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co-workers have investigated salicylaldoxime-based estrogen receptor ligands. In such a system, the oxime hydroxy was designed to mimic the phenol (Figure 13). This proposition appeared attractive since the estrogen A-ring and the aldoxime A-ring have approximately the same size and geometry, the pKa of the oxime OH is roughly the same as a phenol, and the oxime OH would be positioned in the same space as the phenolic OH of E2.

Salicylaldoxime (24) was demonstrated to bind to both receptor subtypes (RBA ERa = 1.13%; RBA ERb = 1.71%, purified, full-length human estrogen receptor) but had 30- to 100-fold lower affinity than the naphthalene analog (26). However, methylation of the oxime hydroxyl (i.e., 25) significantly decreased binding affinity (RBA <0.015% for both receptors), as did the aldehyde precursor to the oxime, suggesting that the oxime hydroxyl may indeed be acting as an A-ring phenol isostere.

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