Compound 17(Fudan University)

GG-8-6, a cyclic peptide with effective anti-hepatocellular carcinoma activity in vitro and in vivo, was synthesized based on the lead compound Grifficyclocin B, which was isolated from the plants of Goniothalamus species (Annonaceae family). Based on the previous study, we synthesized 17 analogues of GG-8-6 to find better potential and higher-yield cyclopeptides. Among these analogues, nine increased their yield compared to GG-8-6, and compound 1 reached a high yield of 14.7 %. In addition, the bioassay results showed that ten analogues exhibited significant anti-hepatocellular carcinoma activities in vitro, which promoted cell apoptosis and reduced intracellular ATP levels. Among them, the activity of compounds 1, 2 and 3 was significantly better than GG-8-6, while the yield of compounds 1 and 3 reached nearly five times that of GG-8-6. Compound 17 was obtained by deprotection from compound 1, which preserved antitumor activity, and more new derivatives could be synthesized based on the hydroxyl group in its structure. A subcutaneous xenografted mice model confirmed the in vivo antitumor activity of compounds 1 and 17. The results indicated that both compounds significantly inhibited the growth of tumours. At 10 mg/kg and 15 mg/kg doses for compounds 1 and 17, the inhibition rates reached 84.3 % and 58.39 %, respectively. Furthermore, the potential mechanism of compounds 1 and 17 was analyzed by transcriptomic analysis. Our results indicated that GG-8-6 analogues as new cyclic peptides might be potential candidates for developing new drugs treating hepatocellular carcinoma.