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

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• 作者：Hitoshi Miyakoshi ; Seiji Miyahara ; Tatsushi Yokogawa ; Khoon Tee Chong ; Junko Taguchi ; Kanji Endoh ; Wakako Yano ; Takeshi Wakasa ; Hiroyuki Ueno ; Yayoi Takao ; Makoto Nomura ; Satoshi Shuto ; Hideko Nagasawa ; Masayoshi Fukuoka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：2960-2969
• 全文大小：483K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationship (SAR) studies of uracil derivatives. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC₅₀ = 0.15 渭M). The X-ray structure of a complex of 16a 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 12a and 16a markedly enhanced the growth inhibition activity of 5-fluoro-2鈥?deoxyuridine against HeLa S3 cells in vitro (EC₅₀ = 0.27鈥?.30 渭M), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors.