In my 25 years of studies on synthesizing vitamin D derivatives, some important compounds with unique biological activity profiles have been found. Introducing an appropriate functional group into the 2α-direction of the A-ring of active vitamin D₃ improved the binding affinity to the vitamin D receptor (VDR). First, a convenient synthetic route to the 2α-substituted A-ring part of active vitamin D₃ from D-glucose was developed. On the other hand, for 2α-substituted-19-nor-1α,25-dihydroxyvitamin D₃, the 2-substituted A-ring precursor was synthesized from quinic acid using a radical C-C bond formation reaction, which was connected to the CD-ring part by the Julia-Kocienski olefination reaction to create MART-10 having a potent anticancer activity without calcemic side effects in vivo. Through simultaneous chemical modification of the 2α- and 24-positions of the VDR antagonist TEI-9647, a new VDR antagonist NS-74c that was 850 times more potent (IC₅₀ 7.4 pM) than the original TEI-9647 (IC₅₀ 6.3 nM) was discovered. Furthermore, by introducing a tetrazolylalkyl group into the 2α-position of active vitamin D₃, AH-1, which showed a potent bone formation effect in vivo, was discovered. Knowledge about the synthesis of tachysterol analogues was also gained. The first 15-substituted active vitamin D₃ was synthesized and X-ray co-crystallographic analysis with human VDR was performed. Furthermore, a vitamin D derivative, KK-052 was synthesized and this KK-052 was found to impair sterol regulatory element-binding protein (SREBP) that is a master transcriptional factor of lipogenesis. This led to the construction of a chemical library of side-chain fluorinated 25-hydroxyvitamin D₃ derivatives, and also side-chain fluorinated MART-10 derivatives with strong inhibitory effects on IL-19 secretion from keratinocytes were obtained. This review provides the overview of the above findings.

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