Synthesis of the CYP24A1 major metabolite of 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D 3

Takano, Masashi; Yasuda, Kaori; Tohyama, Eri; Higuchi, Erika; Sakaki, Toshiyuki; Kittaka, Atsushi

doi:10.1016/j.jsbmb.2016.11.022

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…2 ). In our previous study, major metabolite of AH-1 by rat Cyp24a1 was identified as the 24 R -hydroxylated form, and the k cat / K m (μM −1 min −1 ) value of rat Cyp24a1 for AH-1 24R -hydroxylation was approximately 9% of that for 1,25(OH) 2 D 3 , suggesting that AH-1 is a poor substrate of rat Cyp24a1 compared with 1,25(OH) 2 D 3 24 , 25 . Furthermore, 24 R -hydroxylated AH-1 exhibited high binding affinity for VDR, which was 91% that of AH-1, and high HL-60 cell differentiation activity similar to AH-1 25 .…”

Section: Resultsmentioning

confidence: 84%

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats

Nishikawa

Murose

Mano

et al. 2022

Sci Rep

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Active vitamin D form 1α,25-dihydroxtvitamin D3 (1,25(OH)2D3) plays pivotal roles in calcium homeostasis and osteogenesis via its transcription regulation effect via binding to vitamin D receptor (VDR). Mutated VDR often causes hereditary vitamin D-dependent rickets (VDDR) type II, and patients with VDDR-II are hardly responsive to physiological doses of 1,25(OH)D3. Current therapeutic approaches, including high doses of oral calcium and supraphysiologic doses of 1,25(OH)2D3, have limited success and fail to improve the quality of life of affected patients. Thus, various vitamin D analogues have been developed as therapeutic options. In our previous study, we generated genetically modified rats with mutated Vdr(R270L), an ortholog of human VDR(R274L) isolated from the patients with VDDR-II. The significant reduced affinity toward 1,25(OH)2D3 of rat Vdr(R270L) enabled us to evaluate biological activities of exogenous VDR ligand without 1α-hydroxy group such as 25(OH)D3. In this study, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)2D3 (AH-1) exerted much higher affinity for Vdr(R270L) in in vitro ligand binding assay than both 25(OH)D3 and 1,25(OH)2D3. A robust osteogenic activity of AH-1 was observed in Vdr(R270L) rats. Only a 40-fold lower dose of AH-1 than that of 25(OH)D3 was effective in ameliorating rickets symptoms in Vdr(R270L) rats. Therefore, AH-1 may be promising for the therapy of VDDR-II with VDR(R274L).

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Section: Resultsmentioning

confidence: 84%

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats

Nishikawa

Murose

Mano

et al. 2022

Sci Rep

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“…Similarily, whether the VDR is also expressed in other bone cancers such as chondrosarcoma and Ewing's sarcoma, still needs to be investigated. As to the vitamin D metabolizing enzymes, we can be sure that they are widely expressed in primary bone cancers since a lot of studies on vitamin D metabolites have routinely been performed in osteosarcoma and other cell lines (73)(74)(75)(76). However, almost no studies exist with respect to the biological relevance of the expression of vitamin D metabolising enzymes in primary bone cancer.…”

Section: The Vitamin D Receptor and Bone Cancermentioning

confidence: 99%

The Role of Vitamin D and the Vitamin D Receptor in Bone Oncology

Holzapfel¹,

Jakob²,

Kurth³

et al. 2018

Osteologie

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SummaryVitamin D deficiency is a global health problem of enormous and increasing dimensions. In the past decades, numerous studies have centered on the role of vitamin D in the pathogenesis and course of many diseases including several types of cancer. Indeed, vitamin D has been widely acknowledged to be involved in the regulation of cell proliferation, differentiation and apoptosis in numerous cancer cells. While the full range of molecular mechanisms involveld in cancer cell growth and progression remains to be elucidated, recent research has deepened our understanding of the processes that may be affected by vitamin D or vitamin D deficiency.In this review, we consider the properties of bone that enable cancer cells to grow and thrive within the skeleton, and the role of vitamin D and the vitamin D receptor in the process of primary and secondary cancer growth in bone.

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“…This water molecule network is called a water channel. [4] We synthesized 2α-(3-hydroxypropyl)-1α,25(OH) 2 D 3 (O1C3) [5] and 2α-(3-hydroxypropoxy)-1α,25(OH) 2 D 3 (O2C3), [6] which have 3-times and 1.8-times higher VDR binding affinity, respectively, than 1α,25(OH) 2 D 3 comparing the 1 H NMR and 13 C NMR chemical shifts of the correlated methylene and methine H atoms of 4a and 4b (Scheme 1). [10a] The A-ring precursor 4a and the CDring bromoolefin 5 were connected under Trost coupling conditions.…”

Section: O1c3 and O2c3: Development Of Superagonists Of Hvdr That For...mentioning

confidence: 99%

“…2-4%). [9] We determined by HPLC that the major metabolite of AH-1 by CYP24A1 was (24R)-hydroxylated-AH-1 [13] and found that it had similar VDR binding affinity and human leukemia cell (HL-60 cell) differentiation activity to that of AH-1. In contrast, 1α,25(OH) 2 D 3 was metabolized by multistep monooxygenation reactions of CYP24A1, and the end-product lost binding affinity for VDR.…”

Section: Ah-1: a Potent Therapeutic For Bone Formation In Vivo Withou...mentioning

confidence: 99%

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 the CYP24A1 major metabolite of 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D 3

Cited by 7 publications

References 14 publications

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats

The Role of Vitamin D and the Vitamin D Receptor in Bone Oncology

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

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