Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies

Abstract

The active form of vitamin D3, calcitriol, is a potent antiproliferative compound. However, when effective antitumor doses of calcitriol are used, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim of retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report aims at gaining insights into the structure–activity relationships of the novel oxolane‐containing analogue, AM‐27, recently synthesized. We herein demonstrate that this compound has antiproliferative and antimigratory effects in squamous cell carcinoma, glioblastoma, and breast cancer cell lines. Analyses of the mechanisms underlying the AM‐27 effects on cell viability revealed induction of apoptosis by the analogue. Importantly, nonmalignant cell lines were little or not affected by the compound. In addition, the analogue did not produce hypercalcemia in mice. Also, in silico studies involving docking and molecular dynamics techniques showed that AM‐27 is able to bind to the human vitamin D receptor with a higher affinity than the natural ligand calcitriol, a feature that is mostly derived from an electrostatic interaction pattern. Altogether, the proapoptotic effect observed in cancer cells, the lack of calcemic activity in mice, and the differential effects in normal cells suggest the potential of AM‐27 as a therapeutic compound for cancer treatment.

Vitamin D, the Vitamin D Receptor, Calcitriol Analogues and Their Link with Ocular Diseases

“…As mentioned above, calcitriol takes part in the homeostasis of calcium and phosphate, and seems to be a potent agent in the treatment of many diseases. However, the therapeutic effect of exogenous calcitriol often require it to be present in supraphysiological concentrations resulting in toxic and undesirable effects, primarily hypercalcemia, hypercalciuria, excessive bone resorption and vascular calcification [ 23 , 24 ]. To avoid these side effects, structural analogues of calcitriol have been created, e.g., 22-oxacalcitriol and 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D 3 , and these have been found to have potential efficacy in ocular disorders [ 25 , 26 ].…”

Design, Synthesis, and Biological Evaluation of New Type of Gemini Analogues with a Cyclopropane Moiety in Their Side Chain

“…Accordingly, there is much interest in the design and synthesis of new calcitriol analogues displaying less toxicity . The pharmacodynamic interaction patterns between vitamin D receptor (VDR) and calcitriol and its analogues have been extensively studied, − with key pharmacophoric contacts involved in VDR-mediated bioactivity. Of note, the bioactive compounds are anchored to VDR through three hydroxyl groups forming hydrogen bonds with three pairs of polar amino acids within the ligand binding pocket (LBP) and that correspond to the three pharmacophoric contacts (Figure B).…”