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Published in final edited form as: Synth Commun. 2012 Jun 5;43(10):1439–1446. doi: 10.1080/00397911.2011.639005

THE SYNTHESIS OF 13C9-15N-LABELED 3,5-DIIODOTHYRONINE AND THYROXINE

Sarah A Hackenmueller 1, Thomas S Scanlan 1
PMCID: PMC5607869  NIHMSID: NIHMS847475  PMID: 28943663

Abstract

Thyroid hormones undergo extensive metabolism to regulate hormone activity. A labeled thyroid hormone would be useful to track hormone metabolism through various pathways. While radiolabeled thyroid hormones have been synthesized and used for in vivo studies, a stable isotope labeled form of thyroid hormone is required for studying thyroid hormone metabolism by LC-MS/MS, an analytical technique that has certain advantages without the complications of radioactivity. Here we report the synthesis of 13C9-15N-T2 and 13C9-15N-T4, two labeled thyroid hormone derivatives suitable for in vivo LC-MS/MS studies.

Keywords: 13C9-15N-T2, 13C9-15N-T4, thyroid hormone, thyroxine

Graphical abstract

graphic file with name nihms-847475-f0001.jpg

INTRODUCTION

Thyroid hormones (THs) are important endocrine signaling molecules that regulate a variety of physiological functions, including body temperature, cardiac function, metabolism, and mental status. THs are synthesized and secreted by the thyroid gland predominantly as 3,3′,5,5′-tetraiodothyronine (T4, thyroxine), which undergoes extrathyroidal deiodination to 3,3′,5-triiodothyronine (T3). T3 is largely considered to be the active form of the hormone and exerts its effects by binding to TH nuclear receptors and regulating transcription of TH-responsive genes. In addition to the commonly known transcriptional actions of TH, there are rapid, nontranscriptionally mediated effects of TH that remain less well understood, suggesting the existence of additional biologically active TH metabolites.[1,2]

T1AM is an endogenous compound present in serum and various tissues of rats, hamsters, and humans.[3–6] Acute administration of T1AM in vivo results in induction of a torpor-like state characterized by hypothermia, bradycardia, a shift in respiratory quotient from carbohydrate to lipid utilization, hyperglycemia, and hypoinsulinemia.[3,5,7] In an ex vivo perfused rat heart, T1AM decreases cardiac output.[3,8] These effects tend to be oppose those normally attributed to T3 and suggest that T1AM may also play a role in TH signaling by modulating the effects of T3.

Structural similarities between T4 and T1AM (Fig. 1) have led to speculation that T1AM is a deiodinated and decarboxylated derivative of TH, but this relationship has not been directly investigated. To test this metabolic question, it is necessary to definitively trace the fate of a suspected precursor, which can be accomplished through incorporation of a label in T4. Several methods for analyzing T1AM by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) have been reported.[4,9,10] This technique is ideal for analysis of isotopically labeled compounds, because any metabolites arising from a labeled precursor would contain a mass signature distinct from endogenous compounds. T4, as the predominant form of TH produced endogenously, is the first candidate to test as a suspected precursor to T1AM. Based on in vitro data showing that T3 is not a substrate for outer ring deiodination, it remains unclear if 3,5-diiodothyroinine (3,5-T2), another endogenous TH, arises from extrathyroidal metabolism of T4 or some alternate biosynthetic pathway.[10] This indicates a second potential candidate for a biosynthetic precursor to T1AM. Herein we describe the novel syntheses of 13C9-15N-3,5-T2 and 13C9-15N-L-thyroxine (13C9-15N-T4) that can be used to study TH metabolism by liquid chromatography–tandem mass spectroscopy (LC-MS/MS).

Figure 1.

Figure 1

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Structures of T4, 3,5-T2, and T1AM.

