Thyroxine

Salbutamol works by imitating the action of a hormone thyroxine is a hormone—it is part of the body s control over its metabolic rate. Lack of thyroxine (or rather, of the iodine needed to make it) causes hyperthyroidism, or goitre. Our next synthesis is one that has been used on an industrial scale for the manufacture of synthetic thyroxine (identical with, but less macabre than, naturally extracted thyroxine). 

Thyroxine has two aromatic rings, and you should be prepared to draw upon what you learned about aromatic chemistry in Chapters 22 and 23. It is also an amino acid and, in order to make the synthesis as cheap as possible, the chemists at Glaxo who developed the method used the amino acid tyrosine as a starting material. Nitration of tyrosine puts two nitro groups ortho to the OH group in an electrophilic aromatic substitution (make sure that you understand why ). 

These make the aromatic ring electron-poor, ready for a nucleophilic aromatic substitution that will introduce the other aromatic ring of the target. We need to displace OH, but OH is a bad leaving group, so we must first make it into a tosylate. The trouble is—there is a free amine in the starting material and we do not want that to react with the TsCl. The answer—as you should be able to predict after Chapter 24—is to protect the amine. 

We haven t yet discussed amine protection (that will come later in this chapter) but, since it is the amino group s nucleophilicity that is the problem, it makes sense to react it with an acylating agent an amide is much less nucleophilic than an amine because the nitrogen s lone pair is involved in conjugation with the carbonyl group. The same method was used to reduce the nucleophilicity of aromatic amines in bromination (Chapter 22). The carboxylic acid also needs protecting, and it is made into an ethyl ester. 

Now the tosylation—under the usual conditions—followed by the nucleophilic aromatic substitution (Chapter 23). The leaving group is ortho to two electron-withdrawing groups, and so the substitution pattern is right for nucleophilic aromatic substitution. The nucleophile is 

Finally, electrophilic substitution on the left-hand ring in the manner of the first nitration step puts in the third and fourth iodine substituents of thyroxine. Notice that the free O- (the phenol is ionized with Et2NH) group is more activating (electron-donating) than the ether oxygen atom. 

This synthesis shows how important electrophilic substitution in aromatic compounds is in industrial processes. It involves four separate such reactions as well as three nucleophilic aromatic substitutions. The chemistry of Chapters 22 and 23 is well represented here. 

Many insects attract a mate by releasing a volatile organic compound known as a pheromone. Pheromones are highly specific to species, and provide a cunning means of controlling pests place a pad of cotton wool soaked in male pheromone inside a trap, and in drop all the female pests—no next generation. If insect control is to rely on a supply of the pheromone, that supply has to be synthetic—it takes enormous numbers of squashed insects to provide even a few milligrams of most pheromones. 

We will start by looking at two syntheses of the very simple pheromone of a very common insect—the house-fly. The pheromone, known as muscalure, is a Z-alkene. 

One approach, used by some American chemists in the early 1970s, was very simple. These chemists noted the similarity between the structures of muscalure and the fatty acid known as erucic acid, which is abundant in rapeseed oil, and decided to make muscalure from erucic acid. They first reacted the acid with two equivalents of methyllithium—the first equivalent deprotonates the acid to make a lithium carboxylate salt, while the second reacts with the lithium carboxylate to make a ketone. 

In 1802, the French coroner Fran9ois-Emmanuel Fod e (1764-1835) published a paper, which concerned the combined occurrence of goitre (struma) and cretinism in the Aosta valley (Italy) and in Valais (Switzerland). He systematically collected information about the customs and traditions of the region, its vegetation and minerals, and its folk medicine. Fodere believed that cretinism was a hereditary disease. 

The Scottish phj idan Allan Bums (1781-1813) was the first to differentiate thyroid cancer from goitre. In 1830, a connection was found between diseases of the thyroid gland (Fig. 6.19), and certain heart and eye diseases. In 1835, 

19 The thyroid gland (Latin Glandula thyreoidea) is an organ weighing 20-60 grams, which is located in the neck below the larynx, and surrounds the trachea with two butterfly-shaped lobes. 

