Tributyltin propionate and tributyltin salicylate represent novel RXR ligands: Effects on transcriptional activity of thyroid hormone receptor and vitamin D3 receptor.

Several organometallic trialkyltins or triaryltins are known to act as retinoid X receptor (RXR) agonists, which were also reported to exert eminent cytotoxic properties. In the present study, binding properties of tributyltin propionate (TBT-P) and tributyltin salicylate (TBT-S) in RXRα molecule were theoretically investigated using docking in Schrödinger small molecule drug discovery suite. Our data has shown that TBT-P and TBT-S bind in the binding pocket of RXRα and represent novel RXR agonists. In vitro data has shown that both TBT-P and TBT-S exert transcriptional activity under basal and ligand-activated conditions through RXR - nuclear thyroid hormone receptor (TR) heterodimer in the human reporter cell line for the assessment of thyroid receptor transcriptional activity (PZ-TR). In the human reporter cell line, enabling sensitive and selective identification of nuclear dihydroxyvitamin D3 receptor (VDR) agonists (IZ-VDRE), TBT-P and TBT-S did not exert any transcriptional activity through VDR under basal and ligand-activated conditions, which is in agreement with the properties of the non-permissive type of RXR-VDR heterodimer. Our in silico and in vitro data demonstrate that both organometallic compounds TBT-P and TBT-S represent new nuclear retinoid X receptor agonists.