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

Abstract

In pursuit of novel biologically active Vitamin D compounds of potential therapeutic value, 1α,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 1α,25-(OH) 2D 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.