Design And Synthesis Of Six Kinds Of Flavone-7-Phosphoramidate Derivatives

Flavonoids are very important and extensively distributed polyphenol natural products which have been reported to show many biological activities, including antioxidative, antiviral, anti-tumor, protecting liver and detoxification activities. Nowadays the phosphate pro-drug approaches, known as "ProTides" methods, have interested many researchers in antiviral and anti-HIV field. So a series of novel flavone-7-phosphoramidate derivatives were designed and synthesized to investigate their antiviral activity.First, the designed target compounds and the flavones themselves were docked into the core domain of HIV-1integrase using docking program CDOCKER. The result showed that this kind of compounds could interact well with the key amino acid residues to form hydrogen-bond and π-cation interaction. And the phosphoramidate derivatives could bind the active pocket of integrase better than the flavones. Therefore the flavone-7-phosphoramidate derivatives may have potential anti-HIV activity.Then the phosphoramidate derivatives of flavones were synthesized by a facile phosphorylated reaction starting with six different flavones, including chrysin, apigenin, luteolin, quercetin, daidzein and genistein. Thus43target compounds were obtained and41of them were new. Finally their chemical structures were confirmed by1H NMR,13C NMR and MS.By researching the condition of removing the acetyl groups of4’,5-diacetylapigenin-7-phosphoramidates and3’,4’,5-triacetylluteolin-7-phosphoramidates, pyrrolidine in THF was found to be ideal and the yield could reach up to85.5%. Besides, the phosphorylated reaction of isoflavones under microwave radiation was successfully completed. The microwave conditions were found to be the radiation frequency of600W and the reaction time of4to5hours.Three flavone-7-phosphoramidate derivatives were evaluated for their anti-HIV activity in vitro. The inhibition of compound3a,3b and14a were55.7%,52.8%and9.2%respectively at a concentration of0.25μg/mL. In the meantime this kind of compounds showed cytotoxicity unfortunately. So it is needed to investigate the structure-activity relationship to find compounds with better activity and lower toxicity. In addition,12target compounds were tested for their antitumor activities versus Hela cervical cells. All the derivatives tested emerged as low micromolar inhibitors of Hela cells. Compunds11d and11e showed the best antitumor activites with the IC50of5.2μmol/L and8.6μmol/L.