Design, semi-synthesis and bioevaluation of koumine-like derivatives as potential antitumor agents in vitro and in vivo

Abstract

Aims: Five series of novel koumine-like compounds were designed, semi-synthesized and systematically evaluated for antitumor activities. Methods: All compounds were evaluated for antiproliferative activity against four human cancer cell lines, including HT-29, HCT-116, HCT-15 and Caco-2. Results: Most compounds exhibited much higher antiproliferation activities (IC₅₀ <10 μM) than koumine. Two selected compounds A4 and C5 showed comparable antitumor effects to 5-FU in vivo, as well as better safety profiles. Further studies suggested that A4 and C5 could arrest HT-29 cell cycle in G2 phase and raise reactive oxygen species level, thus inducing cell apoptosis related to Erk MAPK and NF-κB signaling pathways inhibition. Conclusion: These results will greatly promote the druggability study of these koumine-like compounds.

GRAPHICAL ABSTRACT

Article highlights

• A diverse library containing 41 koumine-like compounds (A–E series) was designed and semi-synthesized based on the koumine skeleton.

• Compounds A–E were evaluated for their antiproliferative activity against four colon cancer cell lines (HT-29, HCT-116, HCT-15 and Caco-2) and one normal colon cell line (NCM-460), and the results showed that most of the compounds with nucleophilic addition of N₁=C₂ double bond exhibited much higher antiproliferation activities (IC₅₀ <10 μM) than koumine (IC₅₀ >200 μM).

• The representative compounds A4 and C5 can arrest HT-29 cell cycle in G2 phase.

• Compounds A4 and C5 can induced apoptosis and raise reactive oxygen species levels of HT-29 cells more effectively than koumine.

• Western blotting assays indicated that compounds A4 and C5 inhibited the Erk MAPK and NF-κB signaling pathways in HT-29 cells.

• The in vivo antitumor experiments showed that A4 and C5 significantly suppressed HT-29 tumor growth with comparable efficacy to the positive control 5-FU, but with higher safety than 5-FU.

• These results represented great progress in the development of antitumor drugs based on koumine.

Keywords: :

• antitumor
• Koumine
• structural modification
• structure and activity relationship

Supplemental material

Supplementary data for this article can be accessed at https://doi.org/10.1080/17568919.2024.2350878

Financial disclosure

This work was supported by project of Science and Technology Plan of Liaoning Province (2023-MS-013) and Jiangxi Provincial Natural Science Foundation (20224BAB216003). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that their study has been approved by the Ethical Committee of Jiangsu Hanjiang Biotechnology Co., Ltd. They have followed the guidelines outlined in the “Guide for the Management and Use of Laboratory Animals” of the Ethical Committee (Study approval number: HJSW-22060101).

Additional information

Funding

This work was supported by project of Science and Technology Plan of Liaoning Province (2023-MS-013) and Jiangxi Provincial Natural Science Foundation (20224BAB216003).