LAUSR

Natural products have been widely considered as an important resource for new drugs or lead compounds. Sinomenine (SIN) and its derivatives exert antitumor activity via regulation of inflammatory mediators. For these reasons we synthesized three series of SIN derivatives (compounds 4a-i, 7a-c and 11a-c) as antitumor agents from this natural product. All compounds were prepared by the modification at the C1 and C4 positions of A ring, the C4 position of A ring and the C6 and C7 positions of C ring, respectively. All the derivatives were subjected to in vitro antitumor activity against HeLa, A549, HepG-2, MCF-7 and HT-29 cell lines. To observe the apoptotic induction of SIN derivatives and its mechanism, fluorescent staining and western bolt were carried out for active compound against MCF-7. Based on the screening results, most of SIN derivatives showed better antitumor activity than SIN. Some of them were found to possess broad spectrum antitumor activity. Most notably, 11c exhibited obvious antitumor activity in both cell lines with IC50 value less than 11 μM. Besides, 11c induced apoptosis of MCF-7 in a dose-dependent manner. Western blot assay demonstrated that 11c inhibited IL-6-mediated activation of PI3K/Akt pathway. A docking study revealed that 11c had stronger binding interaction with the residues of IL-6 than SIN. All these results indicate that 11c may be a potential anti-breast cancer agent by directly targeting IL-6.