Design,Synthesis And Anticancer Activity Of A New Type Of Dibenzo [2,3:6,7] Oxepino [4,5-d] Thiazole Analogues

Lung cancer is still the leading cause of cancer deaths throughout the world.Approximately 80-85%of all lung cancers are classified as non-small-cell lung cancer(NSCLC),type with a 5 year survival rate of only 16%that has improved little over the last 35 years.Even in patients with early stage NSCLC,about half will relapse despite surgery/radiation and adjuvant chemotherapy.Therefore,the search for better therapeutic agents with enhanced activity against lung cancer continues.In the past few decades,a large number of plant-derived bioactive compounds have been isolated that are now widely used to treat cancers,including paclitaxel,vinblastine,and camptothecin.In recent years,more and more people begin to study on Combretastatin A-4 and its analogues who act on the colchicine site.Combretastatin A-4 is a natural product isolated by Pettit and coworkers from the bark of the South African bush willow tree Combretum caffrum.CA-4 is a gathering of tubulin binding agents,which can inhibit cancer cells.In 1991,GRPettit applied for a US patent after determing the structure.Pharmacological studies have shown that,Combretastatin A-4 can selectively inhibit the growth of new blood vessels to target cells,and has toxic side effects on normal cells.CA-4 has a basic structure of a cis-ethylene bridge which connects the two benzene rings,and some of methoxy substituent groups,which is similar to colchicine.According to the research,the structure-activity relationships indicates that maintaining the cis configuration is necessary for the biological activity of structural groups.At present,in accordance with the structure of CA-4,some people have synthesized a series of compounds containing nitrogen,amino and nitro on the benzene ring.Some people have designed and synthesized 1,5-disubstituted-1,2 3-triazole compounds based on CA-4,CA-4.Between the two benzene rings we use oxygen atoms as the bridge to connect the two benzene rings,keeping the rigid structure,and at the bottom of the double bond we add a thiazole ring,making the chemical structure as a fiat compound,this design is a good simulation of the CA-4’s cis configurationIn the experiment,a new type of dibenzo[2,3:6,7]oxepino[4,5-d]thiazole analogues were synthesized and screened their activity,to find which has inhibitory activity with the A549 cells.In this paper we used dibromoethoxychlorophosphonazo acid acted as the starting material,then connected with substituted phenol,dehydrated with PPA,reacted with bromo and thiourea to form a ring,prepared dibenzoxepinacetic tropylium cation and thiazoles analogues.After the series of reactions connected to thezamino,we have synthesized 20 new dibenzoxepinacetic Tropylium cation and thiazoles analogues.By querying the CA database,these are new compounds.Finally,by screening the activity of theses compounds,to find out the inhibition activity on A549 cells.Objective:The aim is to establish a new type of dibenzo[2,3:6,7]oxepino[4,5-d]thiazole analogues about its design,synthetic compounds and its activity analysis,and to detect the inhibition activity.Methods:Using o-bromophenyl acetic acid(1)as starting materials,at first,compoud(1)was esterified in methanol under sulfuric acid as catalyzed conditions,then was reacted with substituted phenol(3),cesium carbonate as base,under cuprous iodide,N,N-dimethyl glycine catalytic conditions to give the corresponding product(4),and then under basic conditions the ester was hydrolyzed to give the acid(5);compoud(5)was dehydrated with PPA under high-temperature to get(6);Compound 6 was reacted with bromine in glacial acetic acid to afford brominated product(7);finally(7)was reacted with thiourea to generate the isoxazole ring compound(8).By MS,NMR and other means of identification of various intermediates,and these target compounds were identified.Finally by screening theses compounds,to find out which has better activity.Results:Twenty new type of dibenzo[2,3:6,7]oxepino[4,5-d]thiazole analogues are designed and synthesized,all of the structures are characterized by MS,NMR.By querying the CA database,these are new compounds.Conclusion:Designed and successfully synthesized 20 new compounds.Through active screening and found that some compounds have anti-cancer activity.