Thioimidazoline based compounds reverse glucocorticoid resistance in human acute lymphoblastic leukemia xenografts

Abstract

Glucocorticoids form a critical component of chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL) and the initial response to glucocorticoid therapy is a major prognostic factor, where resistance is predictive of poor outcome. A high-throughput screen identified four thioimidazoline-containing compounds that reversed dexamethasone resistance in an ALL xenograft derived from a chemoresistant pediatric ALL. The lead compound (1) was synergistic when used in combination with the glucocorticoids, dexamethasone or prednisolone. Synergy was observed in a range of dexamethasone-resistant xenografts representative of B-cell precursor ALL (BCP-ALL) and T-cell ALL. We describe here the synthesis of twenty compounds and biological evaluation of thirty two molecules that explore the structure–activity relationships (SAR) of this novel class of glucocorticoid sensitizing compounds. SAR analysis has identified that the most effective dexamethasone sensitizers contain a thioimidazoline acetamide substructure with a large hydrophobic moiety on the acetamide.