Design, Synthesis, And Evaluation Of No-donation Coumarin Derivatives As Anti-tumor Agents In Vitro

Malignant tumor has become a major threat to human health.Chemotherapy is the main treatment for malignant tumors.However,there are a lot of chemotherapy drugs in the clinic,but it is unfavorable that they have many shortcomings such as low efficacy,drug resistance and high toxic effect.Therefore,it is more significant to develop the new anti-tumor drugs with higher efficacy and lower toxicity.Coumarins are a class of natural heterocyclic compounds containing nucleus of benzo-α-pyrone,which have many biological activities such as anti-coagulation,anti-platelets,anti-bacteria,anti-tumor,anti-viral,anti-inflammatory,anti-oxidant,anti-osteoporosis and anti-Alzheimer.It is obvious that the antitumor activity of coumarins is a major highlight.Recently,a lot of studies have shown that coumarin compounds have varying degrees of anti-tumor activity,but it’s clinical application is limited due to low activity,poor water solubility and other shortcomings.In order to obtain more coumarins derivatives with high activity and good water solubility,these target compounds were designed and synthesized by using the structural modification method.Nitric oxide is one of the most important molecular signatures that plays important role in physiological activity of human body.Recently,it has been found that high concentration of NO displayed cytotoxic effect and could induce apoptosis of tumor cells,hold back tumor cells ability to proliferate,and assist macrophage to devour tumor cells.Furoxan nitrogen oxide is a common class of NO-donors,which can not only produce high concentration of NO,but also display a strong anti-tumor activity.It can enhance their antitumor activity by coupling of furoxan nitrogen oxides with natural active lead compounds.Our research group has synthesized a series of matrine-furoxan derivatives,and the results found these compounds also have displayed strong anti-proliferative activities against many tumor cells.Based on the combination principles,24 derivatives were designed,synthesized from coumarin-3-carboxlic acid and bis(phenylsulfonyl)furoxzan by a varaities of connecting arms.In addition,the anti-proliferative activities of these compounds were evaluated by MTT method.The results indicated that they had potent anti-proliferative activities against tumor cell lines.Furthermore,it is obvious that these compounds show stronger anti-proliferative activities than coumarin-3-carboxlic acid and 5-FU.Especially,compound Ⅰi displayed the strongest activity against He La(IC50 = 0.88 μM)and MCF-7(IC50 = 0.61 μM).At same time,another class of compounds showed different selectivity in different tumor cells.For example,compound Ⅱc displayed strong activity against MCF-7(IC50 = 0.29 μM),Bel-7402(IC50 = 0.33 μM)and HCT-116(IC50 = 0.48 μM),compound Ⅱl against He La(IC50= 0.24 μM)and Hep G2(IC50 = 0.38 μM).What is more,Compound Ⅱm displayed better selectivity against SW620(IC50 = 0.35 μM).The further study showed that compound Ⅱc possessed high sensitivity against Bel-7402/5-FU(IC50 = 0.63μM)and low inhibition on proliferation of human normal liver cells LO2(IC50 = 1.07 μM).Preliminary pharmacological mechanism research indicated that compound Ⅱc can promote the apoptosis and arrest in G2/M phase of Bel-7402 cell.