Steroid hormones chemical synthesis

In the early 1930 s, when the prime research aim was the commercial synthesis of the sex hormones (whose structures had just been elucidated), the principal raw material available was cholesterol extracted from the spinal cord or brain of cattle or from sheep wool grease. This sterol (as its 3-acetate 5,6-dibromide) was subjected to a rather drastic chromic acid oxidation, which produced a variety of acidic, ketonic and hydroxylated products derived mainly by attack on the alkyl side-chain. The principal ketonic material, 3j -hydroxyandrost-5-en-17-one, was obtained in yields of only about 7% another useful ketone, 3 -hydroxypregn-5-en-20-one (pregnenolone) was obtained in much lower yield. The chief acidic product was 3j -hydroxy-androst-5-ene-17j -carboxylic acid. All three of these materials were then further converted by various chemical transformations into steroid hormones and synthetic analogs ... 

There are five basic sources of pharmaceuticals. By dollar value of products, fermentation is probably the most important, whereas by tonnage, chemical synthesis is dominant. Fermentation is used for antibiotics such as penicillins and tetracyclines. Chemical synthesis provides drugs such as the psychotropics and antihistamines. Animal extracts provide hormones. Biological sources lead to vaccines and serums. Vegetable extracts provide steroids and alkaloids. The top ten pharmaceutical companies in order of revenues are the following Merck, Pfizer, Bristol-Myers Squibb, Johnson ... 

Table 1.10. Some pharmaceutical substances originally isolated from animal sources. While some are still produced by direct extraction from the native source, others are now also produced by direct chemical synthesis (e.g. peptides and some steroids), or by recombinant DNA technology (most of the pol5 peptide products). Abbreviations hGH = human growth hormone FSH=follicle stimulating hormone hCG=human chorionic gonadotrophin HSA=human serum albumin HBsAg=hepatitis B surface antigen...

While these steroids can be extracted directly from human tissue, in most instances they can also be synthesized chemically. Direct chemical synthesis methodology has also facilitated the development of synthetic steroid analogues. Many such analogues exhibit therapeutic advantages over the native hormone, e.g. they may be more potent, be absorbed intact from the digestive tract, or exhibit a longer duration of action in the body. The majority of sex steroid hormones now used clinically are chemically synthesized. 

The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the oxidative metabolism of drugs and other chemicals. These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds, such as steroid hormones and prostaglandins. 

Increased clearance of steroid hormones due to induction of hepatic biotransformation enzymes following chemical exposure often has been cited as a possible mechanism by which toxicants could lower circulating testosterone or 17/3-estradiol levels. While enhanced clearance of sex steroids has been demonstrated following chemical exposure and induction of hepatic biotransformation enzymes, elegant feedback control mechanisms tend to ensure that more hormone is produced and homeostasis is maintained (Figure 17.2). Enhanced clearance of sex steroids can contribute to endocrine disruption if the toxicity also results in impaired hormone synthesis (i.e., gonadal toxicity or interference with the feedback control of hormone synthesis). 2,3,7,8-Tetrachlorodibenzodioxin appears to lower circulating sex steroid levels via this dual effect. 

Cadmium decreases testosterone production by preventing the synthesis of cholesterol, a precursor of all steroid hormones. Other chemicals that interfere with steroid hormone synthesis include aminoglute-thimide, cyanoketone, and ketoconazole. Copper chelating compounds, such as dithiocarbamates, metam sodium, and carbon disulfide, suppress the conversion of dopamine to norepinephrine and subsequently to epinephrine. 

SITOSTEROL Sitosterol is another phytosterol and is an analogue of stigmasterol with a saturated side chain. It is obtained from soy oil and com oil. The side chain cannot be degraded chemically, but microbiologically it is possible to produce intermediates of valne to the steroid industry. Sitosterol can therefore be used as a starting material for the synthesis of steroid hormones. 

Combined use of microbial enzymes as biocatalysts with chemical synthesis has its origin in the steroid transformation developed in the USA in the early 1950s. Arima and his group [11] invented a unique microbial conversion process, in which the aliphatic side-chain of cholesterol was cleaved to produce a steroid core as a starting material for chemical synthesis of steroid hormones. Yamada et al. discovered the reverse reaction of the pyridoxal-containing L-amino acid lyases and applied them to synthesize L-tryptophan and l-DOPA [12] from pyruvate, ammonia and corresponding aromatic compounds. Since these early achievements, a variety of unique processes with newly screened microbial enzymes as biocatalysts have been invented. 

The endoplasmic reticulum (ER) is a network of membranous tubules within the cell consisting of smooth endoplasmic reticulum (SER), which lacks ribosomes, and rough endoplasmic reticulum (RER), which is studded with ribosomes (Eig. 10.23). The SER has a number of functions. It contains enzymes for the synthesis of many lipids, such as triacylglycerols and phosphohpids. It also contains the cytochrome P450 oxidative enzymes involved in metabohsm of drugs and toxic chemicals such as ethanol and the synthesis of hydrophobic molecules such as steroid hormones. Glycogen is stored in regions of liver cells that are rich in SER. 

Shortly after testosterone was isolated, Butenandt and Hanisch (13) reported its synthesis. In that same year, extracts of urine from males were shown to cause nitrogen retention as well as the expected androgenic effects (14). Many steroids with androgenic activity have subsequently been synthesized. Steroid hormones may have many potent effects on various tissues, and slight chemical alterations of androgenic steroids may increase some of these effects without altering others. 

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