Thyronine derivatives

The thyroid protein, thyroglobulin, contains 3-monoiodotyrosine, 3,5-diiodotyrosine and several iodinated thyronine derivatives (Salvatore and Edelhoch 1973). lodohistidines may also be present in this protein. 3-Bromotyrosine has been reported in serum proteins (Firnau and Fritze 1972). Methods for separating and analyzing these and other halogenated tyrosines are presented in 2.2.3. 

Further st udy of the effect of various analogs of thyroxine on the swelling of mitochondria in vitro (Shaw el al., 19,59) has revealed that thyronine derivatives la( king a halogen substitution in cither ring of the diphenyl ether have little or no activity there is a similar structural requirement for... 

Compounds formed by cleavage of the aromatic ring and recyclization of l-DOPA (D 22.1.4) lodinated tyrosine and thyronine derivatives (D 22.1.5)... 

The reaction of thyronine derivative 56b under the same conditions yielded the deiodinated product 57b (65% from 56b) and selenenyl iodide 55 (55% from 49). These results provide the chanical evidence for the proposed deiodination of a 2,6-diiodophenol derivative by a selenol. It is notable that, in the reaction of 56b, only deiodination at the outer ring took place—similar to the conversion of T4 to T3 in the ID-1 catalytic cycle. 

PNP-DTP has been used to photoaffinity label the thyroid hormone nuclear receptors in intact cells by preparing a derivative of 3,5,3 -triiodo-L-thyronine with the crosslinker (Pascual et al., 1982 Casanova et al., 1984). Effective photoreactive conjugation was found to occur after irradiation with UV light at 254 or 310 nm. 

Triiodothyronine is not classified as a thyroid inhibitor it is an amino acid derivative of thyronine and results from the oxidative coupling of monoiodotyrosyl and diiodotyrosyl residues. Iodine 131, the most often used radioisotope of I, is rapidly absorbed by the thyroid and is deposited in follicular colloid. Prom the site of its deposition, Bll causes fibrosis of the thyroid subsequent to pyknosis and necrosis of the follicular cells. 

The thyroid hormone thyroxine (tetraiodo-thyronine, T4) and its active form triiodothyronine (T3) are derived from the amino acid tyrosine. The iodine atoms at positions 3 and 5 of the two phenol rings are characteristic of them. Post-translational synthesis of thyroxine takes place in the thyroid gland from tyrosine residues of the protein thyro-globulin, from which it is proteolytically cleaved before being released, iodothyronines are the only organic molecules in the animal organism that contain iodine. They increase the basal metabolic rate, partly by regulating mitochondrial ATP synthesis, in addition, they promote embryonic development. 

Fig. 3 (a) HPLC chromatogram of standard solution containing tyrosine, thyronine, and some of their iodo derivatives. Detection was... 

The generic term thyroid hormones refers to the iodinated amino acid derivatives T3 (3,3, 5-triiodo-L-thyronine) and T4 (3,3, 5,5 -tetraiodo-L-thyronine), the only iodinated hormones produced endogenously. T3 is the biologically active hormone and is, for the most part, produced from T4 in extrathyroidal tissues. T4 lacks significant bioactivity and is a hormone precursor however,... 

Structure of 3,3, 5,5 -tetraiodo-L-thyronine (T4). T4 is a substituted tyrosine or a diphenylether derivative of alanine. Positions in the outer phenolic ring have prime designations, in contrast to those in the inner ring. T4 is iodinated at positions 3 and 5 in both rings. [Modified and reproduced with permission from V. Cody, Thyroid hormone interactions molecular conformation, protein binding, and hormone action. Endocr. Rev. 1,140 (1980). (c)1980by the Endocrine Society.]... 

The reaction of phenols with diaryliodonium salts leads to the diaryl ethers in modest to good yields, depending on the substrate and the reaction conditions.31 0>5l-i03 number of studies have dealt with this reaction as it was involved in the synthetic sequence towards diaryl ethers of biological importance, such as bisbenzylisoquinoline alkaloidsl04 or thyronine and tyrosine derivatives.105 The reaction requires relatively harsh conditions, as it is performed under reflux of the solvent. In the case of unsymmetrical diaryliodonium salts, the less electron-rich aryl group of the iodonium salt is preferentially transferred. 

Despite the fact that they can be much more reactive than nitrenes, carbene derivatives are less frequently cited in reports on photoaffinity labels. Two such derivatives of thyroid hormone have been described in which the amino group of the alanine side chain of 3,5,3 -triiodo-L-thyronine or 3,5,3, 5 -tetraiodo-L-thyronine was derivatized with 2-diazo-3,3,3-trifluoropropionate (246). Irradiation at 254 nm of these compounds with several cell lines yielded low incorporation of reagent (0.5-13.5%) into two forms of thyroid hormone receptor proteins. Low incorporation was also characteristic of early reports of photoaffinity labeling (e.g., 247) in which 0 -ethyl-2-diazomalonyl-cAMP and A, C)2. (ji(ethyl-2-diazomalonyl)-cAMP were used to generate carbenes which modify rabbit muscle phosphofructokinase. Similarly, only 3-14% of the potential sites of lactate dehydrogenase were labeled by the carbene derived from 3-(3//-diazirino)pyridine adenine dinucleotide (248). 

Primary or secondary aliphatic amines in aqueous or methanolic solution may replace the ammonia, for these do not form explosive iodo derivatives.468,469 This method can be recommended for preparative purposes and has proved very valuable in the preparation of thyroxine from 3,5-diiodo-thyronine in 20% aqueous ethylamine (KI3), of thyroxine methyl ester from 3,5-diiodothyronine methyl ester in 1 2 butylamine-methanol (I2)4 9 and of 3,5-diiodotyrosine in 20% aqueous ethylamine (Nal3),470 as well as in iodination... 

The principal hormones of the thyroid gland are iodine-containing amino add derivatives of thyronine and U Figure 56-1). is a prohormone that is converted to the biologically... 

Fig. 3 A, HPLC chromatogram of standard solution containing tyrosine, thyronine, and some of their iodo derivatives. Detection was performed with a Shimadzu SPD-M6A photodiode array detector at 240 nm. The spectrum B, of the selected peak (thyronine) is acquired automatically and stored in the UV spectral library for comparison in further identification procedures. C, Normalized spectral comparison and report results of chromatogram s thyronine peak with the best matching library spectrum. The similarity index indicates the closest match.

L-3-Iodotyrosine, L-3,5-diiodotyrosine, L-triiodothyronine and L-thyroxine are the most important iodinated phenylpropanoids found in nature. L-3-Iodo-tyrosine and L-3,5-diiodotyrosine are derivatives of L-tyrosine. L-Triiodothyro-nine and L-thyroxine are derived from the chemically related amino acid L-thyronine. 

The iodinated amino acids which have been identified to date in the thyroid gland are 3-monoiodo-L-tyrosine or MIT (8,38,40,62), 3,5-diiodo-L-tyrosine or DIT (9,20), 3,5,3 -triiodo-L-thyronine or TRITh (17,41,42), 3,5,3, 5 -tetraiodo-L-thyronine or thyroxine or Tx (19,24), and 2 (or 4)-monoiodo-L-histidine or MIH (43). TRITh and Tx are the two constituents of the thyroid hormone MIT and DIT are their precursors. The formation of all of these iodo derivatives during the hormone genesis, their secretion, the circulation of some of them in blood, and their metabolism can be followed by radiochromatography and, for certain problems, by paper electrophoresis. 

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