TY - JOUR
T1 - Synthesis and biological activity of novel thyroid hormone analogues
T2 - 5′-aryl substituted GC-1 derivatives
AU - Chiellini, Grazia
AU - Nguyen, Ngoc Ha
AU - Apriletti, James W.
AU - Baxter, John D.
AU - Scanlan, Thomas S.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (DK 52798, T.S.S.; DK 41842, J.D.B.). J.D.B. has proprietary interests in, and serves as a consultant and deputy director to Karo Bio AB, which has commercial interests in this area of research.
PY - 2002
Y1 - 2002
N2 - Compounds that selectively modulate thyroid hormone action by functioning as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be useful for medical therapy. We have synthesized a high affinity TRβ-selective agonist ligand, GC-1, and optimized the synthetic route to provide large quantities of the compound for animal testing. In addition to an improvement in efficiency, the new synthetic route offers a chemical handle for selective modification of the thyronine skeleton to produce new derivatives. To explore the effect of GC-1 core structure modifications on binding to TR isoforms and activation of transcription, we developed here an efficient and flexible route to a new series of 5'-substituted GC-1 analogues. This route relies on ortho lithiation and in situ boration of the biarylmethane compound 1, a key intermediate of the revised GC-1 synthesis, followed by Suzuki cross-coupling. Using this approach we prepared and tested eleven 5'-substituted GC-1 analogues. Substitution at the 5'-position decreased binding affinity, but retained TRβ-selectivity for most of the compounds. Transactivation assays reveal that most of these compounds function as thyroid hormone agonists, but one compound (GC-14) antagonizes the response to thyroid hormone.
AB - Compounds that selectively modulate thyroid hormone action by functioning as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be useful for medical therapy. We have synthesized a high affinity TRβ-selective agonist ligand, GC-1, and optimized the synthetic route to provide large quantities of the compound for animal testing. In addition to an improvement in efficiency, the new synthetic route offers a chemical handle for selective modification of the thyronine skeleton to produce new derivatives. To explore the effect of GC-1 core structure modifications on binding to TR isoforms and activation of transcription, we developed here an efficient and flexible route to a new series of 5'-substituted GC-1 analogues. This route relies on ortho lithiation and in situ boration of the biarylmethane compound 1, a key intermediate of the revised GC-1 synthesis, followed by Suzuki cross-coupling. Using this approach we prepared and tested eleven 5'-substituted GC-1 analogues. Substitution at the 5'-position decreased binding affinity, but retained TRβ-selectivity for most of the compounds. Transactivation assays reveal that most of these compounds function as thyroid hormone agonists, but one compound (GC-14) antagonizes the response to thyroid hormone.
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U2 - 10.1016/S0968-0896(01)00284-X
DO - 10.1016/S0968-0896(01)00284-X
M3 - Article
C2 - 11741782
AN - SCOPUS:0036132531
SN - 0968-0896
VL - 10
SP - 333
EP - 346
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 2
ER -