Design, synthesis and biological evaluation of nonsecosteroidal vitamin D3 receptor ligands as anti-tumor agents.

Abstract

1α,25-dihydroxyvitamin D3 (1,25-(OH)2D3, also known as calcitriol), the active form of vitamin D3, is being increasingly recognized for cancer therapy. Our previous work showed that phenyl-pyrrolyl pentane analogs, which mimicked anti-proliferative activities against several cancer cell lines of the natural secosteroidal ligand 1,25-(OH)2D3. Here, in order to optimize the structural features and discover more potent derivative, a series of nonsecosteroidal vitamin D3 receptor (VDR) ligands bearing acetylene bond linker was designed, synthesized and evaluated. Most of them showed moderate to good binding affinities and agonistic activities. Especially, compound 19f displayed the most anti-proliferative activities against MCF-7 and PC-3 cells with the IC50 values of 1.80 and 5.35μM, respectively, which was comparable to positive control 1,25-(OH)2D3. Moreover, compound 19f exhibited reduced toxicity against human normal liver cell line (L02) compared with the parental compound 7. Besides, the preliminary structure-activity relationships (SARs) were also analyzed.

• Authors: Bin Wang, Meixi Hao, Can Zhang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 6 Pg. 1428-1436 (03 15 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28216405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Ligands
• Receptors, Calcitriol
• Steroids

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Inhibitory Concentration 50
• Ligands
• Models, Molecular
• Receptors, Calcitriol (metabolism)
• Steroids (chemistry, metabolism, pharmacology)
• Structure-Activity Relationship