RESULTS AND DISCUSSION

Synthesis of 13C9-15N-3,5-T2

The synthesis of 13C9-15N-L-T2 was carried out in parallel with unlabeled T2 according to the route shown in Scheme 1. Commercially available 13C9-15N-L-tyrosine 1 was N-Boc and O-methyl ester protected and bis-iodinated with N-iodosuccinimide in dichloromethane (DCM), a modification of the method of Bovonsombat et al., to give 13C9-15N-3,5-diiodo-L-tyrosine 3 in 59% yield over the three steps.[11,12] 4-(Triisopropyl)silyloxyphenyl boronic acid was synthesized as previously described and coupled to 3 via a copper(II)-mediated biaryl ether formation.[13,14] Deprotection with tetrabutylammonium flurodie (TBAF) gave N-boc-3,5-diiodo-13C9-15N-L-thyronine-OMe 4 in 30% yield over two steps. Sequential deprotection with lithium hydroxide to cleave the methyl ester and hydrochloric acid to cleave the t-Boc gave 13C9-15N-3,5-T2 5, in 28% yield as the trifluoroacetic acid (TFA) salt after purification by preparative high-performance liquid chromatography (HPLC).[15] Because of the difficulty in interpreting 1H NMR spectra as a result of 13C coupling effects, labeled intermediates and 13C9-15N-3,5-T2 were characterized by high-resulution mass spectrometry (HRMS) and chromatographic comparison to unlabeled standards, which were synthesized in parallel to 13C9-15N-labeled compounds.

Scheme 1.

Scheme 1

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Reagents and conditions: (a), HCl, 2,2-dimethoxypropane; (b), BOC2O, NaHCO3, THF/H2O; (c), NIS, DCM; (d), 4-(triisopropyl)silyloxyphenyl boronic acid, Cu(OAc)2, DIPEA, pyridine, DCM; (e), TBAF, THF; (f), LiOH, MeOH/H2O; and (g), HCl, dioxane. An asterisk (*) indicates 13C or 15N.

Synthesis of 13C9-15N-L-T4

The synthesis of 13C9-15N-L-T4 was carried out in parallel with unlabeled T4 according to the route shown in Scheme 2. Biaryl ether 4 was bis-iodinated on the outer ring with iodine monochloride and butylamine to give N-Boc-13C9-15N-T4-OMe 6 in 37% yield.[13] Sequential deprotection of 6 as described previously produced 13C9-15N-T4 7, which was purified by preparative HPLC as the TFA salt in 23% yield from 6. As described for 13C9-15N-3,5-T2, synthetic intermediates and 13C9-15N-L-T4 were characterized by HRMS and chromatographic comparison to unlabeled standards, which were synthesized in parallel.

Scheme 2.

Scheme 2

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Reagents and conditions: (a), ICl, BuNH2, 4:1 DCM/DMF; (b), LiOH, MeOH/H2O; and (c), HCl, dioxane. An asterisk (*) indicates 13C or 15N.

125I, 131I, and 14C labeled THs have been used to study TH metabolism and pharmacokinetics but the use of radiolabels in metabolism studies is limited to tracing the fate of the radioactivity and does not provide information on metabolic pathways that do not involve radiolabeled portions of the hormones.[16–25] In addition, the use of outer ring labeled 125I-T4, the most commonly employed labeled form of T4, could not be used to follow T4 metabolites that are extrathyroidally deiodinated in the outer ring, such as 3,5-T2 and T1AM. The incorporation of nonradioactive isotopes such as 13C or 15N into T4 and other THs allows for more in-depth investigations of alternate pathways of TH metabolism by LC-MS/MS. The syntheses of unlabeled and of 13C-labeled T4 and T3 have been reported, but here we report an alternate synthetic route to produce a novel labeled T4 containing 15N and 13C.[14,26–29] Although the synthesis of 125I-3,5-T2 has been reported, to our knowledge this is the first reported synthesis of a stable isotope labeled T2.[30]

