The application of flow chemistry techniques in medicinal chemistry programs: the development of flow-photocyclization methods for the synthesis of phenanthridinone-type compounds.

Abstract

Flow chemistry can be characterized as a continuous chemical reaction system performed in solution in connecting tubing and flow reactors which is efficient. Photochemistry is the chemical reaction initiated by light, and is the result of the absorption of photon by a reagent or starting material. Poly (ADP-ribose) polymerase is a big family of proteins related to cellular repair and death. Phenanthridinones have been shown to exhibit PARP inhibitory potency as competitive inhibitors. Instead of using conventional costly and low-efficiency coupling reactions, we have managed to develop a method to synthesize phenanthridinone-type compounds by photo-cyclization under flow conditions for the purposes of generating novel PARP inhibitors. In total, we have generated a series of phenanthridinones in yields ranging from 13 % to 99%, 18 examples. Additionally, we have also developed a flow photocyclization method for the synthesis of complex heterocycles, naphthyridinones (5 examples, yields ranging from 24-52%) and thieno-quinolinones (18 examples, yields ranging from 23-90%), molecules that would be much more difficult to construct using conventional batch methods. Overall, we have demonstrated that a flow photocyclization pathway is a robust synthesis route for producing phenanthridinone-type compounds for the purposes of developing novel PARP inhibitors.