糖苷類抗生素-糖基前藥教學(xué)課件

糖苷類抗生素1)天然糖苷類抗生素,Glycorandomization策略2)糖苷類前藥設(shè)計(jì)實(shí)例天然糖苷類抗生素DaunorubicinVancomycinCalicheamiciny結(jié)構(gòu)特殊的脫氧糖蒽環(huán)類抗癌藥天然糖苷類抗生素OMeOHoDNAintercallDomain+1糖基參與了:藥物DNA/Topoisomerase復(fù)合物的形成二糖衍生物中a(1-4)衍生物活性最好蒽環(huán)類抗癌藥天然糖苷類抗生素OMeOOH0OHOgenerationoDoxorubicincubicinMEN10755糖基結(jié)構(gòu)與心臟毒性相關(guān):1stgeneration>2ndgeneration>3rdgeneration蒽環(huán)類抗癌藥天然糖苷類抗生素OHOHOHOMeOOHOOMeOOHOOHOHOADNRADOX糖基結(jié)構(gòu)與抗藥性相關(guān):ADNR和ADOX不再是P-gp的底物P-gp:p-glycoprotein,oneofthemembranetransporterproteins,responsibleformultipledrugresistance萬古霉素天然糖苷類抗生素HOH2NNH2HO2C萬古霉素Oritavancin合DAa-D-Ala干擾細(xì)胞壁合成通過形成dimmer來增強(qiáng)結(jié)合能疏水性的聯(lián)苯基團(tuán)在細(xì)胞壁表面有“anchor”作用新的作用機(jī)制Science1999.284.50天然糖苷類抗生素結(jié)論糖基結(jié)構(gòu)的衍生化是得到新型抗生素的重要途徑。Glycorandomization策略天然糖苷類抗生素AglyconeSugarMoietyMoiety○■○DrugDrugfromNaturesugarLibraryLibrarSARofSugarMoietyDaunorubicinJons.torsoJACS,(2006),14224-14225兩大挑戰(zhàn):Chem&Bo(2008),393-401)糖庫合成NatChemB0(②2007),657-6622)糖基化反應(yīng)PNAS(2005),12305-12310合成稀有糖天然糖苷類抗生素L-axenose6-deoxysuoar2,6-dideoxysug2,3,6-trideoxy-3-aminosugarlOHMeoOHZToTOH0-4,6-dideoxy2.3,6-trideoxysugar3.6-dideoxysugar4,6-dideoxysugarline3-amino-3,6-dideoxy2,4,6-trideoxy-4-aminosugar3.6-trideoxy-3-aminosugar合成稀有糖天然糖苷類抗生素L.Activation-substifufionreactionafthecarbohydrateringR-OHR-LGR-XLG:leavinggroupLeav