Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens, the (cyclobutadiene)cobalt analogues of hydroxytamoxifen

The McMurry coupling of (tetraphenylcyclobutadiene)cobalt(cyclopentadienyl) ketones, (C4Ph4)Co[C5H4C(O)R], where R = Me, 3a, or Et, 3b, with a range of substituted benzophenones furnished a series of cobaltifens, organometallic analogues of tamoxifen whereby a phenyl ring has been replaced by an organo-cobalt sandwich moiety. These systems of the general formula (η4-C4Ph4)Co[η5-C5H4C(R)C(Ar)Ar′], where R = Me or Et, and Ar = Ar′ = p-C6H4X where X is OH, 2a and 2b, OMe, 2c and 2d, OBn, 2e and 2f, or O(CH2)2NMe2, 12a and 12b, and where Ar = C6H4OH and Ar′ = C6H4O(CH2)2NMe2, 2g and 2h, have been characterised by NMR spectroscopy and/or X-ray crystallography. The effect of 2a and 2b, 2g and 2h, and 12a and 12b on the growth of MCF-7 (hormone-dependent) and MDA-MB-231 (hormone-independent breast cancer cells) was studied. The dihydroxycobaltifens 2a and 2b exhibit a strong estrogenic effect on MCF-7 cells while the aminoalkyl-hydroxycobaltifens, 2g and 2h, were found to be only slightly cytotoxic on MDA-MB-231 cells (IC50 = 27.5 and 17 μM); surprisingly, however, the bis-(dimethylaminoethoxy)cobaltifens, 12a and 12b were shown to be highly cytotoxic towards both cell lines (IC50 = 3.8 and 2.5 μM).

A novel organometallic cobalt sandwich analogue of tamoxifen demonstrates antiproliferative activity in vitro against standard breast cancer cell lines. Unexpectedly, the introduction of a second dialkylaminoalkyl chain at the other oxygen markedly enhances the effect.Figure optionsDownload as PowerPoint slide