1,2,3-Triazole-Containing Uracil Derivatives with Excellent Pharmacokinetics as a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors

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• 作者：Hitoshi Miyakoshi ; Seiji Miyahara ; Tatsushi Yokogawa ; Kanji Endoh ; Toshiharu Muto ; Wakako Yano ; Takeshi Wakasa ; Hiroyuki Ueno ; Khoon Tee Chong ; Junko Taguchi ; Makoto Nomura ; Yayoi Takao ; Akio Fujioka ; Akihiro Hashimoto ; Kenjirou Itou ; Keisuke Yamamura ; Satoshi Shuto ; Hideko Nagasawa ; Masayoshi Fukuoka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6427-6437
• 全文大小：559K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

Deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as a 5-fluorouracil-based combination chemotherapy. We describe the design and synthesis of a novel class of human dUTPase inhibitors, 1,2,3-triazole-containing uracil derivatives. Compound 45a, which possesses 1,5-disubstituted 1,2,3-triazole moiety that mimics the amide bond of tert-amide-containing inhibitor 6b locked in a cis conformation showed potent inhibitory activity, and its structure鈥揳ctivity relationship studies led us to the discovery of highly potent inhibitors 48c and 50c (IC₅₀ = 0.029 渭M). These derivatives dramatically enhanced the growth inhibition activity of 5-fluoro-2鈥?deoxyuridine against HeLa S3 cells in vitro (EC₅₀ = 0.05 渭M). In addition, compound 50c exhibited a markedly improved pharmacokinetic profile as a result of the introduction of a benzylic hydroxy group and significantly enhanced the antitumor activity of 5-fluorouracil against human breast cancer MX-1 xenograft model in mice. These data indicate that 50c is a promising candidate for combination cancer chemotherapies with TS inhibitors.