Synephrine analogues as glucocorticoid receptor agonists

The glucocorticoid receptor (GR) is a known antitumor target. Activation of GR by glucocorticoids (GC) leads to suppression of growth and viability of tumor cells, inducing their apoptosis. Synthetic GC Dexamethasone (Dex) belongs to the class of glucocorticoid receptor agonists. The use of Dex as a direct chemotherapy agent for some types of malignancies leads to serious side effects. The activity of Dex outside the zone of therapeutic interest can lead to a wide range of various complications, including systemic toxicity, local allergic reactions, changes in heart function, which makes it especially important to explore and develop other, less toxic compounds. Recently it was shown that the compound CpdA acts as a non-steroidal analog of Dex. CpdA appears to be unstable under physiological conditions, and the main product of its hydrolysis is synephrine, which exhibits the desired properties. This fact makes the search for active molecules among synephrine analogues promising.

In the proposed work, a number of new synephrine analogues were synthesized. Some of the obtained compounds exhibited cytotoxic effects on the chronic myeloid leukemia and acute lymphoblastic leukemia cell line. In order to suggest a possible mechanism of such analogues’ action, molecular docking was performed using the GR model (PDB ID: 1P93) in comparison with the known receptor agonist – dexamitasone. The simulation showed similarity of synephrine analogues’ binding to the binding of Dex in the GR ligand-binding domain.