Fluorous tolerance of the estrogen receptor alpha as probed by 11-polyfluoroalkylestradiol derivatives

The concern of this work was to try to delineate factors, inherent to fluorination, susceptible to influence estradiol binding to the estrogen receptor alpha (ERα). For this purpose, fluorinated chains were linked at 11β position of the steroid (i.e., C6F13, CH2CH2C4F9, CH2CH2C8F17). Relative binding affinity (RBA) for ERα of these compounds and of other related fluorinated derivatives was compared to those of non-fluorinated analogs. Despite being relatively well accepted by the receptor, investigated compounds exhibited lower RBA values at 0 °C than their non-fluorinated counterparts. Nevertheless, heavily fluorinated chains were tolerated in so far as they are not too long (C-4) and insulated from the steroidal core by a two methylene spacer unit. Increase of the temperature of our binding assay (25 °C) failed to change the RBA values of two selected polyfluorohexyl derivatives while it drastically enhanced the value of the corresponding non-fluorinated analogs. Rigidity of the chain induced by fluorination as well as the oleophilic (fluorophobic) nature of the estradiol binding cavity of ERα is proposed to explain these properties.