EXPERIMENTAL

All chemicals used for synthesis were purchased from Aldrich, Sigma-Aldrich, Fluka, Acros or TCI. Anhydrous solvents were obtained from an in-house solvent distillation system. Intermediates were purified by flash chromatography (HPFC) on a Biotage SP1 purification system with a fixed wavelength ultraviolet detector (Biotage, Charlotte, NC). Syntheses of unlabeled and 13C-15N labeled compounds were carried out in parallel. The synthetic scheme was prospected using unlabeled material, which also served as standards to match 13C-15N-labeled compounds by thin-layer chromatography (TLC). NMR spectra for 13C -labeled compounds were difficult to interpret due to 13C J-couplings. For this reason, 13C labeled compounds were characterized by high-resolution mass spectrometry (HRMS) only. 1H NMR were taken for unlabeled compounds only. 1H NMR spectra were taken on a Bruker 400 (400 MHz), and spectra were processed using ACD/NMR Processor Academic Edition software. HRMS and MS/MS fragmentation (contained in the Supplemental Figures, available online) using electrospray ionization (ESI) in positive polarity was performed at the Mass Spectrometry Laboratory at the University of Illinois at Urbana–Champaign. HRMS are reported for all novel compounds, and MS/MS fragmentation for 13C9-15N-labeled compounds are available in the Supplementary Material, available online.

Boc-OMe-L-tyrosine

Concentrated hydrochloric acid (2.7 ml) was added dropwise to a stirring solution of L-tyrosine (0.500 g, 2.76 mmol) in 2,2-dimethyoxypropane (33 ml). The reaction was stirred at room temperature for 24 h, and the crude reaction mixture was used in the next step.

NaHCO3 (7.5 ml, 1.1 M in water) was added to crude OMe-L-tyrosine and Boc2O (0.620 g, 2.85 mmol) in THF (12 ml). The reaction was stirred at room temperature for 24 h. The reaction was diluted with ether (20 ml), and the aqueous layer was extracted twice with ether. The combined organic layers were washed with 0.5 M HCl and brine and dried over MgSO4. The crude material was purified by HPFC (10–80% ethyl acetate / hexanes over 10 column volumes) to give Boc-OMe-L-tyrosine (0.787 g, 2.66 mmol, 96.5% yield). 1H NMR (400 MHz, chloroform-d)δ ppm 1.41 (s, 9 H) 2.86–3.21 (m, 2 H), 3.75 (s, 3 H), 4.47–4.63 (m, 1 H), 5.13 (br. s., 1 H), 5.48 (br. s., 1 H), 7.10 (s, 2 H), 7.64 (s, 2 H).

Boc-OMe-13C9-15N-L-tyrosine 2 was synthesized using the same procedure with 13C9-15N-l-tyrosine (0.500 g, 2.62 mmol) as starting material, in 87.2% yield (0.702 g, 2.30 mmol). HRMS (ESI+) for C613C9H2215NO5 [M + H] calculated 306.1770, found 306.1776. MS/MS fragmentation spectrum is available in Supplemental Fig. S1, available online.

3,5-Diiodo-Boc-OMe-L-tyrosine

N-Iodosuccinimide (1.2 g, 5.32 mmol) was added to a stirring solution of Boc-OMe-L-tyrosine (0.787 g, 2.66 mmol) in DCM (17.7 ml) at 0 °C. The reaction was monitored by TLC (40% ethyl acetate / hexanes) for consumption of starting material, which occurred in ~40 min. A solution of 10% Na2S2O3 was added dropwise, and the reaction mixture was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and dried over MgSO4. The crude material was purified by HPFC (10–80% ethyl acetate / hexanes over 10 column volumes) to give 3,5-diiodo-Boc-OMe-L-tyrosine as a white solid (0.908 g, 1.66 mmol, 67.5% yield). 1H NMR (400 MHz, chloroform-d)δ ppm 1.45 (s, 9 H), 2.96 (s, 2 H), 3.68–3.79 (m, 3 H), 4.49 (d, J = 7.07 Hz, 1 H), 5.03 (d, J = 7.58 Hz, 1 H), 5.70 (s, 1 H), 7.44 (s, 2 H).

