Studies on organometallic selective estrogen receptor modulators.: (SERMs) Dual activity in the hydroxy-ferrocifen series

Synthesis of 7, a ferrocene derivative of the antiestrogenic drug hydroxytamoxifen bearing a basic chain-O(CH2)(n)N(CH3)(2) with n = 4 is presented, together with both studies of its antiproliferative effect on the hormone-dependent MCF7 cell line (estrogen receptor positive cells) and of its genotoxicity. This molecule is easily prepared via a McMurry coupling reaction. The antiproliferative effect found for 7 at an incubation molarity of 1 muM was very close to that found for the usual reference molecule, namely OH-tamoxifen. In addition to its structural antiestrogenic effect, 7 showed cytotoxic activity probably due to the vectored ferrocene. This genotoxic component was confirmed by a 3D (damaged DNA detection) test, that permits identification and quantification of lesions induced on DNA. Some key interactions of 7 docked into the alpha-estrogen receptor binding site were also shown. (C) 2001 Elsevier Science B.V. All rights reserved.