Synthesis and biological activity of novel thyroid hormone analogues: 5′-aryl substituted GC-1 derivatives

Grazia Chiellini, Ngoc Ha Nguyen, James W. Apriletti, John D. Baxter, Thomas S. Scanlan

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)333-346
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number2
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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