Nitric Oxide-Releasing Selective Estrogen Receptor Modulators: A Bifunctional Approach to Improve the Therapeutic Index

Research output: Contribution to journalResearch articleContributedpeer-review


  • Nicole Bechmann - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Torsten Kniess - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Jens Pietzsch - , Helmholtz-Zentrum Dresden-Rossendorf (Author)


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 (IC50(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 5d. This antiproliferative effect was diminished by the additional release of •NO by the corresponding NO-SERM 4d. Moreover, targeted release of •NO by 4d counteracted the antiproliferative effect of 5d in normal vascular tissue cells. Summarizing, the therapeutic index of SERMs might be improved by this bifunctional approach.


Original languageEnglish
Pages (from-to)6525-6539
Number of pages15
JournalJournal of medicinal chemistry
Issue number14
Publication statusPublished - 25 Jul 2019
Externally publishedYes

External IDs

Scopus 85067014305
ORCID /0000-0002-6932-333X/work/148144981


Sustainable Development Goals


  • Alkenes/chemistry, Antineoplastic Agents/chemistry, Breast Neoplasms/drug therapy, Cell Proliferation/drug effects, Estrogen Receptor alpha/antagonists & inhibitors, Estrogen Receptor beta/antagonists & inhibitors, Female, Human Umbilical Vein Endothelial Cells, Humans, Melanoma/drug therapy, Nitric Oxide Donors/chemistry, Selective Estrogen Receptor Modulators/chemistry, Therapeutic Index