Synthesis and Antitumor Activity Evaluation of γ-Monofluorinated and γ,γ-Difluorinated Goniothalamin Analogues

Authors

  • Yi Yang,

    Corresponding author
    1. School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, Zigong, Sichuan 643000, China
    • School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, Zigong, Sichuan 643000, China, 0086-0813-5505601
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  • Zhenjun Yang,

    1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100083, China
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  • Chunru Cheng,

    1. School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, Zigong, Sichuan 643000, China
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  • Fengling Qing

    Corresponding author
    1. Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
    • Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China, 0086-021-64166128
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Abstract

A series of novel γ,γ-difluorinated Goniothalamin analogues 4a4i and 6a6i were synthesized. The key steps included the construction of C-5 stereocenter adjacent to gem-difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduction of aryl group via Stille coupling, and lactonization by 1,5-oxidative cyclization. These γ,γ-difluorinated Goniothalamin analogues 4a4i and their enantiomers 6a6i, together with several corresponding γ-monofluorinated Goniothalamin analogues were biologically evaluated against four different cancer cell lines. Compound 7h showed a nearly equivalent potency as the parent (R)-Goniothalamin in the micromolar range. The different fluorine effects between fluoromethylene and gem-difluoromethylene on antitumor activity were discussed through the analysis of bioassay data.

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