Most of these compounds may lead to long-term toxic effects. For instance, tamoxifen induces liver cancer in rats after prolonged administration, which has been attributed to the generation of DNA-alkylating species from the metabolism of the stilbene framework. It has been proposed that cytochrome P450 hydroxy-lates tamoxifen at the allylic position of the ethyl side chain, leading to an alcohol, which can generate a highly delocalized allylic cation 3.6 and therefore alkylate DNA to give product 3.7 through an SN1 mechanism (Fig. 3.6).

This proposal also explains the lack of carcinogenicity of toremifene, which can be attributed to destabilization of the positive charge in 3.8 by the inductive effect of the chlorine substituent at the position adjacent to the allylic carbon (Fig. 3.7).

Because of the toxic effects associated to the central double bond in tripheny-lethylene derivatives, a new family of antiestrogens has been developed where the incorporation of this double bond into a cyclic system increases its chemical and metabolic stability. Another structural difference of these compounds with the traditional triphenylethylene derivatives is the presence of a ketone bridging

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