The Red Shift in Estrogen Research: An Estrogen-Receptor Targeted aza-BODIPY-Estradiol Fluorescent Conjugate.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Boron Compounds*/chemistry ; Estradiol*/chemistry ; Estradiol*/pharmacology ; Fluorescent Dyes*/chemistry ; Estrogen Receptor alpha*/metabolism ; Estrogen Receptor alpha*/chemistry ; Estrogens*/chemistry ; Receptors, Estrogen*/metabolism ; Receptors, Estrogen*/chemistry; Humans ; Molecular Docking Simulation ; Binding Sites

Estradiol (E2) plays an important role in cell proliferation and certain brain functions. To reveal its mechanism of action, its detectability is essential. Only a few fluorescent-labeled hormonally active E2s exist in the literature, and their mechanism of action usually remains unclear. It would be of particular interest to develop novel labeled estradiol derivatives with retained biological activity and improved optical properties. Due to their superior optical characteristics, aza-BODIPY dyes are frequently used labeling agents in biomedical applications. E2 was labeled with the aza-BODIPY dye at its phenolic hydroxy function via an alkyl linker and a triazole coupling moiety. The estrogenic activity of the newly synthesized fluorescent conjugate was evaluated via transcriptional luciferase assay. Docking calculations were performed for the classical and alternative binding sites (CBS and ABS) of human estrogen receptor α. The terminal alkyne function was introduced into the tetraphenyl aza-BODIPY core via selective formylation, oxidation, and subsequent amidation with propargyl amine. The conjugation was achieved via Cu(I)-catalyzed azide-alkyne click reaction of the aza-BODIPY-alkyne with the 3-O-(4-azidobut-1-yl) derivative of E2. The labeled estrogen induced a dose-dependent transcriptional activity of human estrogen receptor α with a submicromolar EC50 value. Docking calculations revealed that the steroid part has a perfect overlap with E2 in ABS. In CBS, however, a head-tail binding deviation was observed. A facile, fluorescent labeling methodology has been elaborated for the development of a novel red-emitting E2 conjugate with substantial estrogenic activity. Docking experiments uncovered the binding mode of the conjugate in both ABS and CBS.

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SNN 139323 nkfih

Keywords: CuAAC reaction; aza-BODIPY; docking; estradiol; fluorescent labeling; luciferase; red-emission

0 (Boron Compounds)
4TI98Z838E (Estradiol)
0 (Fluorescent Dyes)
0 (Estrogen Receptor alpha)
0 (Estrogens)
0 (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)
0 (azaBDPBA compound)
0 (Receptors, Estrogen)

Date Created: 20250814 Date Completed: 20250826 Latest Revision: 20250826

20260130

PMC12346466

10.3390/ijms26157075

40806208