2-Methylene analogs of 1$alpha;-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor*1

Abstract

In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1α-hydroxy-19-norvitamin D 3 analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig–Horner coupling of Windaus–Grundmann type ketones 9 , possessing different 17β-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1α,25-dihydroxyvitamin D 3 (1α,25-(OH) 2 D 3 ) ( 1 ) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported.