Synthesis and anti‐hepatocellular carcinoma activity in vitro of cyclic peptide GG‐8‐6 analogues

Our previous study reported a cyclic peptide, GG‐8‐6, possessing effective activity against hepatocellular carcinoma both in vitro and in vivo. In order to seek out better analogues in synthetic yield or bioactivity, we synthesized 15 cyclopeptide GG‐8‐6 analogues. Their purities were detected by HPLC, and their structures were characterized by HR‐QTOF‐MS, 1H and 13C NMR together with X‐ray crystal analysis. Among these analogues, compound 8, containing two d‐amino acids, gave the highest total yield of 72.5%. Moreover, all analogues were evaluated for their antihepatocellular carcinoma activities by MTT experiments. Compound 14 showed better specificity against Huh7 and HepG2 cell lines with IC50 values of 8.59 ± 0.97 μM and 7.34 ± 0.33 μM, respectively, while possessing more than four times total yield compared to the lead compound GG‐8‐6. In addition, an ATP assay for some representative compounds was carried out to confirm their anti‐hepatocellular carcinoma activity.