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J Med Chem. 2018 Jun 14;61(11):4928-4937. doi: 10.1021/acs.jmedchem.8b00337. Epub 2018 May 22.

Aromatic-Based Design of Highly Active and Noncalcemic Vitamin D Receptor Agonists.

Author information

1
Department of Organic Chemistry, Research Laboratory Ignacio Ribas , University of Santiago de Compostela , Avenida das Ciencias s/n , 15782 Santiago de Compostela , Spain.
2
Department of Physiology-Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) , University of Santiago de Compostela , Avenida Barcelona s/n , 15706 Santiago de Compostela , Spain.
3
Department of Integrative Structural Biology , IGBMC-Université de Strasbourg, CNRS UMR 7104, INSERM U1258 , 67400 Illkirch , France.
4
Laboratoire ICube , Université de Strasbourg, CNRS UMR 7357 , 67000 Strasbourg , France.
5
Department of Chemistry-CICA , University of A Coruña , Campus da Zapateira s/n , 15071 A Coruña , Spain.

Abstract

We report the design, synthesis, biological evaluation, and structural analysis of a new class of vitamin D analogues that possess an aromatic m-phenylene D-ring and an alkyl chain replacing the C-ring. A key feature of the synthetic strategy is a stereoselective Pd-catalyzed construction of the triene system in aqueous medium that allows the rapid preparation of small amounts of VDR ligands for biological screening. Analogues with the shorter (2a) and longer (2d, 2e) side chains attached to the triene system have no calcemic activity. Compound 2a binds to VDR with the same order of magnitude than calcipotriol and oxacalcitriol. It also reduces proliferation in normal and tumor cells similarly to the natural hormone 1α,25-dihydroxyvitamin D3, calcipotriol, and oxacalcitriol, suggesting preclinical studies related to hyperproliferative disorders such as psoriasis and cancer.

PMID:
29733645
DOI:
10.1021/acs.jmedchem.8b00337
[Indexed for MEDLINE]

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