| The traditional chemotherapy drug can be divided into two main types: cell poison medicine and antimetabolites.Due to their low selectivity,they also kill normal cells in the treatment of tumor.Therefore,early chemotherapy has high toxicity and strong side effects to the extent that the patient was difficult to accept or felt extremely pitiful.It has become a vital task for researchers to develop antitumor drugs with higher selectivity,less toxicity and less adverse effect.The development of modern cell biology reveals the relation between the process of cell growth and cellular signal processes.The processes of biochemical reaction were very complex and it involved involve many pathways and enzymes.The protein tyrosine kinases(PTKs)and its catalyzed way play an important role in the signal transduction pathways,which is a kind of kinases transferred ?-phosphoric acid on adenosine triphosphate(ATP)to protein tyrosine residues.Over-expression of the PTKs will affect proliferation,growth differentiation,migration and apoptosis of cancer cells.By inhibiting the activities of protein tyrosine kinases,we can achieve the treatment of tumor.Quinazoline as the parent nucleus of antitumor drug is the most classic and researched among clinical PTKs inhibitors.Through the study of the structureactivity relationship,the quinazoline ring is not necessary component for PTKs inhibitors.Lots of nuclear nitrogen heterocycles similar to quinazoline also possess good antitumor activity.Pteridine is a kind of compounds fused of pyrimidine and pyrazine ring.According to the bioisosterism,the pteridine would have similar biological activity.The reports proved that pteridine compounds have a variety of activities in anticancer,antiviral,antibacterial,adenosine kinase inhibitors,NO synthesis inhibitors,etc.Therefore,it is expected to develop into a kind of new anticancer medicines through connecting the basic ring pterdine with other aromatic rings which have biological activity.In this paper,with Gefitinib as lead compound,by using the bioisoster principles,some new pteridine PTKs inhibitors have been designed.The content mainly involved three aspects.(1)17 new pteridine compounds were synthesized with 3-aminopyrazine-2-formic acid as a raw material by amidation,bromination,cyclization,alkoxylation,chlorination and ammoniation reaction of chlorinated product.Their structure was determined by IR,MS and 1H-NMR analysis.(2)The synthesis of intermediates and target compounds was optimized.The chlorinated intermediates reacted with aryl amine to give the desired corresponding products under microwave irradiation for 20 min in high yields up to 43~76%.It has an advantage of short time and high yield compared to the conventional method.(3)The antitumor activity of new pteridine compounds on the squamous cancer cells VX-2 and human non-small cell lung cancer cell A549 was evaluated by CCK-8 detection method.The result indicates that the series of pteridine compounds have higher inhibition activity towards human non-small cell hung cancer A549 than squamous carcinoma VX-2 cell.4-(Aromatic amino)-6-ethoxy pteridine(7b)showed stronger biological activity than 4-(aromatic amino)-6-methoxy pteridine(7a).The IC50 values of 7b-1 and 7b-4 on A549 are both 0.04 ?g/mL,which is 10 times lower than positive drug Gefitinib and almost 100 times lower than Imatinib,respectively.The antitumor activity of 7b-12 towards VX-2 is the most effective among the target compounds.The IC50 value is 3.83 ?g/mL,which is close to Gefitinib and Imatinib. |
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