Synthesis of two ligands for nuclear receptors of thyroid hormones

Abstract

In this project, we want to obtain new molecules with the potential as future drugs, by the synthesis of various compounds similar to thyroid hormones thyronine (T3) and thyroxine (T4). We also should be synthesized other derivatives, which may be obtained by functionalization of certain structural positions of the molecules and/or synthetic intermediates.Recently, a new synthetic route was developed in our laboratory to obtain the ligands agonists known as GC-1 and G-24. Through a new synthetic route, was possible to synthesize the ligand GC-1, with greater overall yield and fewer steps compared to the original synthesis of this ligand described in the literature. The ligand GC-1 will be used as starting material for the synthesis proposed in this project. For this, the GC-1 should be obtained on a larger scale (a few grams) and then it will be converted in a new ligand, known as NH-3, in two synthetic steps [a bromination, using N-bromo-succinimide in acid medium, and a reaction of Sonogashira, catalyzed by palladium acetate and 1,4-diazabicyclo[2.2.2]octane (DABCO)].To complement this research project, we also should synthesized new ligands analogous to the hormone thyronine (T3), using the following synthetic strategy: (i) phenolic derivatives substituted at ortho position, commercially obtained, will be brominated and converted to the corresponding methoxymethylether; (ii) the compound 4-benzyloxy-2,6-dimethylphenol will be prepared from the commercial reagent 2,6-dimethyl-hydroquinone by selective protection of the less hindered hydroxyl group of the molecule, (iii) these compounds will be coupled, using as catalyst a specific ligand of palladium described in literature. The efficiency of this reaction should be studied by changing the reaction conditions (because of the presence of different substituent groups on the synthesized molecules). By this synthetic route several diaryl ethers must be obtained. After the selective deprotection of the benzyl group of the obtained compounds, the intermediary products should be alkylated and, thereafter, the methoxymethyl protecting group should be removed to produce the derivatives of interest, analogous to the hormone T3.The obtained ligands will be submitted to biological essays and crystallographic studies (work to be performed at the Institute of Physics of São Carlos - USP), in order to understand how the interactions of these ligands can to prompt the responses in the three-dimensional structure of the nuclear receptors.