Design and synthesis of lactam analogs of andrographolide and discovery of their anticancer activity as dual EGFR and VEGFR2 inhibitors
- Eur J Med Chem. 2025 Dec 5:299:118042. doi: 10.1016/j.ejmech.2025.118042.
- 1. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, Jiangsu, China; Xitaihu Lake Industrial College, Nanjing Tech University, Changzhou, 213149, Jiangsu, China.
- 2. School of Basic Medical Sciences, Chengdu University, Chengdu, 610106, China.
- 3. Key Laboratory of Coarse Cereal Processing (Ministry of Agriculture and Rural Affairs), School of Food and Biological Engineering, University of Chengdu, Chengdu, 610106, China.
- 4. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, Jiangsu, China.
- 5. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of China.
- 6. Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China.
- 7. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, Jiangsu, China; Xitaihu Lake Industrial College, Nanjing Tech University, Changzhou, 213149, Jiangsu, China. Electronic address: [email protected].
The diterpene andrographolide, a nature-derived product, exerts a wide range of pharmacological effects, including anti-inflammatory, Antiviral, immunostimulatory, and Anticancer activities, due to its ability to target multiple pathways. In this study, some andrographolide derivatives of an enlarged decalin structure with a seven-membered ring or an isoxazole-fused decalin structure were designed, synthesized, and evaluated for their activity against Cancer cell growth and angiogenesis. Among them, compound AGW-11 (designated as compound 8) showed potent and broad-spectrum Anticancer activity and anti-angiogenic activity in vitro. Mechanistically, 8 was found to effectively suppress the phosphorylation of EGFR and ERK½ and induce 4T1 cell Apoptosis in a gradient concentration-dependent manner; while 8 inhibited angiogenesis by reduction of HUVEC proliferation, tube formation and cell invasion, and decreased VEGFR2 kinase activity and lowered VEGFR2 and ERK1/2 phosphorylation. The results from in vivo anti-4T1 tumor-bearing mouse model showed that treatment with 8 significantly suppressed tumor growth and decreased the probability of lung tumor metastasis, as previously reported AGS-30 (2). Consistent with the in vitro results, the in vivo data demonstrated that the anti-angiogenic and anti-tumor effects of 8 in a mouse xenograft model. Treatment with 8 effectively inhibited expressions of Ki67, CD31 and VEGF in tumors, suggesting that 8 inhibits tumor angiogenesis. Meanwhile, the apoptotic factor cleaved Caspase 3 was elevated that tumor cells was induced to death after treatment with 8. These findings will facilitate our andrographolide-related drug discovery efforts.