2. Academic Validation
  3. Harnessing cell cycle intervention and evading P-glycoprotein efflux: natural product-inspired C2-aminophenyl chromones as dual modulators against multidrug-resistant cancer

Harnessing cell cycle intervention and evading P-glycoprotein efflux: natural product-inspired C2-aminophenyl chromones as dual modulators against multidrug-resistant cancer

  • Eur J Med Chem. 2025 Nov 15:298:117978. doi: 10.1016/j.ejmech.2025.117978.
Yi-Han Chang 1,  I-Ting Wu 2,  Po-Yu Chien 3,  Ching-Hui Su 2,  Yu-Hsun Chen 4,  Chin-Chuan Hung 5,  Hsin-Yi Hung 6
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; Department of Pharmacy, College of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist., Taichung, Taiwan, ROC.
  • 2 Department of Pharmacy, College of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist., Taichung, Taiwan, ROC.
  • 3 Department of Pharmacy, College of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist., Taichung, Taiwan, ROC; Department of Pharmacy, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung, Taiwan, ROC.
  • 4 Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany; Max Planck School Matter to Life, Jahnstraße 29, D -69120, Heidelberg, Germany.
  • 5 Department of Pharmacy, College of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist., Taichung, Taiwan, ROC; Department of Pharmacy, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung, Taiwan, ROC; Department of Healthcare Administration, Asia University, No. 500, Lioufeng Rd., Wufeng, Taichung, Taiwan, ROC. Electronic address: cchung@mail.cmu.edu.tw.
  • 6 School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. Electronic address: z10308005@ncku.edu.tw.
PMID: 40752344 DOI: 10.1016/j.ejmech.2025.117978
Abstract

The resilience of Cancer cells to current anti-neoplastic agents remains a significant challenge in oncology, underscoring the pressing requirement for novel candidates to overcome multidrug-resistant (MDR) malignancies. Building on the C2-functionalized chromone scaffold, herein, a structure-activity relationship (SAR) investigation centered on the C2-atomic bridge identified C2-aminophenyl chromone as a privileged scaffold for tumoricidal compounds. Within this chemotype, 12m and 12n emerged as promising candidates, exhibiting potent anti-proliferative activity against not only drug-sensitive KB cells (IC50 = 0.78 μM and 0.42 μM, respectively) but also MDR KBvin cells (IC50 = 0.69 μM and 0.43 μM, respectively). Mechanistic investigations revealed that both molecules effectively triggered Apoptosis and hampered cell cycle transition at the G2/M stage, marked by the upregulation of cyclin B1 and cyclin A2. Moreover, 12m and 12n demonstrated collateral sensitivity and chemosynerstic interactions in MDR Cancer cells, significantly suppressing P-glycoprotein (P-gp) expression while bypassing P-gp-mediated efflux. In vivo evaluations using a zebrafish xenograft model further validated their therapeutic potential in terms of KBvin tumor growth without eliciting acute toxicity at 1.0 μM. Harnessing chemoresensitizing properties, these molecules further reduced KBvin tumor burden in zebrafish when co-administered with paclitaxel. To encapsulate, the C2-aminophenyl chromone scaffold represents a novel chemical framework for the development of dual-functional anti-neoplastic agents targeting MDR Cancer.

Keywords

2-Aminophenyl chromone; Cell cycle; Multidrug resistance; P-glycoprotein; Structure-activity relationship.

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