains for ecdysone, cmstecdysone, brassinoHde, withanoHde, and vitamin D have been reviewed (185). Also, other manuscripts, including reviews on the partial synthesis of steroids (186), steroid dmgs (187—189), biologically active steroids (190), heterocychc steroids (191), vitamin D (192), novel oxidations of steroids (193), and template-directed functionali2ation of steroids (194), have been pubhshed. 

Steroids are plant and animal lipids with a characteristic tetracyclic carbon skeleton. Like the eicosanoids, steroids occur widely in body tissues and have a large variety of physiological activities. Steroids are closely related to terpenoids and arise biosynthetically from the triterpene lanosterol. Lanosterol, in turn, arises from cationic cyclization of the acyclic hydrocarbon squalene. 

Purdy, RH, Morrow, AL, Moore, PHJ and Paul, SM (1991) Stress-induced elevations of a amino butyric acid type A receptor-active steroids in the rat brain. Proc. Natl. Acad. Sci. USA 88 4553 557. 

Retinoic acid works through a family of retinoic acid receptors. Activated retinoic acid receptors act as transcription factors, just as activated steroid receptors do (chapter 20), and alter the transcription of genes affecting cell division and survival. This underlies both the teratogenic potential and the therapeutic utilities of these potent molecules. 

In Figure 3, the active steroid (triamcinolone acetonide) and preservative (benzyl alcohol) are determined from a steroid cream. The higher molecular weight components of the cream base are well separated from the analytes. The ability to elute all the components of a cream or ointment in a SMGPC analysis gives an important sample preparation advantage over competing separation techniques. 

Examples of co-activators are the steroid receptor co-activator (SRC) family [48] and the components of the mammalian mediator complex, which possesses chromatin remodelling ability and tethers activated steroid hormone receptors to the basal transcription machinery [49]. Additional co-... 

Furthermore, post-translational modifications activate steroid hormone receptors in a ligand-independent fashion (Fig. 5), as shown for the ERa which is phosphorylated on serine residue 118 in the AF-1 domain by the Erkl/2 kinase [71]. In vitro, the serine-118 phosphorylated ERa is transcriptionally active in a ligand-independent fashion. 

TAS-108 (SR16234) is a novel and orally active steroidal compound with a proposed additional molecular mode-of-action that is different from that of SERMs such as tamoxifen and raloxifene [157]. TAS-108 is a full estrogen receptor-a antagonist, and it should also recruit co-activator transcriptional intermediary factor 2 to ER-j6, which may have a preventive effect on bone loss [157]. 

Dne to their estrogenic activity, steroids have been inclnded in preliminary lists of EDCs. These chemicals are even more diffnsely fonnd in waters, also dne to sensitivities nowadays achieved in advanced LC/MS and LC/MS/MS instrumentations. The interfaces most widely nsed for the LC/ MS determination of steroids, drngs, surfactants, and organic pollntants in an aqnatic environment are ESI, which is particnlarly well suited for the analysis of polar componnds, and APCI, that is more effective in the analysis of medium- and low-polarity snbstances. LC/MS and LC/MS/MS have been mostly applied in the SIM mode and in the MRM mode. 

The efficient asymmetric intramolecular aldolization of certain triketones with a reflective symmetry axis using chiral amino acid catalysts has been reported with a view at obtaining optically active steroids. 

A chiral recognition was observed in aminolysis of 3-acyl-4(R)-methoxycarbonyl-l,3-thiazolidine-2-thione, a derivative of (R)-cysteine, by racemic amines to give an optically active amide [(S)-excess] and amine [(R)-excess]264). In the reaction of cyclic meso-1,3-diols with chiral N-protected phenylalanyl chlorides, Yamada et al.26S) observed the preferential formation of one of the two possible diastereomeric monoesters, which has been used for the synthesis of optically active steroids 266) and prostaglandins 267). 

An interesting and fimctionally important aspect of transcriptional activators is that one and the same protein can act as both an activator and a repressor. The alternative functionality is determined by the sequence environment, the presence of other transcriptional activators (steroid receptors, see ch. 4), by specific repressors or by low molecular weight effectors. Examples are the receptors for vitamin A acid, which, in the absence of its ligand, represses the genes with cognate DNA elements. TTie repression is exerted in the DNA-bound form. In the presence of its hgand, vitamin A acid, the same receptor acts as a transcriptional activator (see ch. 4). 

Abiraterone is the newest of the steroid synthesis inhibitors to enter clinical trials. It blocks 17a-hydroxylase (P450cl7) and 17,20-lyase (Figure 39-1), and predictably reduces synthesis of cortisol and gonadal steroids in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and has been studied in the treatment of refractory prostate cancer. 

FIGURE 21-47 Side-chain cleavage in the synthesis of steroid hormones. Cytochrome P-450 acts as electron carrier in this mixed-function oxidase system that oxidizes adjacent carbons. The process also requires the electron-transferring proteins adrenodoxin and adrenodoxin reductase. This system for cleaving side chains is found in mitochondria of the adrenal cortex, where active steroid production occurs. Pregnenolone is the precursor of all other steroid hormones (see Fig. 21-46). 

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

Plant Sterols. Sterols have been identified in almost all types of living organisms and can be isolated, in varying quantities, from many different plants. Similar to cholesterol, plant sterols have a structural and functional role in biological systems and serve as intermediates in the biosynthesis of an assortment of biologically active steroids. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

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