DNA-Dependent Protein Kinase (DNA-PK) Inhibitors. Synthesis and Biological Activity of Quinolin-4-one and Pyridopyrimidin-4-one Surrogates for the Chromen-4-one Chemotype

Following the discovery of dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441) ( Leahy J. J. J. ; Golding B. T. ; Griffin R. J. ; Hardcastle I. R. ; Richardson C. ; Rigoreau L. ; Smith G. C. M. Bioorg. Med. Chem. Lett. 2004, 14, 6083−6087 ) as a potent inhibitor (IC50 = 30 nM) of DNA-dependent protein kinase (DNA-PK), we have investigated analogues in which the chromen-4-one core template has been replaced by aza-heterocyclic systems: 9-substituted 2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-ones and 8-substituted 2-morpholin-4-yl-1H-quinolin-4-ones. The 8- and 9-substituents were either dibenzothiophen-4-yl or dibenzofuran-4-yl, which were each further substituted at the 1-position with water-solubilizing groups [NHCO(CH2) n NR1R2, where n = 1 or 2 and the moiety R1R2N was derived from a library of primary and secondary amines (e.g., morpholine)]. The inhibitors were synthesized by employing a multiple-parallel approach in which the two heterocyclic components were assembled by Suzuki−Miyaura cross-coupling. Potent DNA-PK inhibitory activity was generally observed across the compound series, with structure−activity studies indicating that optimal potency resided in pyridopyrimidin-4-ones bearing a substituted dibenzothiophen-4-yl group. Several of the newly synthesized compounds (e.g., 2-morpholin-4-yl-N-[4-(2-morpholin-4-yl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzothiophen-1-yl]acetamide) combined high potency against the target enzyme (DNA-PK IC50 = 8 nM) with promising activity as potentiators of ionizing radiation-induced cytotoxicity in vitro.