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Synthesis and Structure–Activity Relationships of Ferrocenyl Tamoxifen Derivatives with Modified Side Chains
Author(s) -
Nguyen Anh,
Top Siden,
Pigeon Pascal,
Vessières Anne,
Hillard Elizabeth A.,
Plamont MarieAude,
Huché Michel,
Rigamonti Clara,
Jaouen Gérard
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200801108
Subject(s) - side chain , tamoxifen , chemistry , side effect (computer science) , combinatorial chemistry , medicine , organic chemistry , computer science , polymer , breast cancer , cancer , programming language
We report here the synthesis and cell‐proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the O(CH 2 ) 2 N(CH 3 ) 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(CH 2 ) 2 C(O)[(η 5 ‐C 5 H 4 )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 1 – 4 , with a side chain lacking the carbonyl function (O(CH 2 ) n [(η 5 ‐C 5 H 4 )FeCp], n =1–4) and which show a decreasing affinity for ERα (ER=estrogen receptor) with increasing chain length, act as estrogens on MCF‐7 cells, and mild cytotoxics on PC‐3 prostate cancer cells, with IC 50 values around 10 μ M . The two monophenolic derivatives of 2 , 2 a and 2 b , which show a reduced affinity for ERα 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 ( 5 a and 5 b ). Molecular modeling studies of the ligand–ERα binding stability are broadly consistent with the experimental binding affinity results for compounds 2 , 2 a , 2 b , 5 , 5 a , and 5 b . Electrochemical experiments show that 1 – 4 , 2 a , and 2 b are stable to oxidation on the electrochemical timescale, unlike 5 , 5 a , and 5 b , 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 a bulky side chain.