The Sythesis And Anticancer Activity Eveluation Of 2-arylalkyl Acid Morpholine Ethyl Esters

Non-steroidal anti-inflammatory drugs(NSAIDs)with anti-inflammatory,analgesic and antipyretic effects are the preferred drugs for the therapy of acute and chronic rheumatoid arthritis.Their clinical application is extremely widespread with the world's second dosage compared to the antibiotic drugs.In recent years,abundant researches found that NSAIDs had certain curative effect on the prevention and treatment of cancers including colorectal cancer,breast cancer,gastric cancer,et al.The mechanism of inhibiting tumor was related to the inhibition of COX-2 which caused the depressed synthesis of prostaglandins,inducing tumor cell apoptosis and suppressing tumor angiogenesis and tumor metastasis.Naproxen,indomethacin,ibuprofen,as three typical arylalkyl acids drugs of NSAIDs,were studied a lot on their synthesis processes,structure optimizations and antitumor activity.Based on above views,the sythesis route of the key intermediate of naproxen was optimized and a series of 2-aryl alkyl acids derivatives were prepared,then several potential compounds were tested against human breast cancer.The optimal process of naproxen intermediate 2-(2-bromine propionyl)-6-methoxy-5-bromine naphthalene(B)was that 2-propionyl-6-methoxy naphthalene(A)as raw material reacted under NaBr-H2O2 bromine generation system by orthogonal experiment methods.The ratios of raw materials,reaction temperature and time,post-processing method have been optimized,and finally the best synthesis process conditions were obtained.Using CCl4 as solution,the reaction materials were added following the mole ratio of n(A):n(NaBr):n(H2SO4):n(H2O2)=1.0:2.2:2.2:3.0 under the optimum reaction temperature 76? for 4 hours,and the yield of compound B reached 90%.As a replacement of traditional bromine generation methods,NaBr-H2O2 bromide alternative has both higher activity and greatly improved utilization rate of Br atom.This method have been proved safer,easier operation,and more environmentally friendly compared to other methods.The synthesis process of 2-arylalkyl acid 2-(2-aryl morpholino-4-yl)ethyl esters C1-C12,D1?D9,E1?E9 were optimized using DCC/DMAP catalytic esterification method or "one pot" chloride esterification method.Comparing the superiority of two methods,we optimized several factors including solvents,material proportion,reaction time and post-treatment,and then the best "one pot" chloride esterification scheme were obtained.Using CH2Cl2 as solution,the arylalkyl acids reacted with(COCl)2 under anhydrous anaerobic conditions in ice bath,and then 2-aryl morpholines were added following the ratio of n(arylalkyl acid):n(2-aryl morpholine)=1.5:1.0 for 5-6 h.Products without column chromatography,and dry HCl gas were directly added to form salts,the yield of target products reached 70%- 80%.The selected compounds 2-(2-arylmorpholino)ethyl ester of indometacin hydrochlorides(C3?C12)were tested for their anticancer activity against mammary tumor cell line MCF-7 in vitro by the MTT method.Biological assay indicated that compounds C3?C4?C5?C9?C10?C12 possessed favorable activity against breast cancer and the compound C10 exhibited the best activity against MCF-7(IC50=0.018 mM),which was relatively equivalent with cisplatin.This result also strongly confirmed that compounds C3-C12 as novel COX-2 inhibitors can be used as powerful agents for breast cancer chemoprevention.