The Synthesis Of Goniocyclopeptide B And Its Analogs

Goniocyclopeptide B, cyclo(-Gly-Leu-Val-Leu-Leu-Val-Pro-Ile-Gly-Leu-), a cyclic peptide isolated from the seeds of Annona glabra L., exhibits potent cytotoxicity against several cancer cell lines with the ED50 in the range of 1.9 - 5.7 μg/mL(1.96-5.86 μM).With proofs inferring the structure of Goniocyclopeptide B, using Goniocyclopeptide B as a natural leads, we designed and synthesized GG-110824 and its analogs by SPPS-Liquid Phase Cyclization-Column chromatography method. Three crystals, GG-110824:cyclo(-G--L-V-L-L-V-P-I-G-L-), GG5F:cyclo(-G-L-V-L-F-V-P-I-G-L-), GG4F:cyclo(-G-L-V--F-L-V-P-I-G-L-), were obtained, and three other cyclic peptides, GG2F:cyclo(-G-F-V-L--L-V-P-I-G-L-), GG3F:cyclo(-G-L-F-L-L-V-P-I-G-L-), GG8F:cyclo(-G-L-V-L-L-V--P-F-G-L-), were synthesized which still need further purification. The SPPS was carried out on Wang resin with 20% piperidine/DMF for deprotection and 2.0 equiv. HATU/HOAt as coupling reagent,5.0 equiv. NMM as base, DMF as solvent; linear precursors were cleaved in a mixture of TFA:H2O:Thioanisole:Phenol:EDT (44:2:2:3:1,10 ml/g resin); cyclization was carried out in a solution of DMF in 10-3～10-4 mol/L, with 3.0 equiv. HATU/HOAt as coupling reagent,10.0 equiv. NMM as base, stirred under 0℃, and then continued stirring for 2 days under room temperature; The purification was by gel LH-20 and silica gel (DCM:MeOH 95:5) column chromatography.The growth inhibition activities of the synthetic compounds were studied on a cancer cell line SMMC-7721 in MTT method, and the result showed that the IC50 values were always>100 μM. The analogues GG2F and GG4F showed a different tend from other 4 compounds, which are all in a similar tend against SMMC-7721. According to the research, we can infer that GG-110824 is much weaker than Goniocyclopeptide B against SMMC-7721. Therefore, we still have a long journey to be continued in researching the inhibition activity against cancer of Goniocyclopeptide B.