Background/Objectives: Glucocorticoids (GCs) present effective anti-cancer drugs for the treatment of hematological malignancies but their clinical use is limited due to their multiple adverse effects. Selective glucocorticoid receptor agonists/modulators (SEGRAMs) modify glucocorticoid receptor (GR) function shifting it towards therapeutically important transrepression and, therefore, could be safer alternative to GCs. Here we report on biological activity of four novel ligands of glucocorticoid receptor (GR), derivatives of natural origin molecule, synephrine. Methods: We demonstrated the affinity of synephrine derivatives in silico and in vitro by molecular dynamics simulation and radioligand binding assay, correspondingly. Further, we tested the induction of apoptosis in cultured cells and cytotoxic effects in primary lymphoblasts from the patients with acute lymphoblastic leukemia. Therapeutically important GR transrepression was evaluated by luciferase reporter assay and Q-PCR of transrepression marker genes, while GR transactivation associated with side effects was evaluated by Q-PCR analysis and by the level of GR phosphorylation at Ser211. Anti-cancer effects of leader compound, 1-4-(benzyloxy)phenyl-2-(hexylamino)ethanol (10S-E2), was studied on murine transplantable lymphoma P388 model. 10S-E2 potential to avoid the development of atrophic complication was evaluated on the murine model of glucocorticoid-induced osteoporosis. Results: All studied synephrine derivatives demonstrated high GR affinity; the effects on GR function were controversial. The leader compound, 10S-E2 revealed SEGRAM properties in vitro and demonstrated anti-cancer effects in vivo. Conclusion: Although the anti-cancer effect of 10S-E2 was less pronounced to the reference drug dexamethasone, non-atrophogenic properties of 10S-E2 make this molecule an attractive candidate for long-term GR-associated therapies.
Zhidkova et al. (Fri,) studied this question.