The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands

Since the discovery of vitamin D a century ago, a great number of metabolites, analogs, hybrids and nonsteroidal VDR ligands have been developed. An enormous effort has been made to synthesize compounds which present beneficial properties while attaining lower calcium serum levels than calcitriol. This structural review covers VDR ligands published to date.


Introduction
Since the chemical structure of vitamin D 3 (1, Figure 1  , cholecalciferol) was established in 1932, successive studies have shown it to be essential in physiological processes. Two hydroxylations of 1 are necessary before attaining its most biologically active form. The first is a 25-hydroxylation, which occurs mainly in the liver and produces the most abundant circulating metabolite, 25-hydroxyvitamin D 3 (11, Figure 1, 25-hydroxycholecalciferol, calcidiol, 25OHD 3 ) [12]. Subsequently, a second hydroxylation at the 1α position generates the vitamin D hormone, 1α,25-dihydroxyvitamin D 3 (13, Figure  1, 1α,25-dihydroxycholecalciferol, calcitriol, 1,25(OH) 2 D 3 ) [14]. This is a pleiotropic hormone that exerts genomic actions by binding to its specific receptor (the vitamin D receptor, VDR), which is present on target cells and found in more than 200 different tissues.
The biological role of 1,25(OH) 2 D 3 has been related to calcium and phosphorus homeostasis. However, the effects of vitamin D are not limited to mineral homeostasis, skeletal health maintenance, or immune modulation. In addition, this hormone also has fundamental effects on cellular proliferation and differentiation, regulating genes involved in the cell cycle and apoptosis both in normal and tumor cells. These properties and its wide distribution have led to the study of its effects on various pathologies, such as osteoporosis and cancer, thus arousing interest in the field of health and the pharmaceutical industry. Unfortunately, the therapeutic use of 1,25(OH) 2 D 3 also leads to an increase in the concentration of calcium in blood (hypercalcemia), which can cause significant side effects. Therefore, numerous attempts have been made to synthesize noncalcemic analogs of 1,25(OH) 2 D 3 for use in health treatment.
In recent decades, structure-function relationships (SARs) have been determined to support the chemical modifications of the secosteroid structure of 1,25(OH) 2 D 3 . The novel structures' goal is to reduce their calcemic activity in comparison with calcitriol while exerting their interesting biological properties. A huge synthesis effort has been carried out, yielding interesting chemical reviews in this regard [2]. The current review updates the scientific information on the structural library of VDR ligands and incorporates nonsteroidal VDR ligands.

Materials and Methods
All compounds contained in this review were collected from published papers and patents. Most of the materials were freely accessible via the Internet, and paper copies Side-chain modification with extra double and/or triple bonds, heteroatoms, and/or branched hydrocarbons.

Conclusions
A century has passed since vitamin D was discovered. The structural diversity achieved among vitamin D receptor ligands (1785 ligands involving metabolites, analogs, hybrids, and nonsteroidal ligands). Seeing as vitamin D plays a ubiquitous role in human physiology, VDR ligands have been found to cure or ameliorate the symptoms of various diseases. It is disheartening to note that for more than twenty years no drug based on a VDR ligand (i.e., analogues, hybrids, or nonsteroidal ligands) has been placed on the market because the structural diversity achieved in the VDR ligands might encode new therapies for other illness different than the calcium-phosphorous homeostasis.