3,5-Diiodo-Boc-OMe-13C9-15N-L-tyrosine 3 was synthesized following the same procedure from Boc-OMe-13C9-15N-L-tyrosine (0.702 g, 2.30 mmol) starting material, in 67.5% yield (0.864 g, 1.55 mmol). HRMS (ESI+) for C613C9H19I215NNaO5 [M + Na] calculated 579.9523, found 579.9528. MS/MS fragmentation spectrum is available in Supplemental Fig. S2, available online.

3,5-Diiodo-Boc-OMe-L-thyronine

Molecular sieves 4 Å were added to a round-bottom flask that was then flame dried and flushed with dry air. 4-(Triisopropyl)silyloxyphenyl boronic acid (0.612 g, 2.08 mmol), DCM (6.3 ml), diisopropylethylamine (4.15 mmol), and pyridine (4.15 mmol) were added under argon. Dry copper(II) acetate (0.151 g, 0.83 mmol) was added, and the reaction mixture was stirred under argon for 10 min. 3,5-Diiodo-Boc-OMe-L-tyrosine (0.452 g, 0.83 mmol) was added in DCM (2 ml) over 5 min. The reaction was stirred at room temperature under dry air for 48 h. The reaction was diluted with ether; filtered through silica/celite; sequentially washed with HCl, H2O, and brine, and dried over MgSO4. The crude reaction material was taken into the next reaction.

Crude biaryl ether was dissolved in THF and cooled to 0 °C. Tetra-N-butyl-ammonium fluoride (3.15 mmol) was added dropwise over 5 min. The reaction was stirred at room temperature for 15 min. The reaction was diluted with ethyl acetate and washed with HCl. The aqueous layer was washed with ethyl acetate, and the combined organic layers were washed sequentially with H2O and brine and dried over MgSO4. The crude product was purified by HPFC (10–80% ethyl acetate / hexanes over 10 column volumes) to yield 3,5-diiodo-Boc-OMe-13C9-15N-L-thyronine as a solid (0.196 g, 0.31 mmol, 37.0% yield over two steps). 1H NMR (400 MHz, chloroform-d)δ ppm 1.45 (s, 9 H), 2.83–3.19 (m, 2 H), 3.66–3.88 (m, 3 H), 4.54 (br. s., 1 H), 4.69 (br. s., 1 H), 5.10 (br. s., 1 H), 6.62–6.92 (m, 4 H), 7.63 (s, 2 H). HRMS (ESI+) for C21H23I2NNaO6 [M + Na] calculated 661.9512; found 661.9512.

3,5-Diiodo-Boc-OMe-13C9-15N-L-thyronine 4 was synthesized following the same procedure from 3,5-diiodo-Boc-OMe-13C9-15N-L-tyrosine (0.547 g, 0.98 mmol) starting material, in 29.9% yield (0.190 g, 0.29 mmol). HRMS (ESI+) for C1213C9H24I215NO6 [M + H] calculated 649.9965; found 649.9966. MS/MS fragmentation spectrum is available in Supplemental Fig. S3, available online.

3,5-Diiodo-13C9-15N-L-thyronine (13C9-15N-T2) 5

To cleave the methyl ester, lithium hydroxide (0.39 mmol, 100 μl of 3.9 M in H2O) was added to a stirred solution of 3,5-diiodo-Boc-OMe-13C9-15N-L-thyronine (0.051 g, 0.078 mmol) in methanol (300 μl) at 4 °C. The reaction was stirred at 4 °C for 90 min. Solvent was removed under argon, and the crude reaction product was dried in a modified Abderhalden drying apparatus for use in the next step.

