Synthesis Of Novel Quinazoline Compounds And Preliminary Evaluation Of Their Antitumor Activity In Vitro

Cancer has been becoming one of the diseases which cause serious damage to human health,and its morbidity and mortality are rapidly growing.How to conquer cancer has long been a focus in the study of human health career.The intracellular signaling pathways in cancer cell play a vital role in the progress of cell growth,proliferation and differentiation.Epidermal growth factor receptor(EGFR)as a protein tyrosine kinase plays a crucial role in cell growth,proliferation,metastasis and differentiation during the biological processes.In cancer cell,abnormal activation of EGFR signaling pathway can make tumor cells avoid cell apoptosis,eventually leading to its unlimited proliferation.In recent years,EGFR tyrosine kinase has been becoming an important target in the process of studying antitumor drugs.Lapatinib is a small oral reversible tyrosine kinase dual target inhibitor,which can interact with EGFR and HER2 intracellular kinase domain of ATP binding sites,thereby inhibiting growth and proliferation of cancer cell.It has been found that quinazoline compounds and isatin derivatives have better inhibitory effect on tyrosine kinase.In this paper,a series of quinazoline derivatives were designed and synthesized by using the drug-aided group heterozygous method and the computer-aided drug software SYBYL.The chemical structures of the synthesized compounds were characterized by NMR,IR,HRMS and X-ray diffraction,as well as the compounds have carried on the preliminary antimour activity.This paper mainly includes the following aspects of the research.1.The carcinogenic mechanism of epidermal growth factor overexpression and the antitumor principle of quinazoline and isatin compounds were briefly described,and a series of quinazoline derivatives were designed by the method of heterozygous drug.Lapatinib was a reference ligand and 2ITZ as the target protein receptor combined with the ligand database for molecular docking using the computer-aided drug software Sybyl.A total of 16 compounds were screened to synthesize.2.According to the literature methods,the more reasonable synthetic route of the target compound was designed,which was divided into the following two parts.The first part was the synthesis of lapatinib analogue,cheap and easily available ortho nitrobenzaldehyde as the starting material,through the cyanation of aldehyde,the sodium hydrosulfite reduction,ammonium iodide as iodine reagent got intermediates 2-amino-5-iodine cyanobenzene,then condensed into amidine,Dimorth rearrangement,Suzuki coupling,NaBH4 reduction and esterification reaction synthesized the target compounds.The second part was the synthesis of heterozygous isatin-quinazoline compounds.Easily available isatin was chosen as the starting material,then the isatin hydrazone was synthesized under the action of hydrazine hydrate.After reacted with 4-replace-6-(5-formyl furan-2-base)quinazoline which has been synthesized by Suzuki coupling reaction,12 heterozygous isatin-quinazoline compounds were synthesized.At the same time the reaction temperature,reaction time,solvent and ratio of reactants in the process of the two parts also have been explored.The chemical structures of the synthesized compounds were characterized by NMR,IR and HRMS.The structure of the target compounds were further determined by crystallization and X-ray diffraction.In general,the reaction routes were reasonable which have many advantages on a shorter route,convenient operation,high yield and simple post-processing,also accord with the requirement of industrial production.3.With lapatinib as positive control drug,The antiproliferative activity of these new compounds was evaluated in vitro by MTT assay in human colorectal carcinoma cells SW480,human epidermoid squamous carcinoma cells A431,human non-small cell lung cancer cells A549 and NCI-H1975.The results showed that most of the synthetic compounds have significant inhibitory effect on the proliferation of the four tested tumor cell lines.In particular,compounds L1,L3 and L5 showed highly potent inhibition of proliferation in four tumor cell lines,and the effect is equal to that of anti-tumor drug Lapatinib.