Preliminary Study On Synthesis And Anti-tumor Activity Of Isatin Hybrid Quinazoline Compounds

Cancer has been becoming one of diseases which cause serious damage to human health.Statistics from the World Health Organization show that the incidence and mortality of cancer have been on rise in recent years.People have paid high attention to the prevention and treatment of cancer for a long time.With the development of molecular biology techniques and the further understanding of the mechanism of cancer,molecular targeted therapies have become one of important methods in treatment of malignant tumor.It has been found that quinazoline and isatin derivatives have better anticancer effects.Many quinazoline derivatives as target drugs,such as gefitinib and lapatinib,have been shown particularly beneficial for tumor treatment,and many isatin derivatives as target drugs,such as sunitinib,have been shown better effects in treatment of advanced renal-cell carcinoma and gastrointestinal stromal tumours.Clinical data showed that drug resistance and side effects would be occurred after using the target drug for a period time.Therefore,it is imprtant to synthesis novel antitumor drugs with low drugs resistance,low toxicity and novel structure.In this paper,a series of heterozygous isatin-quinazoline compounds were designed and synthesized by using pharmacophore hybrid approach and computer-aided drug software SYBYL.The chemcial structures of the synthesized compounds were characterized by NMR,HRMS and IR,as well as 15 compounds were evaluated on antitumor activity in vitro.The main work exhibited as the following:1.The research progress of molecular targeted therapies and pharmacophore hybrid approach on antitumour were summarized,the structure-activity relationship of isatin and quinazoline derivatives as well as the synthetic methods of quinazoline compounds were introduced.Using the computer-aided drug software SYBYL,the molecular docking were proceeded to screen the designed compounds,and the wild type EGFR was used as the target protein recepter,lapatinib was used as a reference ligand,total of 15 compounds were prepared to synthesize.2.Synthesis of the 15 target compounds.It is divided into the following two parts.The first part is the preparation of isatin hybrid 6,7-dialkoxyl substituted quinazoline derivatives.Firstly,2-amino-4,5-dimethoxybenzoic acid was used as starting material,cyclization to give quinazoline,which was subjected to chlorination,and reacted with isatin hydrazone to obtain the target compounds G1-G3.Secondly,compounds G4-G6 were synthesized from 3,4-dihydroxybenzaldehyde as starting material via 10 steps reactions inciuding cyanation,alkylation,nitration,conversion of nitrile to amide,nitro reduction,cyclization to give quinazolinone,which was subjected to chlorination,and reacted with isatin hydrazone.The second part is the preparation of isatin hybrid 6-(5-instead of furan-2-yl)quinazoline derivatives.Using ortho nitrobenzaldehyde as the starting material,through 9 steps reactios including cyanation,conversion of nitrile to amide,ammonium iodide as iodine reagent to get 2-amino-5-iodine cyanobenzene,which reacted with DMF-DMA to give a kind of amidine intermediates,through Dimorth rearrangement,Suzuki coupling reaction,reacted with 1-substituted isatin hydrazone,9 heterozygous isatin-quinazoline derivatives were synthesized.At the same time,the reaction temperature,reaction time,solvent and ratio of the reactant in the process of the two parts also have been optimized.The structures of target compounds were characterized by NMR,HRMS and IR.Generally,the designed routes were easily operate and handle,cost effective and more suitable for the requirements of industrial production.3.With lapatinib,gefitinib and isatin as the positive control,the antiproliferative activity of these target compounds were evaluated in vitro by MTT method in human cancer cells incudling colon cancer cells SW480,skin squamous cell cancer A431,non small cell lung cancer cells A549 and NCI-H1975.The results demostrated that most of the compounds had moderate to potent inhibitory activity against these four tumor cell lines.Compound L1,L2,L5 and L7 had highly potent inhibitory activities on the proliferation of the four cell lines,and the effect better than that of antitumor drug lapatinib.