Design,Synthesis And Activity Of Nitric Oxide-Donating Coumarin

Coumarin widely exists in nature,and it is commonly found in black bean,Hemarthria,vanilla and orchid.It has aroused extensive attention because of its many biological activities,such as anti-viral,anti-tumor,anti osteoporosis and anticoagulant,also it has low toxicity.In recent years,the anti-inflammatory,hypoglycemic and anticancer effects of coumarin and its derivatives have received special attention.Epidemiological studies have shown that there is a certain relationship between diabetes（especially type 2 diabetes）and cancer.The possible link is the chronic symptoms of hyperinsulinemia,hyperglycemia and dyslipidemia,which can promote tumor growth and metastasis.Therefore,research and development of drugs have hypoglycemic and anticancer effects,which can reduce the risk of cancer in patients with diabetes.Nitric oxide（NO）,as an important signal factor in the organism,has a very extensive regulatory effect.And exogenous NO release therapy has been used in clinical treatment.A novel NO donor coumarin was synthesized by linking coumarin with NO donor.It is expected to improve the biological activity of coumarin through the synergistic effect with NO donor,so as to obtain new compounds with potential medicinal value.In this research,12 NO coumarins of organic nitrates were designed and synthesized,The structures of the synthesized compounds were characterized by¹HNMR and MALDI-TOF.The NO release capacity andα-glucosidase inhibition capacity of 12 compounds were determined in vitro;4 compounds with strongα-glucosidase inhibition capacity were screened out for postprandial hypoglycemic test in mice;12 compounds were exposed to MCF7,A549 and HT29 cancer cells respectively,and their cytotoxicity was detected by MTT assay.The experimental results show that,In the test of NO releasein in vitro,except compound 9a,the other 11 compounds had certain NO release ability.In the experiment ofα-glucosidase inhibition in vitro,The IC₅₀of coumarin is146.87μM,The IC₅₀of positive control acarbose is 50.53μM,compounds 5b,5c,7b and 11c show good activity with IC₅₀range of 37.77～62.84μM,and the best activity is 5c(IC₅₀=37.77μM),its inhibitory activity is better than that of acarbose.In mice postprandial hypoglycemic experiment showed that compounds 5b,5c and 11c had the ability to reduce postprandial blood glucose compared with the model group,and 11c had the best hypoglycemic effect.At a concentration of 50 mg/kg,only compounds 5b had the hypoglycemic effect.Increasing the concentration does not enhance the hypoglycemic ability,the result show that the hypoglycemic effect is not dose-dependent.therefore,5b,5c,and 11c perhaps become potential hypoglycemic drugs.Cytotoxicity experiments show that,the cytotoxicity of compounds 5a,5b,7b,7c and 9a to MCF7,A549 and HT29 cells was 30～90 times higher than the parent coumarin.The toxicity of these compounds to MCF7cell was higher than A549 and HT29cells,and the most active compound was 5a(IC₅₀=29.17μM),the second was5b(IC₅₀=40.09μM).5a maybe turn into a potential anticancer drug.In conclusion,compound 5b can reduce postprandial blood glucose in mice and has high cytotoxicity to three kinds of cancer cells.It is expected to develop into a new drug with hypoglycemic and anticancer effect.