Vitamin D and Its Synthetic Analogs.

Miguel A Maestro,Carsten Carlberg,Ferdinand Molnár

doi:10.1021/acs.jmedchem.9b00208

Abstract

For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR’s ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein.

Highlights

An UV-B (290−315 nm)-dependent, nonenzymatic reaction in human skin converts the cholesterol precursor 7-dehydrocholesterol into previtamin D3 that further isomerizes into vitamin D3[1] (Figure 1)
The physiological role of vitamin D is the regulation of calcium homeostasis for maintaining bone mineralization[6] as well as the modulation of innate and adaptive immunity[7] for improving the response to infections by microbes, such as Mycobacterium tuberculosis,[8] and preventing autoimmune diseases, such as multiple sclerosis.[9]
Like in secosteroidal vitamin D analogs, fluorination is an effective modification as shown by crystal structure analysis of the vitamin D receptor (VDR)-ligand-binding domain (LBD) complexed with 155

Summary

■ INTRODUCTION

An UV-B (290−315 nm)-dependent, nonenzymatic reaction in human skin converts the cholesterol precursor 7-dehydrocholesterol into previtamin D3 that further isomerizes into vitamin D3 (calciferol, 1)[1] (Figure 1). Like in secosteroidal vitamin D analogs, fluorination is an effective modification as shown by crystal structure analysis of the VDR-LBD complexed with 155 In this case helix H12 is stabilized in the agonistic position allowing interaction with coactivator proteins. A novel class of analogs,[83] where the C-ring and D-ring were replaced by an aromatic m-phenylene D-ring and an alkyl chain, were synthesized based on the formation of the triene system through a Pd-catalyzed ring-closure of an enol trifate and a subsequent Suzuki−Miyaura reaction with appropriate boronate in aqueous medium.[84] Compounds 166a−e efficiently induce the differentiation of human keratinocytes and show antiproliferative activity in MCF-7, PC-3, SKOV-3 (human ovary cancer), and HaCaT cells comparable to 1,25(OH)2D3. 166a shows high efficacy for tumor growth inhibition and overall survival

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES