Thyroid receptor ligand

An alternate strategy was utilized in the synthesis of a potential thyroid receptor ligand [30]. Electrophilic bromination was followed by the Miyaura boronic ester synthesis to yield 49 [31]. Suzuki coupling between 49 and 2-bromothiazole was then accomplished to provide 50, a precursor to the derivative 51. Unfortunately, the presence of the thiazole at C(3), in 51 resulted in a decrease in binding affinity and selectivity as compared to the lead compound. 

In contrast to the steroid receptor family, members of the thyroid receptor family typically do not associate with accessory proteins and are not localized to the extranucleus matrix. Rather, these receptors exist in the basal state associated with chromatin in the cell nucleus. When bound by hormone ligand, thyroid receptor family members dissociate from the chromatin and typically form heterodimeric combinations with the retinoid-X receptor (RXR). RXR also is capable of homodimerization in association with its ligand 9-cis retinoic acid. Thus high 9-cis retinoic acid levels apparently promote homodimerization, and low levels are permissive of heterodimerization of RXR with activation by the partner ligand. 

Another forefront technique to improve the function of the stratum corneum and enhance barrier repair in dry skin is the use of epidermal differentiation. A number of hormone receptors for epidermal differentiation have been identified. This family of receptors includes retinoic acid receptors, the steroid receptors, the thyroid receptors, the Vitamin D receptors, the peroxisome proliferator-activated receptors, the farnesol-activated receptors, and the liver-activated receptors. It is reported that these transcription factors bind their respective ligands and regulate many of the aspects of cellular proliferation and differentiation. Examples of ligands for the last three transcription factors are fatty acids for the peroxisome proliferator-activated receptor, famesol for the farnesol-activated receptor, and hydroxylated cholesterol derivatives for the liver-activated receptor. The stimulation of epidermal differentiation stimulated the synthesis of involucrin, filaggrin, and the enzymes of the ceramide synthesis pathway (74). 

Figure 12.6 Stereo view of the Raptor surrogate for the thyroid receptor p with the largest ligand of the training set depicted. The front section has been clipped to display inner (wireframe) and outer shells (smooth surface). Areas colored in brown represent hydrophobic properties areas in red correspond to H-bond acceptors, areas in blue to H-bond donors and green reflects H-bond flip-flops. See color plates.

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptors superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid receptors. All members of this superfamily have a similar structure the amino-terminal region allows ligand-independent activation, confers con-... 

Kelley MW, Turner JK, Reh TA. 1995. Ligands of steroid/ thyroid receptors induce cone photoreceptors in vertebrate retina. Development 121 3777-3785. 

More than 70% of differentiated thyroid cancer concentrates radioiodine after TSH stimulation (Robbins et al., 1991 Jarzab et al., 2003). Some differentiated thyroid cancer (approximately 10-20%), as well as anaplastic thyroid cancer, however, do not concentrate radioiodide, even after TSH stimulation (Robbins et al., 1991). Since almost all differentiated thyroid cancer expresses TSHR (Brabant et al, 1991), the absence of NIS induction in response to TSH is most likely due to defects in postreceptor signaling pathways. Recent studies have demonstrated the potential for NIS induction in poorly differentiated thyroid cancer by redifferentiation agents, such as nuclear receptor ligands, RA and peroxisome proliferator-activated receptor- (PPAR ) ligands, and inhibitors of epigenetic modifications. 

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