Abstract
The aim of this project is to design target-specific drugs for hormone-dependent breast cancer. Hormone-dependent breast cancer overexpresses estrogen receptor alpha (ERα). Thus, our hypothesis is that functionalized ferrocenes with hormones as pendant groups (ferrocene-estrogen conjugates) will enhance the selectivity to target more effectively breast cancers, particularly those overexpressing ERs. Previously, we have synthesized ferrocene-estradiol conjugates with enhanced antiproliferative activity on MCF-7 cell line1,2. As part of our continuing effort in this area, we have designed a series of ferrocene-estrogen conjugates with various links between the ferrocene and the estrogen moiety, modulating hydrophobic/hydrophilic character. The species were characterized by analytical methods, including X-ray crystallography. The new species were tested on hormone-dependent breast cancer cell line MCF-7 and their antiproliferative activity determined. Their IC50 values were between 50 and 9 μM. The lowest IC50 was determined for 17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-ferrocenylcarbamate, which ensure further development for testing in other breast cancer cell lines. To explain their antiproliferative activity and assuming that the ERα is the target for these compounds, we performed docking studies between the receptor and the ferrocenes. The compound with the highest binding affinity to the estrogen receptor alpha was the one with the lowest IC50 value. A structure-activity relationship is discussed.
References