Investigation of 20S-hydroxyvitamin D3 analogs and their 1alpha-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities

Zongtao Lin (1) , Srinivasa Marepally (1) , Emily Goh (2) , Chloe Cheng (2) , Zorica Janjetovic (3) , Tae-Kang Kim (3) , Duane Miller (1) , Arnold Postlethwaite (1) , Andrzej Slominski (3) , Robert Tuckey (2) , Carole Peluso-Iltis (4) , Natacha Rochel-Guiberteau (4) , Wei Li (1)

1 UTHSC - The University of Tennessee Health Science Center [Memphis]
2 UWA - The University of Western Australia
3 UAB - University of Alabama at Birmingham [ Birmingham]
4 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1alpha-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1alpha-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1alpha-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1alpha-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1alpha-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.

Domaines: Chimie thérapeutique

Zongtao Lin, Srinivasa Marepally, Emily Goh, Chloe Cheng, Zorica Janjetovic, et al.. Investigation of 20S-hydroxyvitamin D3 analogs and their 1alpha-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities. Scientific Reports, 2018, 8, pp.1478. ⟨10.1038/s41598-018-19183-7⟩. ⟨hal-03671899⟩