Abstract
In the course of the preparation of a series of ferrocenyl derivatives of diethylstilbestrol (DES), in which one of the 4-hydroxyphenyl moieties was replaced by a ferrocenyl group, the McMurry reaction of chloropropionylferrocene with a number of mono-aryl ketones unexpectedly yielded the hydroxylated ferrocenyl DES derivatives, 5a–c, in poor yields (10%–16%). These compounds showed high activity on the hormone-independent breast cancer cell line MDA-MB-231 with IC50 values ranging from 0.14 to 0.36 µM. Surprisingly, non-hydroxylated ferrocenyl DES, 4, showed only an IC50 value of 1.14 µM, illustrating the importance of the hydroxyethyl function in this promising new series. For comparison, McMurry reactions of the shorter chain analogue chloroacetylferrocene were carried out to see the difference in behaviour with mono-aryl ketones versus a diaryl ketone. The effect of changing the length of the alkyl chain adjacent to the phenolic substituent of the hydroxylated ferrocenyl DES was studied, a mechanistic rationale to account for the unexpected products is proposed, and the antiproliferative activities of all of these compounds on MDA-MB-231 cells lines were measured and compared. X-ray crystal structures of cross-coupled products and of pinacol-pinacolone rearrangements are reported.
Highlights
Bioorganometallic chemistry, otherwise known as organometallic chemical biology, a field that encompasses organometallics in biology and medicine, is one of the fastest growing fields
We have previously reported the synthesis of organochromium complexes of hexestrol, a hydrogenated version of DES [23,24], and ferrocenyl derivatives of estradiol and of hexestrol are known [25]
The IC50 values of ferrocidiphenol 1 and ferrociphenol are included for the sake of comparison [10,34]
Summary
Bioorganometallic chemistry, otherwise known as organometallic chemical biology, a field that encompasses organometallics in biology and medicine, is one of the fastest growing fields. Many organo-transition metal complexes have attracted great interest in a wide range of medicinal areas [1,2,3,4,5,6,7]. As part of our programme to study ferrocene derivatives with anticancer properties, we have previously reported that ferrocidiphenol (4-HO-C6H4)2C=C(Et)Fc, 1, [8,9] shows an effective cytostatic effect (IC50 = 0.7 μM on hormone-dependent MCF-7 and IC50 = 0.6 μM on hormone-independent MDA-MB-231 breast cancer cell lines) [10]. Toremifene (TOR, Scheme 1), a chlorinated derivative of tamoxifen, is an effective and well-tolerated agent for the therapy of postmenopausal women with hormonal positive receptor advanced breast cancer [11,12,13,14].
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