Steroids biosynthesis inhibition

High-dose progestins are used as last-line endocrine therapy [223]. They inhibit the adrenal steroid biosynthesis. The decrease of estrogen levels is comparable to that caused by the administration of aromatase inhibitors. In post-menopausal women, the progestin megestrol acetate (MGA) decreases serum plasma level of DEAH, androstenedione and cortisol to less than 10% [223,224]. 

Enzyme-catalysed desulfuration of steroids plays an important role in steroid biosynthesis and may provide a source of steroids in the growth and proliferation of breast cancer. Inhibition studies of estrone sulfatase with both steroidal and non-steroidal phosphate compounds have now shown that the best inhibitors contain phosphate mono anions and that the basic structure for inhibition does not require the steroid nucleus. ... 

Svoboda and co-workers (Svoboda and Robbins, 1967 1968 Svoboda et al., 1967 1969) found that triparanol, 2-(4-chlorophenyl)-l-[4-(2-diethylamino-ethoxy)phenyl]-l-(4-tolyl) ethanol and 22,25-diazacholesterol (99) inhibit sterol reductase and also disrupt the normal growth and development of the larvae of tobacco homworm, Manduca sexta. Both compounds are known as inhibitors of steroid biosynthesis in vertebrates. 22,25-DiazacholesteroI is a hypocholeste-rolaemic agent acting as a competitive antagonist of cholesterol. A similar activity was found later for 25-azacholesterol (100). For the determination of the minimum structural requirements of activity, Svoboda and Robbins synthesised and tested... 

Agents that inhibit steps in the steroidogenic pathway and thus alter the biosynthesis of adrenocortical steroids are discussed, as are synthetic steroids that inhibit glucocorticoid action. The effects of corticosteroids are numerous and widespread, and include alterations in carbohydrate, protein, and lipid metabolism maintenance of fluid and electrolyte balance and preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system, and the nervous system. 

Maines, M.D. and R.D. Mayer (1985). Inhibition of testicular cytochrome P-450-dependent steroid biosynthesis by cis-platinum. J. Biol. Chem. 260, 6063-6068. 

There is evidence that anti-inflamnatory steroids can inhibit prostaglandin biosynthesis by the inhibition of arachidonic acid release fron phospholipid stores (17-19). It was of interest, therefore, to examine the effects of an anti-inflairmatory steroid on PGF-M excretion in man (20). Six healthy male subjects (aged 27-34) were screened for any possible predisposition to the side-effects of antiinflammatory steroids Consecutive 24 hour urines were then collected... 

FIGURE 52-6 Biosynthesis/metabolism of steroids in the CNS. The conversion of delta5P to dehydroepiandrosterone (DHA) is postulated but not demonstrated. D5P and DHA inhibit and 3oc,5oc-THP potentiates GABAa receptor function, as summarized in Figure 52-7. Solid arrows indicate demonstrated pathways dotted arrows indicate possible pathways. Metabolic inhibitors of enzymes are indicated by . (Redrawn from [12], with permission.)... 

Pharmacologically active allenic steroids have already been examined intensively for about 30 years [5], Thus, the only naturally occurring allenic steroid 107 had been synthesized 3 years before its isolation from Callyspongia diffusa and it had been identified as an inhibitor of the sterol biosynthesis of the silkworm Bombyx mori (Scheme 18.34) [86d], At this early stage, allenic 3-oxo-5,10-secosteroids of type 108 were also used for the irreversible inhibition of ketosteroid isomerases in bacteria, assuming that their activity is probably caused by Michael addition of a nucleophilic amino acid side chain of the enzyme at the 5-position of the steroid [103, 104]. Since this activity is also observed in the corresponding /3,y-acetylenic ketones, it can be rationalized that the latter are converted in vivo into the allenic steroids 108 by enzymatic isomerization [104, 105],... 

Most of the more recently described allenic steroids bear an allene group at the 17-position, which was usually formed by an SN2 substitution [106] or reduction [86d] process of a suitable propargylic electrophile. Thus, reduction of the pro-pargylic ether 109 with lithium aluminum hydride followed by deprotection of the silyl ether resulted in the formation of the allenic steroid 110, which irreversibly inhibits the biosynthesis of the insect moulting hormone ecdysone (Scheme 18.35) [107]. 

Alternative, also stereoselective, routes to allenic steroids take advantage of cationic cyclization reactions [108] or [2,3]-sigmatropic rearrangements [109]. For example, the allenic Michael acceptor 112 was prepared with 57% chemical yield by reaction of mestranol (111) with diethyl chlorophosphite and was found to inhibit the sterol biosynthesis of the pathogen responsible for Pneumocystis carinii pneumonia (PCP), the most abundant AIDS-related disease (Scheme 18.36) [110]. 

By far most of the reports on addition reactions of hetero-nucleophiles to activated dienes deal with sulfur-nucleophiles17,48,80,120-137, in particular in the synthesis of 7/3-sulfur-substituted steroids which, like their carbon-substituted counterparts (Section n.A), are of interest because of their ability to inhibit the biosynthesis of estrogens80,129-137. Early investigations17,120-122 concentrated on simple acyclic Michael acceptors like methyl sorbate and 2,4-pentadienenitrile. Bravo and coworkers120 observed the formation of a 3 1 mixture of the 1,6- and 1,4-adduct in the reaction of methyl sorbate with methanethiol in basic medium (equation 39). In contrast to this, 2,4-pentadienenitrile adds various thiols regioselectively at C-5, i.e. in a 1,6-fashion (equation 40)17,121,122, and the same is true for reactions of this substrate with hydrogen sulfide (equation 41), sodium bisulfite and ethyl thioglycolate17. 

The dose of aciclovir in patients with renal impairment should be reduced as aciclovir is eliminated by the renal system. Most penicillins are eliminated by the renal system and hence dose reduction of amoxicillin is required in cases of renal impairment. Non-steroidal anti-inflammatory drugs cause the inhibition of the biosynthesis of prostaglandins involved in the maintenance of renal blood flow. This may precipitate acute renal insufficiency in patients with renal impairment. Furthermore non-steroidal anti-inflammatory drugs tend to cause water and sodium retention and hence aggrevate renal impairment. 

The subsequent conversion of HMG-CoA into MVA involves a two-step reduction of the thioester group to a primary alcohol (see Section 7.11), and provides an essentially irreversible and rate-limiting transformation. Drug-mediated inhibition of this enzyme, HMG-CoA reductase (HMGR), can be used to regulate the biosynthesis of the steroid cholesterol. High levels of blood cholesterol are known to contribute to the incidence of coronary heart disease and heart attacks. 

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