Abstract
Glucocorticoids (GCs) represent 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 the biological activity of four novel glucocorticoid receptor (GR) ligands, derivatives of synephrine, a natural-origin molecule. 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 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 the leader compound, 1-[4-(benzyloxy)phenyl]-2-(hexylamino)ethanol (10S-E2), were studied using a murine transplantable lymphoma P388 model. The potential of 10S-E2 to prevent the development of atrophic complication was evaluated using a murine model of glucocorticoid-induced osteoporosis. All studied synephrine derivatives demonstrated high GR affinity, with the IC(50) value of the most active derivative 10S-E2 being 0.56 µM; the effects on GR function were cell-type-specific. The leader compound, 10S-E2, revealed SEGRAM properties in vitro and demonstrated anti-cancer effects in vivo, inhibiting tumor growth by more than 60%. Although the anti-cancer effect of 10S-E2 was less pronounced than that of the reference drug dexamethasone, non-atrophogenic properties of 10S-E2 make this molecule an attractive candidate for long-term GR-associated therapies.