Development of Analogues of 1α,25‐Dihydroxyvitamin D 3 with Biased Side‐Chain Orientation: C20 Methylated Des‐C,D‐homo Analogues

• Published in: European journal of organic chemistry Vol. 2009; no. 11; pp. 1720 - 1737
• Main Authors: Vrielynck, Freek, Van Haver, Dirk, Vandewalle, Maurits, Verlinden, Lieve, Verstuyf, Annemieke, Bouillon, Roger, Croce, Gianluca, De Clercq, Pierre
• Format: Journal Article
• Language: English
• Published: 01-04-2009
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200801183

Abstract
The discovery that 1α,25‐dihydroxyvitamin D
3
is effective in the inhibition of cellular proliferation and in the induction of cellular differentiation has led to a search for analogues in which these activities and the classical calcemic activity of the hormone are dissociated. In this context, the synthesis and biological evaluation are reported for six CD‐ring modified structural analogues that were conceived so as to enforce a particular orientation of the 25‐hydroxylated side chain. The analogues are characterized by the absence of the C‐ring and the presence of an unnatural six‐membered D‐ring. The biased side‐chain orientations are realized through the stereocontrolled incorporation of methyl substituents at positions C13/C20 and C16/C20. Comparison of the results of the biological evaluation and conformational analysis of the side chain confirms the existence of a relationship between inhibition of MCF‐7 breast cancer cell proliferation and side chain geometry.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)