Cascade synthesis of miltirone derivatives via arylation, decarboxylation, and aromatization for their potential as antitumor agents

  • Bioorg Chem. 2025 Jul 1:161:108488. doi: 10.1016/j.bioorg.2025.108488.
Huilian Huang  1 ,  Fucheng Yin  2 ,  Yonglei Zhang  3 ,  Zhongwen Luo  3 ,  Siyuan Wan  3 ,  Liangliang Ma  3 ,  Xiaobing Wang  4
Affiliations
  • 1. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
  • 2. School of Pharmaceutical Science, University of South China, Heng Yang 421001, People's Republic of China; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: [email protected].
  • 3. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 4. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: [email protected].
PMID: 40311246 DOI: 10.1016/j.bioorg.2025.108488
Abstract

Miltirone is a valuable bioactive natural product isolated from the well-known Chinese herb Danshen. In this study, palladium-catalyzed C(sp3) - H arylation, decarboxylation and aromatization cascade approach are reported that allows the direct introduction of various aryl groups at the A-ring benzylic methylene of various miltirone substrates (CA2 - CA31). The evaluation of the cytotoxic activity was performed against three human Cancer cell lines. Among the synthesized compounds, the derivative CA7 (IC50 = 0.45 μM) exhibited excellent MDA-MB-231 cells inhibition activity. Derivative CA7 inhibited MDA-MB-231 cells migration, significantly suppressed the colony formation downregulated mitochondrial membrane potential and induced Reactive Oxygen Species accumulation leads to Apoptosis of MDA-MB-231 cells. CA7 with potential Anticancer properties warranting further development.

Keywords
Antitumor; C(sp3) −H arylation; Cascade synthesis; Miltirone derivatives.
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