Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D3 Derivatives: Stereoselectivity and Biological Activity

Yuka Mizumoto,Masayuki Tera,Ryota Sakamoto,Suzuka Sakane,Akiko Nagata,Minami Odagi,Atsushi Kittaka,Kazuo Nagasawa

doi:10.3390/biom12010069

Yuka Mizumoto, Masayuki Tera + Show 6 more

Open Access

https://doi.org/10.3390/biom12010069

Copy DOI

Abstract

The active form of vitamin D3 (D3), 1a,25-dihydroxyvitamn D3 (1,25D3), plays a central role in calcium and bone metabolism. Many structure–activity relationship (SAR) studies of D3 have been conducted, with the aim of separating the biological activities of 1,25D3 or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D3 derivatives with alkoxy groups at C2, by means of the Julia–Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted C2α-7a was found to show potent cell-differentiating activity, with an ED50 value of 0.38 nM, being 26-fold more potent than 1,25D3.

Highlights

Academic Editor: Christophe BrunetThe active form of vitamin D3 (D3 ), 1a,25-dihydroxyvitamin D3 (1,25D3 ), is involved in various physiological activities, including calcium metabolism, cell differentiation, and immunomodulation, via binding to the vitamin D receptor (VDR) [1,2,3,4]
The ketones 5a–c bearing a methoxy, benzyloxy or 4-NO2 -phenyloxy group were synthesized from diol 2 derived from (-)-quinic acid (1), as follows (Scheme 1) [23]
The diol 2 was reacted with p-anisaldehyde dimethyl acetal, using camphor sulfonic acid as a catalyst, to give benzylidene acetal 3, and the resulting secondary alcohol was converted into a methoxy, benzyloxy or p-nitrophenoxy group by the reaction with methyl iodide, benzyl iodide, or 4-fluoro-p-nitrobenzene, respectively, to give ethers 4a–c. the deprotection of the benzylidene acetal in 4 was conducted with PPTS, followed by oxidative cleavage of the resulting diol with sodium periodate to obtain A ring ketones 5a–c in 20–60% yield from 4

Summary

Introduction

The active form of vitamin D3 (D3 ), 1a,25-dihydroxyvitamin D3 (1,25D3 ), is involved in various physiological activities, including calcium metabolism, cell differentiation, and immunomodulation, via binding to the vitamin D receptor (VDR) [1,2,3,4]. C2 have significant effects on the binding affinity to VDR, as well as on calcium metabolism and cell-differentiating activity. A derivative of ED-71 (C2β-7a’) bearing a hydropropoxy group at C2, shows bone formation activity comparable to that of 1,25D3 despite its weak binding affinity for VDR [5,6]. 19-nor type derivatives (7b’) have been reported to show suppressed hypercalcemic activity, while retaining cell differentiation-inducing activity [7]. There is considerable interest in the synthesis and biological activities of 19-nor type derivatives bearing a substituent at C2

Methods

Results

Conclusion