Synthesis and anti–tumour, immunomodulating activity of diosgenin and tigogenin conjugates

[Display omitted] •A set of diosgenin and tigogenin derivatives substituted with various amino acids, dipeptides or levulinic and 3,4–dihydroxycinnamic acid were synthesized.•Analogue 2c (l–serine in position 3 of tigogenin) showed the highest activity against the breast cancer cell line (MCF–7) and its affinity profile to the active site of the estrogen receptor (ER) was confirmed by molecular docking.•A diosgenin derivative with caffeic acid 16a and the analogue of tigogenin with glutamic acid 4c exhibited preferred immunomodulatory effects.•A strong binding interaction of compounds 4c and 16a (Ki = 0.23 pM and Ki = 1.14 pM) with the active site of the glucocorticoid receptor (GR) was estimated using molecular docking. A series of novel diosgenin (DSG) and tigogenin (TGG) derivatives with diosgenin or tigogenin steroid aglycons linked to levulinic and 3,4–dihydroxycinnamic acids, dipeptides and various amino acids by an ester bond at the C3–oxygen atom of the steroid skeleton has been synthesized. Diosgenyl esters have been prepared by an esterification reaction (DCC/DMAP) of diosgenin with the corresponding acids. All analogues have been evaluated in vitro for their antiproliferative profile against cancer cell lines (MCF–7, MDA–MB–231, PC–3) and human umbilical vein endothelial cells (HUVEC). Analogue2c (l–serine derivative of TGG), the best representative of the series showed IC50 of 1.5 μM (MCF–7), and induced apoptosis in MCF–7 by activating caspase–3/7. The immunomodulatory properties of six synthesized analogues have been determined by examining their effects on the expression of cytokine genes essential for the functioning of the human immune system (IL–1, IL–4, IL–10, IL–12 and TNF–α). Biological evaluation has revealed that new compounds 4c and 16a do not induce the expression of pro–inflammatory cytokines in THP–1 cells after the lipopolysaccharide (LPS) stimulation. They also stimulate the expression of anti–inflammatory IL–10 that acts stronger than diosgenin itself. An in silico ADME properties(absorption, distribution, metabolism, excretion) study was also performed to predict the pharmacokinetic profile of the synthesized compounds. To shed light on the molecular interactions between the synthesized compounds and the glucocorticoid receptor and the estrogen receptor, 2c, 4c and 16a compounds were docked into the active binding sites of these receptors. The in silico and in vitro data suggested that this new group of compounds might be con