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Structural variants of the vitamin D analogue EB1089 reduce its ligand sensitivity and promoter selectivity
Author(s) -
Quack Marcus,
Clarin Andreas,
Binderup Ernst,
Björkling Fredrik,
Hansen Christina Mørk,
Carlberg Carsten
Publication year - 1998
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(19981201)71:3<340::aid-jcb3>3.0.co;2-c
Subject(s) - calcitriol receptor , chemistry , nuclear receptor , ligand (biochemistry) , retinoid x receptor , biochemistry , potency , receptor , cell culture , steroid , biological activity , retinoid , in vitro , stereochemistry , gene , biology , hormone , transcription factor , retinoic acid , genetics
The nuclear hormone 1α,25‐dihydroxyvitamin D 3 (VD) has important cell‐regulatory functions but also a strong calcemic effect. Therefore, various VD analogues have been synthesized and screened for their biological profile. In order to gain more insight into the molecular basis of the high antiproliferative but low calcemic action of the VD analogue EB1089, we characterized this compound in comparison to five structurally related VD analogues. The activities of the six VD analogues in in vitro assays (limited protease digestion assays for determining interaction with monomeric vitamin D receptor (VDR), ligand‐dependent gel shift assays for showing the increase of DNA binding of VDR‐retinoid X receptor (RXR) heterodimers, and reporter gene assays on different types of VD response elements for demonstrating the efficacy in nuclear VD signalling) were found to represent their biological potency (antiproliferative effect on different malignant cell lines). In this series, EB1089 proved to be the most potent VD analogue; that is, every structural modification (20‐epi configuration, cis ‐configuration at position C24, or changes at the ethyl groups at position C25) appeared to reduce the determined activities mediated through the VDR of these analogues. Moreover, the modifications of EB1089 resulted in a loss of VD response element selectivity, suggesting that this parameter is very critical for the biological profile of this VD analogue. J. Cell. Biochem. 71:340–350, 1998. © 1998 Wiley‐Liss, Inc.