Design, Synthesis And Biological Activity Evaluation Of Peptidomimetic PD176252 Analogs

Gastrin-releasing peptide receptor（GRPR）belongs to the g-protein coupled receptor family,and its specific binding to gastrin-releasing peptide（GRP）can promote the release of pro-inflammatory factors and cause certain inflammation.Therefore,GRPR can be used as a potential therapeutic target for inflammation.PD176252,a small molecule GPRP inhibitor,not only has anti-inflammatory activity but also has an anti-tumor effect.But its high toxicity and poor water solubility have limited its use as a drug.In order to solve these disadvantages,we have carried out research on its analogues.Medical research has shown that the anticancer drug cisplatin has severe renal toxicity,and there is currently no effective treatment and treatment.And the mechanism of cisplatin-induced renal injury suggests that inflammation is one of the main causes.we have designed and synthesized 37 novel peptidomimetic PD analogs by introducing active fragments of natural products,active fragments of drugs and hydrophilic fragments.Here,based on the chemical structure of the peptidomimetic class PD176252,37new analogs were designed and synthesized by introducing active fragments of natural products,active fragments of drugs and hydrophilic fragments.They were confirmed by melting point,¹H NMR,¹³C NMR and high resolution mass spectrometry.Then the protective effect was evaluated by MTT assay on the kidney tubular epithelial cells of human（HK-2）cells with ciaplatin.Compounds g15,i8 and i11 could increase the survival rate of cisplatin-stimulated HK-2 cells from about 50%to more than 82%.Also,the designed compounds did not cause significant toxicity to normal cells.Subsequently,the structure-activity relationship indicates that the introduction of an electron-donating group on the benzene ring,the insertion of a natural amino acid in the middle,and the increase in the hydrophilicity of the terminal fragment could enhance the biological activity of the analog.Then,the gene level and protein level of inflammatory substances induced by cisplatin were evaluated by PCR and ELISA.The compounds with better anti-inflammatory effect had a stronger ability to reduce kidney toxicity,suggesting that the target compound can reduce the renal toxicity induced by cisplatin through the anti-inflammatory pathway.In addition,compound i8 not only has the best anti-inflammatory effect,but also enhances the anticancer activity of cisplatin,and the competitive affinity experiment also confirmed that compound i8 is a GRPR inhibitor.The synthetic route of the target compound was also screened,and the starting materials,protecting groups and reaction conditions were optimized.Finally,a highly efficient,economical,safe and environmentally friendly synthetic route was obtained.