Right and left lobes isthmus of Hryroid Trachea 

20 Carl Adolph von Basedow (1799-1854), a renown physician, engaged also in preventive health and hygiene, showed in 1844, that volatile organoarsenic compounds are released from Paris Green by Penicillium brevicaule That explained the cases of intoxication from mouldy wallpapers printed with this pigment. 

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Iodine occurs to a minute extent (less than 0.001 %) in sea water, but is found in greater concentration, combined in organic form, in certain seaweeds, in oysters and in cod livers. Crude Chile saltpetre, or caliche contains small amounts of sodium iodate, NalOj. from which iodine can be obtained (see below). Some insoluble iodides, for example liiose of silver and mercury(II), occur in Mexico. Iodine is found in the human body in the compound thyroxin in the thyroid gland deficiency of iodine in diet causes enlargement of this gland (goitre). 

Iodine compounds are important in organic chemistry and very useful in medicine. Iodides, and thyroxine which contains iodine, are used internally in medicine, and as a solution of KI and iodine in alcohol is used for external wounds. Potassium iodide finds use in photography. The deep blue color with starch solution is characteristic of the free element. 

The term chiral recognition refers to a process m which some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule Very high levels of chiral recognition are common m biological processes (—) Nicotine for exam pie IS much more toxic than (+) nicotine and (+) adrenaline is more active than (—) adrenaline m constricting blood vessels (—) Thyroxine an ammo acid of the thyroid gland that speeds up metabolism is one of the most widely used of all prescription... 

Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

Iodine. Of the 10—20 mg of iodine in the adult body, 70—80 wt % is in the thyroid gland (see Thyroid and antithyroid preparations). The essentiahty of iodine, present in all tissues, depends solely on utilisation by the thyroid gland to produce thyroxine [51-48-9] and related compounds. Well-known consequences of faulty thyroid function are hypothyroidism, hyperthyroidism, and goiter. Dietary iodine is obtained from eating seafoods and kelp and from using iodized salt. 

Thyroid Hormones. Iodine, absorbed as P, is oxidized in the thyroid and bound to a thyroglobulin. The resultant glycoprotein, mol wt 670,000, contains 120 tyrosine residues of which ca two-thirds are available for binding iodine in several ways. Proteolysis introduces the active hormones 3,5,3 -triiodothyronine (T ) and 3,5,3, 5 -tetraiodothyronine (T, (thyroxine) in the ratio Ty.T of 4 1 (121,122). 

Only small amounts of free T are present in plasma. Most T is bound to the specific carrier, ie, thyroxine-binding protein. T, which is very loosely bound to protein, passes rapidly from blood to cells, and accounts for 30—40% of total thyroid hormone activity (121). Most of the T may be produced by conversion of T at the site of action of the hormone by the selenoenzyme deiodinase (114). That is, T may be a prehormone requiring conversion to T to exert its metaboHc effect (123). 

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

ACTH = adrenocortico-trophic hormone T4 = thyroxine T3 = triiodothyronine E, = estradiol T = testosterone I7,20/IP = 17,20/1-dihydroxy-4-pregnen-3-one KT = Il-ketotestosterone VTG = vitellogenin. 

Evidence for chemically mediated disruption of thyroid function in wild reptile populations includes the finding of elevated thyroxine levels in male alligators from Lake Apopka, although a causal relationship with specific chemicals has not been established. ... 

Amphibians. Amphibians are highly susceptible to endocrine disruption during development of the larval form and during metamorphosis. The action of metamorphosis is triggered and controlled by the thyroid gland via an increase in triiodothyronine and a decrease in thyroxine, and differs greatly between oviparous and viviparous species. Experimentally, it has been shown that disruption during this sensitive period can lead to malformations and adverse impacts on immune and reproductive functions. 

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