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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).