New derivative of 1α,25-dihydroxy-19-norvitamin D3 with 3′-alkoxypropylidene moiety at C-2:: synthesis, biological activity and conformational analysis

被引：14
作者：
Glebocka, A [1 ]
Sicinski, RR [1 ]
DeLuca, HF [1 ]
机构：
[1] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA
来源：
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY | 2004年 / 89-90卷 / 1-5期
关键词：
vitamin D compounds; 19-norvitamin D; conformational analysis; vitamin D receptor; ligand docking to rVDR;
D O I：
10.1016/j.jsbmb.2004.03.105
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
In pursuit of novel biologically active Vitamin D compounds of potential therapeutic value, 1alpha,25-dihydroxy-2-[3'-(methoxymethoxy) propylidene]-19-norvitamin D-3 (7) was efficiently prepared in a convergent synthesis, starting with (-)-quinic acid and the protected 25-hydroxy Grundmann ketone 16. The key synthetic step involved Lythgoe type Wittig-Horner coupling of 16, with the phosphine oxide 15. Molecular modeling was employed to establish the A-ring conformation of the synthesized Vitamin 7. Also, preliminary modeling of its complex with the rVDR was performed and interactions between ligand and the binding domain analyzed. Analog 7 was found to be only six times less potent than 1alpha,25-(OH)(2)D-3 (1) in binding to the rat recombinant Vitamin D receptor (VDR). In comparison with hormone 1, it also showed slightly lower cellular HL-60-differentiation activity. Preliminary in vivo tests indicated unusually high calcemic activity of 7. (C) 2004 Elsevier Ltd. All rights reserved.
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页码：25 / 30
页数：6
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