Synthesis, Antiproliferative Activity and Molecular Docking Analysis of Both Enantiomerically Pure Decursin Derivatives as Anticancer Agents

Junseong Ahn; Hyun-Ha Hwang; Soo Yeon Jung; Ja Yeon Lee; Choi Kim; Hye Min Choi; Min Ju Gwon; Min Ji Kim; Youngbin Kwon; Jaehyuk Woo; Bongkyu Park; Seong-Gyu Ko; Jae Yeol Lee

doi:10.1248/cpb.c23-00718

Regular Article

Synthesis, Antiproliferative Activity and Molecular Docking Analysis of Both Enantiomerically Pure Decursin Derivatives as Anticancer Agents

Junseong Ahn ^†, Hyun-Ha Hwang ^†, Soo Yeon Jung, Ja Yeon Lee, Choi Kim, Hye Min Choi, Min Ju Gwon, Min Ji Kim, Youngbin Kwon, Jaehyuk Woo, Bongkyu Park, Seong-Gyu Ko , Jae Yeol Lee

Author information

Junseong Ahn ^†
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Hyun-Ha Hwang ^†
Department of Science in Korean Medicine, Graduate School, Kyung Hee University
Soo Yeon Jung
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Ja Yeon Lee
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Choi Kim
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Hye Min Choi
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Min Ju Gwon
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Min Ji Kim
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Youngbin Kwon
Department of Science in Korean Medicine, Graduate School, Kyung Hee University
Jaehyuk Woo
Department of Science in Korean Medicine, Graduate School, Kyung Hee University
Bongkyu Park
Department of Science in Korean Medicine, Graduate School, Kyung Hee University
Seong-Gyu Ko Corresponding author
Department of Science in Korean Medicine, Graduate School, Kyung Hee University
Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University
Jae Yeol Lee Corresponding author
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University
Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University
Author contributions

†These authors contributed equally: Junseong Ahn, Hyun-Ha Hwang

Keywords: Angelica gigas Nakai, decursin derivative, A549 lung cancer, Janus kinase 1 (JAK1), signal transducer and activator of transcription activation 3 (STAT3) axis

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Supplementary material

2024 Volume 72 Issue 5 Pages 498-506

DOI https://doi.org/10.1248/cpb.c23-00718

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Abstract

Using (S)-decursinol isolated from root of Angelica gigas Nakai (AGN), we semi-synthesized and evaluated a series of both enantiomerically pure decursin derivatives for their antiproliferative activities against A549 human lung cancer cells. All synthesized compounds showed a broad spectrum of inhibitory activities against the growth of A549 cells. Especially, compound (S)-2d with (E)-(furan-3-yl)acryloyl group showed the most potent activity (IC₅₀: 14.03 µM) against A549 cancer cells as compared with the reference compound, decursin (IC₅₀: 43.55 µM) and its enantiomer, (R)-2d (IC₅₀: 151.59 µM). Western blotting assays indicated that (S)-2d more strongly inhibited Janus kinase 1 (JAK1) and signal transducer and activator of transcription activation 3 (STAT3) phosphorylation than decursin in a dose-dependent manner, while having no effect on CXCR7 overexpression and total STAT3 level. In addition, (S)-2d induced cell cycle arrest at G1 phase and subsequent apoptotic cell death in A549 cancer cells. Our combined analysis of molecular docking studies and biological data suggests that the inhibition of JAK1 with (S)-2d resulted in loss of STAT3 phosphorylation and inhibition of cell growth in A549 cancer cells. These overall results strongly suggest that (S)-2d (MRC-D-004) as a novel JAK1 inhibitor may have therapeutic potential in the treatment of A549 human lung cancers by targeting the JAK1/STAT3 signaling pathway.

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