Conceptually New Low-Calcemic Oxime Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃:  Synthesis and Biological Testing

Abstract

New chemical entities 16-ene-25-ketone 2b and the corresponding oxime 3b and oxime ether 4b, analogues of natural calcitriol (1), were rationally designed and synthesized on a milligram scale. Chemical introduction of the oxime ether functionality in analogue 4b was successful via direct oximation of an intact vitamin D conjugated triene system. Even though all three analogues are at least as antiproliferative in vitro as calcitriol (1) even at physiologically relevant low nanomolar concentrations, only side chain ketone 2b is more transcriptionally potent than calcitriol (1). Although oxime O-methyl ether 4b lacks the traditional side chain hydrogen bond-donating OH group of the natural hormone and lacks also the oxime-NOH group of analogue 3b, surprisingly, oxime ether 4b retains 20% of the transcriptional potency of natural calcitriol (1). In terms of in vivo toxicity (hypercalcemia), ketone 2b is strongly calcemic in rats, whereas oxime 3b and oxime ether 4b are considerably less calcemic (i.e., safer) than calcitriol (1).

QW-1624F2-2, a synthetic analogue of 1,25-dihydroxyvitamin D3, enhances the response to other deltanoids and suppresses the invasiveness of human metastatic breast tumor cells

“…The structural modifications in QW have the potential to modify its binding affinity to the VDR as compared with 1,25(OH) 2 D 3 (35). The results shown in Fig.…”

Organic Chemistry of Vitamin D Analogues (Deltanoids)

“…Although it is not a hybrid deltanoid, the conceptually new 16‐ene‐25‐oxime deltanoid 33 has desirably low calcemic activity and is antiproliferatively and transcriptionally potent. Oxime deltanoid 33 was prepared also from the key 16‐ene‐23‐aldehyde building block 22 (Scheme ) 23. Noteworthy in its synthesis is the regiospecific joining of the A‐ring nucleophile 32 with only the C‐8 ketone group in the C‐8,C‐25‐diketone (+)‐ 31 ; also noteworthy is the oximation of the C‐25 ketone group, which occurs without disturbing the sensitive conjugated triene unit.…”

Therapeutic Potential of a Novel Vitamin D3 Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding

“…Among the reported synthetic analogues for calcitriol, different side-chain C-24 and C-25 oxime and oxime ether analogues have been previously described and biologically evaluated [ 23 , 24 ]. Recently, attention has been brought to side-chain oxime-substituted vitamin D 3 analogues as potential bioactive candidates, where the synthesis of three C-24 oxime derivatives has been described [ 22 ].…”