Vitamin
D3 metabolites inhibit the expression of lipogenic
genes by impairing sterol regulatory element-binding protein (SREBP),
a master transcription factor of lipogenesis, independent of their
canonical activity through a vitamin D receptor (VDR). Herein, we
designed and synthesized a series of vitamin D derivatives to search
for a drug-like small molecule that suppresses the SREBP-induced lipogenesis
without affecting the VDR-controlled calcium homeostasis in vivo.
Evaluation of the derivatives in cultured cells and mice led to the
discovery of VDR-silent SREBP inhibitors and to the development of
KK-052 (50), the first vitamin D-based SREBP inhibitor
that has been demonstrated to mitigate hepatic lipid accumulation
without calcemic action in mice. KK-052 maintained the ability of
25-hydroxyvitamin D3 to induce the degradation of SREBP
but lacked in the VDR-mediated activity. KK-052 serves as a valuable
compound for interrogating SREBP/SCAP in vivo and may represent an
unprecedented translational opportunity of synthetic vitamin D analogues.
Two 24-fluoro-25-hydroxyvitamin D3 analogues (3,4) were synthesized in a convergent manner. The introduction of a stereocenter to the vitamin D3 side-chain C24 position was achieved via Sharpless dihydroxylation, and a deoxyfluorination reaction was utilized for the fluorination step. Comparison between (24R)- and (24S)-24-fluoro-25-hydroxyvitamin D3 revealed that the C24-R-configuration isomer 4 was more resistant to CYP24A1-dependent metabolism than its 24S-isomer 3. The new synthetic route of the CYP24A1 main metabolite (24R)-24,25-dihydroxyvitamin D3 (6) and its 24S-isomer (5) was also studied using synthetic intermediates (30,31) in parallel.
The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies.
Two novel 23-fluorinated 25-hydroxyvitamin D
3
analogues were
synthesized using Inhoffen–Lythgoe diol as a precursor of the
CD-ring, efficiently. Introduction of the C23 fluoro group was achieved
by the deoxy-fluorination reaction using
N
,
N
-diethylaminosulfur trifluoride or 2-pyridinesulfonyl fluoride
(PyFluor). Kinetic studies on the CYP24A1-dependent metabolism of
these two analogues revealed that (23
S
)-23-fluoro-25-hydroxyvitamin
D
3
was more resistant to CYP24A1-dependent metabolism than
its 23
R
isomer.
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