title: Synthesis and discovery of N-carbonylpyrrolidine- or N-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. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC(50) = 0.15 μM). 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'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = 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.
authors.affiliation: Drug Discovery Research Center, Taiho Pharmaceutical Co. Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyakoshi
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyahara
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yokogawa
authors.forename: Khoon Tee
authors.initials: KT
authors.lastname: Chong
authors.forename: Junko
authors.initials: J
authors.lastname: Taguchi
authors.forename: Kanji
authors.initials: K
authors.lastname: Endoh
authors.forename: Wakako
authors.initials: W
authors.lastname: Yano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wakasa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ueno
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Takao
authors.forename: Makoto
authors.initials: M
authors.lastname: Nomura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukuoka
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005467:Floxuridine / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011759:Pyrrolidines; D054852:Small Molecule Libraries; D005467:Floxuridine; D014498:Uracil; D013940:Thymidylate Synthase; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; C025034:doxifluridine