Synthesis and Structure-Activity Relationships of Ferrocenyl Tamoxifen Derivatives with Modified Side Chains

We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the -O(CH2)(2)N-(CH3)(2) side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl-ferrocenyl (-O(CH2)(2)C(O)[eta(5)-C5H4)FeCp]) group, and which showed antiproliferative effects against both the hormone-dependent MCF-7 and -independent MDA-MB-231 breast cancer cell lines. We now report the results of a structure-activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 114, with a side chain lacking the carbonyl function (-O(CH2)(n)[eta(5)-C5H4)FeCp], n=1-4) and which show a decreasing affinity for ER alpha (ER=estrogen receptor) with increasing chain length, act as estrogens oil MCF-7 cells, and mild cytotoxics oil PC-3 prostate cancer cells, with IC50 values around 10 mu M. The two monophenolic derivatives of 2, 2a and 2b, which show a reduced affinity for ER alpha compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally. we have reexamined Compound 5 and discovered that its antiproliferative effect against the MCF-7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5a and 5b). Molecular modeling Studies of the ligand-ER alpha binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2a, 2b, 5, 5a. and 5b. Electrochemical experiments show that 1-4. 2a, and 2b are stable to oxidation oil file electrochemical time-scale unlike 5, 5a, and 5b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects. and that all compounds are estrogenic. despite the presence of it bulky side chain.