The first organometallic selective estrogen receptor modulators (SERMs) and their relevance to breast cancer

In the overall scheme of the future development of new drugs for the treatment of breast cancer, specially tamoxifen resistant tumours, we have explored the unprecedented use of organometallic SERMs. The initial idea is to enhance the efficacy of the current standard, i.e. tamoxifen, by modifying the structure through judicious incorporation of an organometallic moiety possessing novel properties. Results have been varied, justifying a systematic approach that has proved to be full of surprised. The following differing situations were observed (a) the anti-proliferative effect is due to the vector and the organometallic moiety does not improve the effects of the SERM, no matter what concentration is used. In particular, this is the case for the hydroxytamoxifen derivative bearing a CpRe(CO)3 group, which behaves almost identically to hydroxytamoxifen. These stable species have future promise for use with radionucleides of Re and Tc (b) the effect of the organometallic moiety counteracts the anti-estrogenic behaviour of the vector and leads to species with proliferative activity; this is the case with Cp2TiCl2 entity, which when attached to tamoxifen behaves as a powerful estrogen, probably due to in situ release of Ti(IV) (c) a synergy exists between the cytotoxic organometallic moiety and its organic vector, leading to unique anti-proliferative effects on breast cancer cells classed ER+ and ER-. This result opens a new window on organometallic oncology. It is also clear that the range of possibilities is broad, varied and currently unpredictable. A systematic study combining organometallic chemistry and biology is the only option in the search for new SERMs with novel properties.