Design, Synthesis And Anticancer Activity Evaluation Of Acidamide And Hydrazone Derivatives As GRPR Inhibitors

Gastrin releasing peptide receptor has close relationship with cancers, and it is overexpressed in gastric, lung, breast, ovarian, prostate and other tumors. The specificbinding of gastrin releasing peptide receptor to gastrin releasing peptide may lead tothe activation of proto-oncogene or the inactivation of tumor suppressor gene, andultimately result in tumorigenesis. So, GRPR may be an effective target fortherapeutic treatment of human malignancies.So far, few small molecule GRPR inhibitors with anticancer activity have beenreported, and the tertiary structure of GRPR has not been found in Protein Data Bank.To discover some innovative drugs, in this paper, rational drug design,computer-aided drug design and me-too drug design were the basic principles. Thetertiary structure and active site of GRPR were predicted with MOE software by blastsearching in the premise of2VT4protein as template. With the reported GRPRinhibitors, especially PD176252, two series of eighteen compounds were designedand synthesized. They were synthesized of L-phenylalanine or L-tryptophan asthe basic skeleton by esterification with the methanol, then amidation withalphatoluic acid derivatives. Six acidamide derivatives (SME09LC001~06) wereobtained by hydrolysis and amidation with2-(1H-imidazol-1-yl) ethanamine. Twelvehydrazone derivatives (SME09LC007~18) were prepared by hydrazinolysis andreaction with picolinaldehyde or4-(dimethylamino) benzaldehyde. The structures ofintermediates and target compounds were confirmed by FT-IR and1H NMR.In recent years, microwave technology has developed rapidly in the field of organicsynthesis. It has many advantages, such as easy operation, short reaction time, highyield, easy purification for the products and so on. The synthesis of three hydrazideintermediates (9a,9c,9e) and three hydrazone compounds (SME09LC007,09,11)were studied by the conventional and microwave assisted methods. The conventionalmethod is reacted by refluxing, while the microwave assisted method by the power of600W and the temperature around73℃.These hydrazide and hydrazone compoundswere synthesized for shorter reaction time with good yields under microwaveirradiation. Finally, the anticancer activities of the terget compounds were tested onhuman non-small cell lung cancer cells A-549, human breast cancer cellsMDA-MB-435and human hepatoma cells HuH-7by MTT assay. The resultsexhibited that these compounds had prominence antiproliferative activitiesand compounds SME09LC005,13,15and17showed significant activities bypreliminary test. Based on the results, the structure-activity relationship ofthese compounds was performed. This study provided some theory basis fordiscovering new compounds with better activities in the future.