Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D3 Analogues and Their Stability to hCYP24A1-Dependent Catabolism

Fumihiro Kawagoe; Sayuri Mototani; Kaori Yasuda; Hiroki Mano; Toshiyuki Sakaki; Atsushi Kittaka

doi:10.3390/ijms222111863

Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D₃ Analogues and Their Stability to hCYP24A1-Dependent Catabolism

Int J Mol Sci. 2021 Nov 1;22(21):11863. doi: 10.3390/ijms222111863.

Authors

Fumihiro Kawagoe¹, Sayuri Mototani¹, Kaori Yasuda², Hiroki Mano², Toshiyuki Sakaki², Atsushi Kittaka¹

Affiliations

¹ Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Tokyo 173-8605, Japan.
² Faculty of Engineering, Toyama Prefectural University, Imizu 939-0398, Japan.

Abstract

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.

Keywords: 24-fluoro-25-hydroxyvitamin D3 analogues; Sharpless dihydroxylation; human CYP24A1; synthesis; vitamin D3 metabolite.

MeSH terms

Calcifediol / analogs & derivatives*
Drug Stability
Fluorides / chemical synthesis*
Fluorides / chemistry
Humans
Molecular Structure
Stereoisomerism
Vitamin D3 24-Hydroxylase / metabolism*

Substances

CYP24A1 protein, human
Vitamin D3 24-Hydroxylase
Calcifediol
Fluorides

Abstract

MeSH terms

Substances

Grants and funding