Synthesis and Discovery of <i>N</i>-Carbonylpyrrolidine- or <i>N</i>-Sulfonylpyrrolidine-Containing Uracil Derivatives as Potent Human Deoxyuridine Triphosphatase Inhibitors

Abstract

Recently, deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy of 5-fluorouracil-based combination chemotherapy. We have initiated a program to develop potent drug-like dUTPase inhibitors based on structure–activity relationship (SAR) studies of uracil derivatives. <i>N</i>-Carbonylpyrrolidine- and <i>N</i>-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (<b>12k</b>) having excellent potencies (IC₅₀ = 0.15 μM). The X-ray structure of a complex of <b>16a</b> and human dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a hydrophobic region, respectively, and are stacked on each other. Compounds <b>12a</b> and <b>16a</b> markedly enhanced the growth inhibition activity of 5-fluoro-2′-deoxyuridine against HeLa S3 cells in vitro (EC₅₀ = 0.27–0.30 μM), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors