Synthesis of 2α- and 2β-substituted-14-epi-previtamin D3 and their genomic activity

Sawada, Daisuke; Katayama, Tomoyuki; Tsukuda, Yuya; Saito, Nozomi; Saito, Hiroshi; Takagi, Ken; Ochiai, Eiji; Ishizuka, Seiichi; Takenouchi, Kazuya; Kittaka, Atsushi

doi:10.1016/j.tet.2010.05.028

Cited by 14 publications

(14 citation statements)

References 66 publications

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“…During the course of screening our in-house collection of vitamin D analogues, we noted that 14- epi -previtamin D 3 ( 4 ) compromised the expression of an SREBP-responsive luciferase reporter at a comparable level to 25(OH)D 3 (data not shown). The 14-epi isomer of 25(OH)D 3 has the tendency to isomerize via [1,7]-sigmatropic hydrogen shifts toward its previtamin form and has been demonstrated to display a lower affinity to VDR and markedly decreased calcemic action .…”

Section: Resultsmentioning

confidence: 99%

“…25(OH)D 3 as an SREBP inhibitor. (A) Structures of 25(OH)D 3 ( 1 ), 1α,25(OH) 2 D 3 ( 2 ), 1,3-bisfunctionalized 19-norvitamin D 3 ( 3 ), 14- epi -previtamin D 3 ( 4 ), and the vitamin D 3 derivatives ( 5 ) newly synthesized in the present study. (B) Proposed mode of action of 25(OH)D 3 and its analogues for SREBP/SCAP inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo

et al. 2021

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“…In our effort to delineate VD 3 activity, we initially searched for VD 3 analogs that activate VDR but lack SREBP inhibitory activity. An in-house library of 250 vitamin D congeners − was screened for their ability to inhibit the activity of an SREBP-responsive luciferase reporter, in which expression of luciferase is controlled by three SREBP binding sites. We found that a series of vitamin D analogs, bearing alkyltriazole and alkyltetrazole substituents at C2 ( 4 – 9 ) (Figure ), displayed limited SREBP inhibitory activities (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Synthetic Chemical Probes That Dissect Vitamin D Activities

Nagata

Akagi

Asano³

et al. 2019

ACS Chem. Biol.

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“…[36c,d] First, 14-epi-19-norprevitamin D 3 analogs were synthesized and compared to 14-epi-previtamin D 3 analogs. [37,38] We found proton-catalyzed isomerization of synthesized 14-epi-19-norprevitamin D 3 skeletons to the stable 14-epi-19-nortachysterols. [39] We synthesized 14-epi-1α,25-dihydroxy-19-nortachysterol and its 2-substituted analogs using a Stille coupling reaction between the A-ring precursor vinylstannane and the CD-ring triflate (Scheme 6).…”

Section: Mart-10: a 2α-modified 19-norvitamin D 3 For Cancer Therapymentioning

confidence: 88%

Creation of Potent Vitamin D Receptor Agonists and Antagonists with 2α-(ω-Hydroxyalkylation) Concept to the seco-Steroid Skeleton

Kittaka

2018

Chimia

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2?-modification on the vitamin D skeleton with a 2?-(?-hydroxyalkyl) or 2?-(?-hydroxyalkoxy) group improves vitamin D receptor (VDR) binding affinity, lengthens the half-life in target cells because of increased resistance to CYP24A1 metabolism, and enhances biological activity. The introduced terminal hydroxy group forms an additional hydrogen bond to Arg274, which is the most important amino acid residue for recognizing the ligand hormone 1?,25-dihydroxyvitamin D3 of human VDR. According to our 2?-functionalization concept, we synthesized several hundred vitamin D analogs, and some had selective potent biological activity, such as bone formation (by AH-1) or anticancer activity (by MART-10), without the side-effects of vitamin D such as hypercalcemia. A potent hVDR antagonist NS-74c and stable 14-epi-tachysterol derivatives are also described in this short review.

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Synthesis of 2α- and 2β-substituted-14-epi-previtamin D3 and their genomic activity

Cited by 14 publications

References 66 publications

Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo

Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo

Synthetic Chemical Probes That Dissect Vitamin D Activities

Creation of Potent Vitamin D Receptor Agonists and Antagonists with 2α-(ω-Hydroxyalkylation) Concept to the seco-Steroid Skeleton

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