Synthesis of potent antileukemic quinazoline-thiohydantoin fused heterocycles enabled by metal-free domino reaction

Heterocyclic compounds play a central role in drug development research and are contained in most pharmaceuticals on the market. Quinazoline and thiohydantoin are heterocycles and hold very prominent positions due to their diverse pharmacological profiles. While quinazolines fused with other heterocyclic units are already found in various clinically used pharmaceuticals, fused quinazoline-thiohydantoin frameworks have yet to be described since no synthetic approaches have been reported so far. Here, we present the development of a highly efficient, operationally simple, and fully metal-free three-step domino reaction towards fused heterocycles using readily available starting materials. Merging the novel three-step domino reaction and a dehydrogenation step in one pot leads to atom-economical, expeditious, and high-yielding (up to 92%) organic synthesis of unprecedented quinazoline-thiohydantoin fused frameworks. This new class of fused heterocycles features high in vitro activities and selectivities against multidrug-resistant P glycoprotein-overexpressing CEM/ADR5000 leukemia cells (IC50 down to 0.127 µM). It exceeds the potency of the clinical reference drug doxorubicin (IC50 23.27 µM). Furthermore, nuclear localization of Myocardin-related transcription factor A (MRTF-A, a.k.a. Megakaryoblastic Leukemia MKL1) as a tumor biomarker and driver of tumor resistance was decreased upon administration of quinazoline-thiohydantoin fused heterocycles. The developed straightforward synthetic approach enables the easy and direct formation of model drugs to overcome multidrug resistance in leukemia cells.