Synthesis and biological evaluation of cyclopeptide GG-8-6 and its analogues as anti-hepatocellular carcinoma agents. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Chen, Jie-Tao; Ma, Ru; Sun, Shi-Chang; Zhu, Xiao-Feng; Xu, Xiao-Li; Mu, Qing
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 3(2018)
• Page Start: 609
• Page End: 622
• Publication Date: 2018-02-01
• Subjects: 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; Goniothalamus -- GG-8-6 -- Cyclic peptide -- Hepatocellular carcinoma -- Solid phase peptide synthesis -- Anti-tumor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.