Dataset Information

New synthetic routes to thyroid hormone analogs: d₆-sobetirome, ³H-sobetirome, and the antagonist NH-3.

ABSTRACT: New synthetic routes for the preparation of isotopically labeled versions of thyroid hormone agonist sobetirome were developed using Knochel's iodine-magnesium exchange. A more efficient synthesis of the thyroid hormone antagonist NH-3 was developed from a common intermediate in the sobetirome route. Using the new synthetic routes, d₆- and ³H-sobetirome were prepared for their use in studying biodistribution and the cellular uptake of sobetirome. The new route to NH-3 allows for a more rapid and efficient synthesis and provides access to an advanced intermediate to facilitate antagonist analog production in the final bond-forming synthetic step.

SUBMITTER: Placzek AT

PROVIDER: S-EPMC5354297 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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New synthetic routes to thyroid hormone analogs: d6-sobetirome, 3H-sobetirome, and the antagonist NH-3.

Placzek Andrew T AT Scanlan Thomas S TS

Tetrahedron 20150520 35

New synthetic routes for the preparation of isotopically labeled versions of thyroid hormone agonist sobetirome were developed using Knochel's iodine-magnesium exchange. A more efficient synthesis of the thyroid hormone antagonist NH-3 was developed from a common intermediate in the sobetirome route. Using the new synthetic routes, d6- and 3H-sobetirome were prepared for their use in studying biodistribution and the cellular uptake of sobetirome. The new route to NH-3 allow ...[more]

PMID: 28316349

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Project description:Patients with metastatic differentiated thyroid cancer (DTC) may be prepared using either thyroid-stimulating hormone withdrawal (THW) or recombinant human thyroid-stimulating hormone (rhTSH) injections before 131I administration for treatment. The objective of this study was to compare the absorbed dose to the critical organs and tumors determined by 124I PET/CT-based dosimetry for 131I therapy of metastatic DTC when the same patient was prepared with and imaged after both THW and rhTSH injections. Methods: Four DTC patients at MedStar Washington Hospital Center were first prepared using the rhTSH method and imaged by 124I PET/CT at 2, 24, 48, 72, and 96 h after administration of approximately 30-63 MBq of 124I. After 5-8 wk, the same patients were prepared using the THW method and imaged as before. The 124I PET/CT images acquired as part of a prospective study were used to perform retrospective dosimetric calculations for 131I therapy for the normal organs with the dosimetry package 3D-RD. The absorbed doses from 131I for the lungs, liver, heart, kidneys, and bone marrow were obtained for each study (rhTSH and THW). Twenty-two lesions in 3 patients were identified. The contours were drawn on each PET image of each study. Time-integrated activity coefficients were calculated and used as input in OLINDA/EXM sphere dose calculator to obtain the absorbed dose to tumors. Results: The THW-to-rhTSH organ absorbed dose ratio averaged over 5 organs for the first 3 patients was 1.5, 2.5, and 0.64, respectively, and averaged over 3 organs for the fourth patient was 1.1. The absorbed dose per unit administered activity to the bone marrow was 0.13, 0.086, 0.33, and 0.068 mGy/MBq after rhTSH and 0.11, 0.14, 0.22, and 0.080 mGy/MBq after THW for each patient, respectively. With the exception of 3 lesions of 1 patient, the absorbed dose per unit administered activity of 131I was higher in the THW study than in the rhTSH study. The ratio of the average tumor absorbed dose after stimulation by THW compared with stimulation by rhTSH injections was 3.9, 27, and 1.4 for patient 1, patient 2, and patient 3, respectively. The ratio of mean tumor to bone marrow absorbed dose per unit administered activity of 131I, after THW and rhTSH, was 232 and 62 (patient 1), 12 and 0.78 (patient 2), and 22 and 11 (patient 3), respectively. Conclusion: The results suggest a high patient variability in the overall absorbed dose to the normal organs per MBq of 131I administered, between the 2 TSH stimulation methods. The tumor-to-dose-limiting-organ (bone marrow) absorbed dose ratio, that is, the therapeutic index, was higher in the THW-aided than rhTSH-aided administrations. Additional comparison for tumor and normal organ absorbed dose in patients prepared using both methods is needed before definitive conclusions may be drawn regarding rhTSH versus THW patient preparation methods for 131I therapy of metastatic DTC.

Project description:BackgroundIn northwest of China, mini Chinese cabbage (Brassica pekinensis) is highly valued by consumers, and is widely cultivated during winter in solar-greenhouses where low light (LL) fluence (between 85 and 150 μmol m-2 s-1 in day) is a major abiotic stress factor limiting plant growth and crop productivity. The mechanisms with which various NH4+: NO3- ratios affected growth and photosynthesis of mini Chinese cabbage under normal (200 μmol m-2 s-1) and low (100 μmol m-2 s-1) light conditions was investigated. The four solutions with different ratios of NH4+: NO3- applied were 0:100, 10:90, 15:85 and 25:75 with the set up in a glasshouse in hydroponic culture. The most appropriate NH4+: NO3- ratio that improved the tolerance of mini Chinese cabbage seedlings to LL was found in our current study.ResultsUnder low light, the application of NH4+: NO3- (10:90) significantly stimulated growth compared to only NO3- by increasing leaf area, canopy spread, biomass accumulation, and net photosynthetic rate. The increase in net photosynthetic rate was associated with an increase in: 1) maximum and effective quantum yield of PSII; 2) activities of Calvin cycle enzymes; and 3) levels of mRNA relative expression of several genes involved in Calvin cycle. In addition, glucose, fructose, sucrose, starch and total carbohydrate, which are the products of CO2 assimilation, accumulated most in the cabbage leaves that were supplied with NH4+: NO3- (10:90) under LL condition. Low light reduced the carbohydrate: nitrogen (C: N) ratio while the application of NH4+: NO3- (10:90) alleviated the negative effect of LL on C: N ratio mainly by increasing total carbohydrate contents.ConclusionsThe application of NH4+:NO3- (10:90) increased rbcL, rbcS, FBA, FBPase and TK expression and/or activities, enhanced photosynthesis, carbohydrate accumulation and improved the tolerance of mini Chinese cabbage seedlings to LL. The results of this study would provide theoretical basis and technical guidance for mini Chinese cabbage production. In practical production, the ratio of NH4+:NO3- should be adjusted with respect to light fluence for successful growing of mini Chinese cabbage.

Dataset Information

New synthetic routes to thyroid hormone analogs: d₆-sobetirome, ³H-sobetirome, and the antagonist NH-3.

Publications

New synthetic routes to thyroid hormone analogs: d<sub>6</sub>-sobetirome, <sup>3</sup>H-sobetirome, and the antagonist NH-3.

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