title: Design, synthesis, and structure-activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors.
abstract: Hypoxia-inducible factor (HIF)-1 is well known as a promising target for cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50=19.1μM). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1μM against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including carbonic anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway.
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yorinobu
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Arakawa
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nawata
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Bioorganic Medicinal Chemistry & Chemogenomics, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: Department of Bioorganic Medicinal Chemistry & Chemogenomics, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hattori
authors.affiliation: Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: scseigyo-hisyo@pharm.kyoto-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D011720:Pyrazoles; D054852:Small Molecule Libraries
keywords: Cancer; Chemotherapy; Hypoxia-inducible factor (HIF); Structure–activity relationship