Synthesis of MR-49, a deiodinated analog of tetraiodothyroacetic acid (tetrac), as a novel pro-angiogenesis modulator

The tyrosine-based hormones 3,3′,5-triiodo-l-thyronine (l-T3) and l-thyroxine (l-T4) that are produced by the thyroid gland control metabolic functions. Iodothyronine deiodinase enzymes convert l-T4 to l-T3, the form of thyroid hormone critical to genomic actions within cells and regulation of metabolism, and to reverse-l-T3, a hormone isoform that is largely inactive. We used tertiary amines in a study of deiodination based on derivatives of tetraiodothyroacetic acid (tetrac)—a naturally occurring derivative of l-T4—to mimic the action of the iodothyronine deiodinases and deiodination of the outer ring iodines. Deiodinated tetrac, MR-49, was found to be pro-angiogenic, with this activity exceeding that of l-T3 and l-T4 in a hemoglobin Matrigel® plug assay of angiogenesis. Tetrac is anti-angiogenic via several nongenomic pathways, and the present studies of MR-49 reveal the critical contribution of outer ring iodines to the angiogenic properties of thyroid hormone analogues, which may have utility as pro-angiogenic pharmaceuticals.

Pro-angiogenic actions of thyroid hormone (T4 and T3) on endothelial cells and vascular smooth cells that are initiated at the cell surface receptor for the hormone on the extracellular domain of integrin αvβ3. A thyroid hormone analogue, tetraiodothyroacetic acid (tetrac), is inhibitory at the integrin receptor. MR-49 is a deiodinated analogue of tetrac, and was found to be pro-angiogenic, with activity exceeding that of l-T3 and l-T4 in a hemoglobin assay.Figure optionsDownload as PowerPoint slide