Syntheses of 25-Adamantyl-25-alkyl-2-methylidene-1α,25-dihydroxyvitamin D3 Derivatives with Structure-Function Studies of Antagonistic and Agonistic Active Vitamin D Analogs

Kazuki Maekawa; Michiyasu Ishizawa; Takashi Ikawa; Hironao Sajiki; Taro Matsumoto; Hiroaki Tokiwa; Makoto Makishima; Sachiko Yamada

doi:10.3390/biom13071082

Syntheses of 25-Adamantyl-25-alkyl-2-methylidene-1α,25-dihydroxyvitamin D₃ Derivatives with Structure-Function Studies of Antagonistic and Agonistic Active Vitamin D Analogs

Biomolecules. 2023 Jul 6;13(7):1082. doi: 10.3390/biom13071082.

Authors

Kazuki Maekawa¹, Michiyasu Ishizawa², Takashi Ikawa³, Hironao Sajiki³, Taro Matsumoto⁴, Hiroaki Tokiwa³, Makoto Makishima², Sachiko Yamada²

Affiliations

¹ Department of Chemistry, Faculty of Science, Rikkyo University, Toshima-ku, Tokyo 171-8501, Japan.
² Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
³ Laboratory of Organic Chemistry, Gifu Pharmaceutical University 1-25-4 Daigaku-Nishi, Gifu 501-1196, Japan.
⁴ Department of Functional Morphology, Division of Cell Regeneration and Transplantation, Nihon University School of Medicine, Tokyo 173-8610, Japan.

Abstract

The active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], is a major regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). We have previously synthesized vitamin D derivatives with large adamantane (AD) rings at position 24, 25, or 26 of the side chain to study VDR agonist and/or antagonist properties. One of them-ADTK1, with an AD ring and 23,24-triple bond-shows a high VDR affinity and cell-selective VDR activity. In this study, we synthesized novel vitamin D derivatives (ADKM1-6) with an alkyl group substituted at position 25 of ADTK1 to develop more cell-selective VDR ligands. ADKM2, ADKM4, and ADKM6 had VDR transcriptional activity comparable to 1,25(OH)₂D₃ and ADTK1, although their VDR affinities were weaker. Interestingly, ADKM2 has selective VDR activity in kidney- and skin-derived cells-a unique phenotype that differs from ADTK1. Furthermore, ADKM2, ADKM4, and ADKM6 induced osteoblast differentiation in human dedifferentiated fat cells more effectively than ADTK1. The development of vitamin D derivatives with bulky modifications such as AD at position 24, 25, or 26 of the side chain is useful for increased stability and tissue selectivity in VDR-targeting therapy.

Keywords: cell selectivity; nuclear receptor; osteoblast differentiation; vitamin D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation
Cholecalciferol* / pharmacology
Gene Expression Regulation
Humans
Vitamin D* / pharmacology

Substances

1,25-dihydroxyvitamin D
Vitamin D
Cholecalciferol

Grants and funding

This research was partly supported by the MEXT-supported Program for the Strategic Research Foundation at Private Universities (S1411018) by the Ministry of Education, Culture, Sports, Science and Technology in Japan, by the Nihon University President Grant Initiative (2018–2020), and by the Research Grant from the Chairperson and the President of Nihon University (2021–2022) by the Nihon University.