title: Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines.
abstract: To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3'-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3'-methoxy moiety on the C-ring phenyl group of AN (6a-e) with 3'-hydroxy (7a-e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g-i) with a 6-hydroxy group (7g-i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above-mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis. In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Yung-Yi
authors.initials: YY
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Ling-Chu
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan; Graduate School of Biotechnology, Hung Kuang University, No. 1018, Sec. 6 Taiwan Boulevard, Shalu District, Taichung 43302, Taiwan.
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chou
authors.affiliation: Graduate School of Biotechnology, Hung Kuang University, No. 1018, Sec. 6 Taiwan Boulevard, Shalu District, Taichung 43302, Taiwan.
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Meng-Tung
authors.initials: MT
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Liao
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Department of Chemistry, National Cheng Kung University, No. 1 Dasyue Road, Tainan 70101, Taiwan.
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.affiliation: Industrial Technology Research Institute, No. 195, Sec. 4 Chung Hsing Rd., Chutung, Hsinchu 31040, Taiwan.
authors.forename: Yen-Fang
authors.initials: YF
authors.lastname: Wen
authors.affiliation: Kunming Institute of Botany, Chinese Academy of Sciences, No. 132 Lanhei Road, Heilongtan, Kunming, Yunnan 650201, China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: sckuo@mail.cmu.edu.tw.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, 2 Yuh-Der Road, Taichung 40447, Taiwan. Electronic address: khlee@unc.edu.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines
keywords: 2-Arylnaphthyridin-4-ones; Antitumor agents; Phosphate prodrug