Design and Synthesis of Fluoro Analogues of Vitamin D

Abstract

The discovery of a large variety of functions of vitamin D3 and its metabolites has led to the design and synthesis of a vast amount of vitamin D3 analogues in order to increase the potency and reduce toxicity. The introduction of highly electronegative fluorine atom(s) into vitamin D3 skeletons alters their physical and chemical properties. To date, many fluorinated vitamin D3 analogues have been designed and synthesized. This review summarizes the molecular structures of fluoro-containing vitamin D3 analogues and their synthetic methodologies.

Synthesis of (22R)-, (22S)-22-Fluoro-, and 22,22-Difluoro-25-hydroxyvitamin D3 and Effects of Side-Chain Fluorination on Biological Activity and CYP24A1-Dependent Metabolism

“…CYP24A1 is one of the main metabolic enzymes involved in the inactivation of 25-hydroxy and 1α,25-dihydroxyvitamin D 3 by hydroxylation at the C23 or C24 position (Scheme ). − Thus, in order to prevent catabolic hydroxylation by CYP24A1, numerous side-chain modified forms of vitamin D, particularly side-chain fluorinated vitamin D 3 analogues, have been designed and synthesized, and their chemical properties, as well as biological activities, have been evaluated …”

Further Studies on the Highly Active Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3 (Calcitriol): Refinement of the Side Chain

“…These new compounds incorporate modifications known to increase the VDR interactions, either a rigidified alkyne side chain or fluorine atoms at the terminus of the side chain. The presence of a triple bond in the side chain of 1,25D 3 analogues has been associated with an enzymatic block of hydroxylation at C-23 and C-24 but not at C-26. − Side chain fluorination has been used to synthesize 1,25D 3 analogues that are metabolically stable and have improved anticancer activity. , …”

The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D3 and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities

“…Vitamin D 3 is no exception. Fluorinated vitamin D 3 analogues have been synthesized to extend the biological half-life and modulate the binding affinity to the vitamin D receptor (VDR), and their biological activities have been evaluated [5]. Among them, the side-chain fluorination of vitamin D 3 has been vigorously pursued because hydroxylation of the side-chain C23 or C24 position and several subsequent oxidation steps by the metabolic enzyme CYP24A1 are the main deactivation processes of 25-hydroxyvitamin D 3 [25(OH)D 3 ] (1) (Scheme 1) [6][7][8].…”

“…As a result, the importance of developing comprehensive and straightforward synthetic methods for fluorinated vitamin D 3 analogues has increased. However, the synthetic methods reported so far are limited and mainly use sterol skeletons as starting materials, followed by photochemical transformation and thermal isomerization (Scheme 2) [5]. This strategy leads to a limited number of vitamin D derivatives even after multi-step synthesis with low chemical yields.…”