Synthesis Of Scutellarin And Scutellarein Derivatives And Their Biological Evaluation

Natural products have been the major sources of chemical diversity for starting materials while driving pharmaceutical discovery over the past century.Of which,flavonoid is one of the most important skeleton types.Flavonoids are secondary metabolites of plants and play important role in various biological processes.They have shown wide range of biological activities,such as cardiovascular protection,anti-tumor,anti-inflammatory,anti-viral,antibacterial,antispasmodic and hypoglycemic activities.Scutellarin,a flavonoid from traditional Chinese herb Erigeron breviscapus(Vant.)Hand-Mazz,is the main effective component of breviscapine injection.Pharmacological studies have shown that scutellarin has a variety of pharmacological activities,such as cardiovascular protection,neuroprotection,anti-tumor,hypoglycemic,antibacterial and anti-inflammatory activities,among which cardiovascular protection and anti-tumor activity are of great importance.However,some perceived disadvantages of scutellarin limited its further application,mainly including low stability,short half-life and poor oral bioavailability.In order to obtain more potent agents with improved pharmacokinetic properties,this dissertation is focused on the design,synthesis,and antitumor and cardiovascular protective evaluation of scutellarin derivatives by means of comprehensive approaches of structure-based design,combination principle,prodrug design and organic synthesis.The anticancer mechanisms of representative compounds were studied,while the pharmacokinetic properties of some scutellarin derivatives were also investigated.This dissertation consists of five parts as follow:Chapter 1:Nitric oxide-releasing derivatives of scutellarin:Design,synthesis and antitumor biological evaluationIn chapter 1,recent research progresses of nitric oxide(NO)and NO donors were reviewed.Then,furoxan and nitrates,two kinds of NO donors,were introduced to the carboxyl group of scutellarin by ester bond or amide bond.Moreover,methyl and benzyl groups were introduced to 6-OH and 4’-OH in order to improve the antitumor activity.In this chaper,twelve NO-donating scutellarin derivatives were synthesized.NO releasing ability and the antiproliferative activities against four cancer cell lines and one human normal cell line were assessed.It could be concluded from the experimental results that most derivatives showed strong antiproliferative activities against four cancer cell lines with NO releasing ability and weak activities against human normal liver cell line.The SARs were discussed according to the data.Furthermore,compounds Ⅰ-19 with better activity and selectivity(HepG-2:IC50=0.5 μM;SI=96)and Ⅰ-22 with higher NO releasing ability were chosen for further investigation.The results suggested that compounds Ⅰ-19 and Ⅰ-22 induced cancer cells apoptosis through promoting caspase cascade reaction and inhibiting the expression of anti-apoptotic proteins.Chapter 2:Design,synthesis and antitumor biological evaluation of scutellarein-4’-O-mustards derivativesRecently,some researchers found that scutellarin was mainly absorbed in the form of its hydrolyzed product scutellarein,which had better activity than scutellarin.To explore more efficacious and less toxic antitumor agents,nine hybrids of scutellarin and nitrogen mustards were designed and synthesized according to the combination principles.The antiproliferative activities of all compounds were screened.The result showed that most conjugates exhibited remarkable antiproliferative activities against tumor cells and low cytotoxicity against human normal cells L-O2 and PBMC.Particularly,compound Ⅱ-14 displayed the most potent antiproliferative activity against MCF-7 cell line with IC50 value of 1.5 μM,and superior to the parent compound scutellarein,clinically used nitrogen mustards and 5-FU.The mechanism of Ⅱ-14 was further investigated,and the results suggested that Ⅱ-14 could induce MCF-7 cells apoptosis through mitochondrial-dependent apoptosis pathway.Chapter 3:Design,synthesis and biological evaluation of novel aniline-derived scutellarin derivativesThirty aniline-derived scutellarin derivatives were designed and synthesized according to the structure-activity relationships.The antiproliferative activities of these compounds were screened.The results showed that these compounds could inhibit the proliferation of HL-60 and THP-1 leukemia cells.Chapter 4:Design and synthesis of scutellarein derivatives containing phosphonate moietyPoor pharmacokinetic properties have been the main limitation of the application of scutellarin.In order to further improve water solubility,stability and bioavailability of scutellarein,the phosphate groups were introduced to the structure of scutellarein.Twenty scutellarein derivatives bearing phosphate groups were designed and synthesized.Chapter 5:Design and synthesis of nitrate NO-donating derivatives of scutellareinPrevious studies showed that the nitrate derivatives of scutellarin exhibited low cytotoxicity,and sustained and low NO releasing ability.These encouraged us to explore nitrate derivatives of scutellarein with cardiovascular protective effects.Therefore,seventeen nitrate derivatives of scutellarein were designed and synthesized.