The dried crude reaction product from the methyl ester deprotection was dissolved in 4 M HCl in dioxane (300 μl). The reaction was stirred under argon at room temperature overnight. The reaction mixture was diluted with 500 μl of 1:1 water/acetonitrile and purified by preparatory HPLC using a Rainin HPXL solvent delivery system and a Prostar PDA detector (Varian Inc., Paolo Alto, CA). Reaction product was injected onto a Varian Dynamax Microsorb C18 21.4 × 250 mm column and monitored at wavelength 254 nm. Mobile phases were A (water + 0.1% TFA) and B (acetonitrile + 0.1% TFA) with gradient conditions as follows: 5% B 0–5 min, 5–95% B 5–50 min, 95% B 50–65 min, 95–5% B 65–75 min, and 5% B 75–90 min. Commercially available 3,5-T2 was used to determine the retention time of the product, 31.5 min. HRMS (ESI+) for C613C9H14I215NO4 [M + H] calculated 535.9284; found 535.9291. MS/MS fragmentation spectrum is available in Supplemental Fig. S4, available online.

3,3’,5,5’-Tetraiodo-N-Boc-OMe-L-thyronine

Iodine monochloride in DCM (0.26 mmol, 260 μl) was added dropwise to a stirring solution of 3,5-diiodo-Boc-OMe-L-thyronine (0.072 g, 0.11 mmol) and butylamine (0.64 mmol, 64 μl) in 4:1 DCM/DMF (3.7 ml) at 0 °C. The reaction was stirred at 0 °C for 20 min. The reaction was diluted with ethyl acetate; washed sequentially with HCl, 10% sodium thiosulfate, H2O, and brine; and dried over MgSO4. The crude product was purified by HPFC (10–80% ethyl acetate / hexanes over 10 column volumes) to yield 3,3′,5,5′-tetraiodo-N-Boc-OMe-L-thyronine as a brown solid (0.022 g, 0.025 mmol, 22.9% yield). 1H NMR (400 MHz, chloroform-d)δ ppm 1.41 (s, 9 H), 2.86–3.21 (m, 2 H), 3.75 (s, 3 H), 4.47–4.63 (m, 1 H), 5.13 (br. s., 1 H), 5.48 (br. s., 1 H), 7.10 (s, 2 H), 7.64 (s, 2 H). HRMS (ESI+) for C21H21I4NNaO6 [M + Na] calculated 913.7445; found 913.7437.

3,3′,5,5′-Tetraiodo-N-Boc-OMe-13C9-15N-L-thyronine 6 was synthesized following the same procedure using 3,5-diiodo-Boc-OMe-13C9-15N-L-thyronine 0.150 g, 0.23 mmol) as starting material, in 36.9% yield (0.076 g, 0.085 mmol). HRMS (ESI+) for C 13C9H21I415NNaO6 [M + Na] calculated 923.7718; found 923.7715. MS/MS fragmentation spectrum is available in Supplemental Fig. S5, available online.

3,3’,5,5’-Tetraiodo-13C9-15N-L-thyronine (13C9-15N-T4) 7

To cleave the methyl ester, lithium hydroxide (0.43 mmol, 110 μl of 3.9 M in H2O) was added to a stirred solution of 3,3′,5,5′-tetraiodo-Boc-OMe-13C9-15N-L-thyronine (0.076 g, 0.085 mmol) in methanol (330 μl) at 4 °C. The reaction was stirred at 4 °C for 90 min. Solvent was removed under argon and the crude reaction product was dried in a modified Abderhalden drying apparatus for use in the next step.

The dried crude reaction product from the methyl ester deprotection was dissolved in 4 M HCl in dioxane (320 μl). The reaction was stirred under argon at room temperature overnight. To the reaction mixture, 500 μl of 1:1 water/acetonitrile was added, and the solution was filtered through a 0.22-μm filter prior to purification by preparatory HPLC as described previously. Commercially available T4 was used to determine the retention time of the product, 37.7 min. HRMS (ESI+) for C613C9H11I415NO4 [M + H] calculated 787.7217; found 787.7218. MS/MS fragmentation spectrum is available in Supplemental Fig. S6, available online.

Supplementary Material

supplemental

ACKNOWLEDGMENT

This work was supported by a grant from the National Institutes of Health (DK-52798, T. S. S.).

Footnotes

Supplemental materials are available for this article. Go to the publisher’s online edition of Synthetic Communications® to view the free supplemental file.

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