Design,Synthesis And Biological Evaluation Of Ursolic Acid Derivatives Bearing Aminoguanidine Moiety

The World Health Organization estimates that cancer will account for approximately 9.6 million deaths globally in 2018,and its incidence is steadily increasing.The major treatments for cancer are surgery,radiation,and chemotherapy.However,traditional chemotherapeutic agents have a number of critical drawbacks,including harmful side-effects,non-specific biodistribution,short circulation times,and poor solubility,which result in poor therapeutic efficiency.Thus,there is a tremendous need to develop new compounds for the prevention and treatment of cancer.Hypoxia is a common feature of many solid tumors and is generally caused by the rapid proliferation of tumor cells,which leads to formation of solid masses and obstruction and compression of the blood vessels surrounding them.7 Hypoxia-inducible factor 1?(HIF-1?)is a transcription factor that regulates the expression of numerous genes involved in nutrient uptake,cell survival,angiogenesis,invasion,and metastasis,and thus plays an important role in cancer development.In this paper,we designed and synthesized three novel series of ursolic acid derivatives containing an aminoguanidine moiety and evaluated them as HIF-la inhibitors and anti-cancer agents using human cancer cell lines.Most of the compounds exhibited significant inhibition of HIF-la transcriptional activity,as measured using a Hep3B cell-based luciferase reporter assay.Among these compounds,7b was the most potent inhibitor of HIF-1? expression under hypoxic conditions(IC50 4.0 ?M)and did not display significant cytotoxicity against any cell lines tested.The mechanism of action of 7b was investigated,and we found that 7b downregulated HIF-la protein expression,possibly by suppressing its synthesis,reduced production of vascular endothelial growth factor,and inhibited the proliferation of cancer cells.In addition,some compounds exhibited potent antibacterial activity against Gram-positive bacterial strains(including multidrug-resistant clinical isolates)and Gram-negative bacterial strains,with minimum inhibitory concentration(MIC)values in the range of 2-64 ?g/mL.Compounds 3a,5a,and 71 showed significant inhibitory activity against the Gram-positive bacterial strain Staphylococcus aureus RN4220,the Gram-negative bacterial strain Escherichia coli 1924,and four multidrug-resistant Gram-positive bacterial strains,with MIC values of 2 and 4?g/mL.In anti-inflammatory tests,most of the compounds exhibited potent activity,in particular,compound 3a displayed the most potent activity with 81.61%inhibition after intraperitoneal administration,which was more potent than ursolic acid and the positive controls(ibuprofen and indomethacin).