2-Ethyl and 2-Ethylidene Analogues of 1α,25-Dihydroxy-19-norvitamin D₃:  Synthesis, Conformational Analysis, Biological Activities, and Docking to the Modeled rVDR Ligand Binding Domain

Abstract

Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann's ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported.

Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer

“…We observed that 19-nor-1␣,25(OH) 2 D 2 had antiproliferative activity comparable to 1␣,25(OH) 2 D 3, as determined by 3 H-thymidine incorporation and cell counting. These findings led to further modification of A-ring, including the synthesis of C-2 modified 19-nor vitamin D compounds by several groups [8,9]. In this report, we investigated the effect of a series of 19-nor-1␣,25(OH) 2 D 3 analogs modified at C-2 position on the proliferation of prostate cells and on the invasiveness of prostate cancer cells.…”

Synthesis of 24,24-Difluoro-1,3-<i>cis</i>-25-dihydroxy-19-norvitamin D₃ Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity

“…The relative stereochemistries were assigned by 1 H-NMR and nuclear Overhauser effect (NOE) correlations, as reported previously in the literature. 14,17,18) Each compound was subjected to two-step deprotection using K 2 CO 3 in methanol, followed by hydrogen fluoride·pyridine (HF·Py) in THF, to afford 6a and b, respectively, in 64% yield (Chart 2).…”

Metabolism and Action of 25-Hydroxy-19-nor-Vitamin D3 in Human Prostate Cells

“…It has been shown that 19-demethylenated analogs of 1α,25(OH) 2 D 3 , i.e., 1α,25(OH) 2 -19-nor-vitamin D 2 and 1α,25(OH) 2 -19-nor-vitamin D 3 , possess similar pro-differentiation and antiproliferative activities as 1α,25 (OH) 2 D 3 (Chen et al, 2000;Chen, Holick, Lokeshwar, Burnstein, & Schwartz, 2003) and are less calcemic than 1α,25(OH) 2 D 3 when administered systemically (DeLuca et al, 2005;Sicinski et al, 2002). Since it is also known that prostate cells possess 1α-hydroxylase, (1α(OH)ase), and can activate 25(OH)D 3 to 1α,25(OH) 2 D 3 intracellularly to inhibit their proliferation (Krishnan, Peehl, & Feldman, 2003;Schwartz & Chen, 2005), we therefore hypothesized that 25-hydroxy-19-nor-vitamin D 3 (25(OH)-19-nor-D 3 ) could exert potent antiproliferative activity toward prostate cells which possess 1α(OH)ase activity through similar activation process and could be used as chemopreventive agents without causing hypercalcemic side effects.…”