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

Abstract

Estradiol conjugated drugs are one of the prime targets toward developing into new treatments of hormone-responsive types of cancer. Due to the overexpression of estrogen receptor (ER) in breast cancer cells, β-estradiol, the most active estrogen ligand, becomes the attractive moiety for such conjugation to enhance selectivity of the attached drugs toward cancer cells and reduce their side effects. The conjugation points on estradiol have been reported at various positions except on the phenolic ring A, concerning the interference with its binding ability to the target receptor. Nevertheless, the interference could be minimized if the conjugation was at 1-position or meta- to the phenolic hydroxy group of ring A. We have achieved the challenging meta-substitutions of phenols, using p-cresol as the model, in 5 steps with 40% overall yield. The strategy was applied on estradiol to obtain the unprecedented 1-amino derivative, the convenient intermediate ready for screening of potential conjugated bioactive agents. Its readily conjugation ability was demonstrated by its connection to part of the known anti-tumor suberoylanilide hydroxamic acid (SAHA) to obtain the 1-estardiol conjugated analogues. Docking calculations supported the stronger binding of this compound to ER than other derivatives connected at other positions. Unfortunately, the preliminary bioactivity test disappointely showed low activity and selectivity toward breast cancer cell lines. A structure optimization or more appropriate selection of the bioactive group to be conjugated would be required.