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

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 D, calcipotriol, and oxacalcitriol, suggesting preclinical studies related to hyperproliferative disorders such as psoriasis and cancer.

Vitamins D: Relationship between Structure and Biological Activity

“…Docking studies to the human ligand-binding domain of the VDR led to the design of these analogues. The analogue with an ethyl substituent to mimic the missing C-ring is active against breast cancer cells and, as expected, has negligible calcemic action [ 36 ]. These analogues provide important information about the structure–activity relationships regarding CD-ring modifications.…”

“…The accumulating of more and more data leads to the viewpoint that the standing model might be of limited significance, because the resulting solid-state structures of various analogues show overlapping of the functional hydroxyls. Very recently, a study of a panel of five analogues of very different structures recorded no detectable differences regarding binding to the VDR [ 36 ].…”

Vitamin D and Its Synthetic Analogs

“…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) 2 D 3 .…”

Update on pharmacologically‐relevant vitamin D analogues

“…Another family of 1,25‐(OH) 2 D 3 analogues, the C/D‐ring modified derivatives (Table ), that are commanding attention are under development for use in other fields include the Hybrigenics drug, Inecalcitol [14‐epi, 23‐yne derivative of 1,25‐(OH) 2 D 3 ], which induces apoptosis in squamous cell carcinoma models and is being tested in a clinical trial for treatment of leukaemia ; and the C‐8 alkyl, C‐ring‐less, m‐phenylene aromatic D‐ring derivatives of 1,25‐(OH) 2 D 3 , which are purported to be noncalcaemic. Although there is optimism with every new family of vitamin D analogues, caution prevails as many have claimed that vitamin D analogues are non‐calcaemic or low‐calcaemic during in vitro testing only to find that the agents are rejected during clinical trials due to their calcaemic side‐effects in vivo .…”