The Synthesis Of Marine Cyclopeptides Hantupetin A And Its Antitumor Activity Research

Hantupeptin A is a cyclolipopeptide isolated from cyanobacteria L.majuscula from Singapore,purified and identified by Tripathi,A and colleagues.Extensive 1D and 2D NMR spectroscopy experiments revealed the planar st-ructure of Hantupeptin A,and the results of the MTT assay demonstrated its strong anticancer activity against MOLT-4leukemia cells and MCF-7 breast cancer cells.In this manuscript,Hantupeptin A was disconnected into two fragments P₁,P₂ based on our retrosyntheticanalysis.There is a?2R,3S?-3-hydroxy-2-Methyl-7-octanoic acid?Hmoya?in the fragment P₂ that has been confirmed to be?2R,3S?,but?2S,3R?Hmoya has been reported in some literatures.In order to further determine the configuration of Hmoya,?2S,3R?Hmoya fragments are synthesized.we have achieve the total synthesis of Hantupeptin A.In order to study its preliminary anti-tumor activity research,MTT?HE staining and flow cytometry to detect apoptosis were also carried out.The results are as follows:1.Synthesis results:Synthesis of fragment P₁:Its synthesis began with the conversion L-Phenyllactic acid,protected by ester group,condensation with Boc-N-Me-Ile,after removal of t he Boc grop,condensation with Boc-N-Val under the typical peptide coupling condit ion?HATU/HOAt/DIPEA?,afforded fragment P₁ in overall 40.9%yield.Synthesis of fragment P₂:Its synthesis began with the conversion Boc-N-Me-Val,removal of the Boc grop,condensation with Boc-N-Pro,removal of the TMS group,condensation with?2R,3S?Hmoya or?2S,3R?Hmoya under the typical peptide coupling condition?DMAP/DIC?,afforded fragment P₂ in overall 38.7%and 38.5%yield?Calculated by Boc-N-Me-Val?.Synthesis of Hantupeptin A and Hantupeptin A':fragment P₁ removal of the TMS group,condensation with fragment P₂ or fragment P₂'?removal of the Boc group?,,removal of the TMS group and Boc group,under the typical peptide coupling condition?HATU/HOAt/DIPEA?,afforded Hantupeptin A and Hantupeptin A'in overall 2.7%and 3.4%yiled?Calculated by Boc-N-Me-Val?.2.The pharmacological activity resultThe MTT assay showed that Hantupmeptin A and Hantuppeptin A'had aninhibitory effect on the growth of H1299 cells.Treated with different concentrations of Hantipeptin A and Hantopeptin A',Microscope observation showed that the cells becomes smaller and rounded;the HE staining showed that some changes were observed in cell morphology,chromatin and nucleus;the apoptosisassay by flow cytometry showed can induce cells to apoptosis.Conclusions1.Its finally 9 steps completes the synthesis of Hantupeptin A and Hantupeptin A',afforded in overall 2.7%and 3.4%yield?Calculated by Boc-N-Me-Val?.2.Hantueptin A and Hantupeptin A' can inhibit the growth of human lung cancer H1299 cells and induce apoptosis.