Synthesis and anti-fibrosis activity study of 14-deoxyandrographolide-19-oic acid and 14-deoxydidehydroandrographolide-19-oic acid derivatives
- Eur J Med Chem. 2018 Sep 5:157:805-816. doi: 10.1016/j.ejmech.2018.08.046.
- 1. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
- 2. School of Science, China Pharmaceutical University, Nanjing 211198, China.
- 3. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
A series of 14-deoxyandrographolide-19-oic acid and 14-deoxy-11,12 (or 14,15)-didehydroandrographolide-19-oic acid derivatives were designed, synthesized and screened in vitro against the mouse fibroblast cell lines NIH-3T3. Thirteen compounds 8a-f, 14a-c, 14e-f, and 18a-b were found to exhibit better anti-fibrotic activities than andrographolide, with compounds 8b and 14e displaying best activity with IC50 values of 12.86 and 13.57 μM against NIH-3T3 respectively. Further anti-fibrotic investigation was performed in terms of PCR and western bolt analysis. Our study demonstrated that compounds 8b and 14e suppressed effectively the expression of α-smooth muscle actin, fibronectin and Collagen in NIH-3T3. Preliminary structure-activity analysis revealed that 14-deoxygenation and 19-carboxylation of andrographolide could significantly improve its anti-fibrotic effect, which made 14-deoxyandrographolide-19-oic acid and 14-deoxy-11,12-didehydroandrographolide-19-oic acid promising leads for the development of new anti-fibrotic agents.