Structure–activity studies of phenanthroindolizidine alkaloids as potential antitumor agents

Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structure–activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7) were among the most active compounds against tumor growth both in vitro and in vivo. In the hepatocellular carcinoma cell line HepG2, the GI50s of DCB-3503 and PA-7 were 35 ± 5 nM and 11 ± 5 nM, respectively. DCB-3503 and PA-7 significantly inhibited HepG2 tumor growth in nude mice at a dose of 9 mg/kg given by intraperitoneal (ip) injections twice a day every third day for a total of four cycles (P < 0.05 for DCB-3503 and P < 0.01 for PA-7). Their potent antitumor activities correlated with their potent NF-κB-inhibitory effects and their cyclin D1 down-regulatory effects.

Graphical abstractStructure–activity relationships were explored based on a series of phenanthroindolizidine alkaloids synthesized or isolated. DCB-3503 and PA-7 (tylophorinidine) were determined to be the most active compounds against HepG2 tumor growth both in vitro and in vivo.Figure optionsDownload full-size imageDownload as PowerPoint slide