Synthesis And Biological Study Of A Tumor Targeting Peptide Quinoxaline Conjugate

Chemotherapy has played an important role in the treatment of cancer.However,the drug resistance and side effects have been the major concern in its clinical applications.Molecular targeted therapy has recently attracted increasing attention due to the low toxicity and high efficacy.The quinoxaline group?QX?is a DNA intercalator that can effectively insert between DNA bases to block DNA transcription,replication and nucleobase repair.Tumor targeting peptides such as RGD,TAT and pHLIP?pH low insertion peptide?can selectively target tumor cells.RGD is the core sequence to bind integrin receptors that are overexpessed in tumor neovascularization and cell surface.Thus,a RGD-drug conjugate can deliver the drug molecule via the?_v?₃ receptor to kill tumor cell.In this thesis,synthesis and biological study of QX derivatives and cell targeting peptide conjugates were investigated.?1?Conjugation of Quinoxaline peptides:QX moiety was first modified with carboxylic acid group through the“click”chemistry to conjugate with the S3 peptide.This was followed by a maleimide moiety to reacted with CS2,iRGD and TAT.We found that although the conjugation could occur none of the products were eluted through the HPLC column due to the aggregation due to the high hydrophobicity.Thus,PEG moiety was introduced to increase the aqueoussolubility of the conjugation.The PEG-QX was synthesized through the reaction of QX-NH₂with SM?PEG?₂₄.The PEG-QX was obtained via the thiol addition on the maleimide and comfirmed by NMR and ESI-MS analysis.?2?Biological activity of the conjugates:Three different representative cancer cells Bel-7402,MCF-7,MDA-MB-231 were used to evaluate the biological activity of the compound under photodynamic therapy.Our results showed that both the compound dT-QX-2Cland cRGD-QXcombined with PDT has a potent antitumour activity on three cells.The IC50 of dT-QX-2Cl is less than 1?M.The IC50 of cRGD-QX was significanty high at 30?M.The possible rational for this decreased activity was hydrophilic PEG chain might affect the uptake of cRGD-QX counpound.That demonstrate it has higher cytotoxicity of Quinoxaline derivatives to target endoenzyme than cell surface marker.