When using selective estrogen receptor modulators (SERMs) in cancer therapy, adverse effects such as endothelial dysfunction have to be considered. Estrogens and, consequently, SERMs regulate the synthesis of vasoactive nitric oxide (NO). We hypothesized that a bifunctional approach combining the antagonistic action of SERMs with a targeted NO release could diminish vascular side effects. We synthesized a series of NO-releasing SERMs (NO-SERMs) and the corresponding SERMs (after NO release) derived from a triaryl olefin lead. Compounds showed antagonistic activity for ERβ (IC(ERβ) = 0.2-2.7 μM), but no interaction with ERα. Growth of ERβ-positive breast cancer and melanoma cells was significantly decreased by treatment with SERM . This antiproliferative effect was diminished by the additional release of NO by the corresponding NO-SERM . Moreover, targeted release of NO by counteracted the antiproliferative effect of in normal vascular tissue cells. Summarizing, the therapeutic index of SERMs might be improved by this bifunctional approach.
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