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Synthesis and biological evaluation of cyclopeptide GG-8-6 and its analogues as anti-hepatocellular carcinoma agents |
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| Authors: | Jie-Tao Chen Ru Ma Shi-Chang Sun Xiao-Feng Zhu Xiao-Li Xu Qing Mu |
| Institution: | 1. School of Pharmacy, Fudan University, Shanghai 201203, China;2. Hospital Fudan University, Shanghai 201203, China |
| Abstract: | GG-8-6, cyclo-(Val-Leu-Pro-Ile-Leu-Leu-Leu-Val-Leu, compound 1), and its twelve analogues (compound 2–13) were synthesized based on the lead compound Grifficyclocin B, a cyclic peptide with anti-tumor activity which was isolated from the plants of Goniothalamus species (Annonaceae). The bioassay results showed that these synthetic cyclopeptides exhibited different extent of cytotoxicity against human hepatocellular carcinoma cell lines. Among them, GG-8-6 (1) was the most active compound with IC50 values of 6.38?μM and 12.22?μM against SMMC-7721 and HepG2, respectively. Further studies on the mechanism demonstrated that GG-8-6 (1) could induce apoptosis and G2/M arrest of HCC cells, and the activation of caspase pathways was probably involved. In vivo anti-tumor experiments showed that GG-8-6 (1) could significantly inhibit the growth of tumor in the mouse xenograft tumor model. At the dose of 40?mg/kg, the inhibition ratio was 67.9% without weight loss. Our results suggested that GG-8-6 (1), a new cyclic peptide, might be a potential candidate for developing new anti-HCC drug in the coming future. |
| Keywords: | HCC hepatocellular carcinoma MDP muramyl dipeptide SAR structure and activity relationship SPPS solid phase peptide synthesis MeOH methanol MTT 3-(4 5-dimethyl-2-thiazolyl)-2 5-diphenyl-2-H-tetrazolium bromide PI propidium iodide VP-16 etoposide FITC fluorescein isothiocyanate DAPI 4′ 6-diamidino-2-phenylindole PARP poly ADP-ribose polymerase HE hematoxylin and eosin IHC immunohistochemistry H-Score histochemistry scores TUNEL TdT mediated dUTP nick end labeling rTdT terminal deoxynucleotidyl transferase HATU O-(7-Azabenzotriazol-1-yl)-N N N' N'-te-tramethyluronium hexafluorophosphate HOAt 1-hydroxy-7-azabenzotriazole DMF N N-dimethylformamide NMM N-methyl morpholine TFA trifluoroacetic acid EDT ethane-1 2-dithiol TLC thin-layer chromatography ACN acetonitrile DMEM Dulbecco's modification of Eagle's medium Dulbecco FBS fetal bovine serum DMSO dimethyl sulfoxide PBS phosphate buffered saline RIPA radio-immunoprecipitation assay SDS-PAGE SDS-polyacrylamide gel electrophoresis NC nitrocellulose filter BSA bovine aerum albumin EL polyoxyethylenated castor oil HRP horseradish peroxidase GG-8-6 Cyclic peptide Hepatocellular carcinoma Solid phase peptide synthesis Anti-tumor |
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