Synthesis of meta-substituted phenols and 1-estradiol conjugated analogues of suberoylanilide hydroxamic acid (SAHA).

Estradiol-conjugated drugs are prime targets for development into new treatments of hormone-responsive cancers. Due to overexpression of the estrogen receptor (ER) in breast cancer cells, β-estradiol (the most active estrogen ligand) becomes an attractive moiety for conjugation to enhance the selectivity of attached drugs toward cancer cells and reduce their side effects. The conjugation points on estradiol have been reported at various positions except on phenolic ring A, which is associated with interference on its binding ability to the target receptor. Nevertheless, such interference could be minimized if the conjugation was at the 1-position or meta to the phenolic hydroxy group of ring A. We achieved challenging meta-substitutions of phenols, using p-cresol as the model, in five steps with 40% overall yield. The strategy was applied to estradiol to obtain the unprecedented 1-amino derivative (a convenient intermediate ready for the screening of potential conjugated bioactive agents). Its conjugation ability was demonstrated by its connection to part of the anti-tumor compound suberoylanilide hydroxamic acid (SAHA) to obtain 1-estardiol-conjugated analogues. Docking calculations suggested the stronger binding of this compound to the ER than other derivatives connected at other positions. Unfortunately, the preliminary bioactivity test showed low activity and selectivity toward breast cancer cell lines. Structural optimization or a more appropriate selection of the bioactive group to be conjugated would be required.