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1、-华中科技大学硕士学位论文AbstractIntegrinαvβ3,wasexpressedinmanycelltypes,includingosteoclasts,leukocytes,vascularsmoothmusclecells,andendothelialcells.Ithadbeenimplicatedinavarietyoftherapiesforcancer,maculardegeneration,andarthritisamongothers.Integrinαvβ3wasassociatedwithadhesionandmigrationofvascula
2、rsmoothmusclecellsandleukocytes.Antagonismofintegrinαvβ3leadtoapoptosisofendothelialcells,blocksthetumorgrowth,eventumorelapsed.Integrinαvβ3receptorhadbeenconsideredasanewtargetofanti-bloodinanti-tumorresearch.Excellentαvβ3antagonistsmaydealcancer.Computeraideddrugdesignhadbeenusedtodesignne
3、wcompoundsthatstronglyinhibitαvβ3receptorinourstudy.Thecontentsofthisstudywereasfollowed:I.Generatedapharmacophoremodelofintegrinαvβ3receptorantagonistsTwentytwocompoundsoffourcategorieswithhighlyinhibitoryactivityofintegrinαvβ3receptor(IC50<1.5nmol•L-1)wereselectedasatrainingset,todevelopap
4、harmacophoremodelwiththeCatalystsoftware.Thepharmacophoremodelofintegrinαvβ3receptorantagonistsconsistedoffourfeatures,namely,twohydrogen-bondingacceptors,analiphatichydrophobiccoreandanaromaticringcenter.RMS=0.44,Correl=0.90,Weight=1.31,Config=16.26.Thepharmacophoremodelthatweestablishedwel
5、lfitactivatecompounds.Itwasbetterthanotherknownones.Itwouldcontributetothedesignandscreeningofintegrinαvβ3receptorantagonists.II.DesignandsynthesisoftargetcompoundsThetripeptideRGDsequence,whichwasidentifiedandcombinedtoαvβ3receptor,wasconsideredastheleadcompoundinthisstudy.Compoundswererati
6、onaldesignedaccordingtotheleadcompoundRGDbybioisostereprinciple.Activitiesofwhichwereestimatedbymatchingthepharmacophoremodel.TargetcompoundsIa～IdandIIa～IIdwerescreenedout.Thirteenmidwaycompoundsandeighttargetcompoundsweresynthesized.TheIII----华中科技大学硕士学位论文targetcompoundswerenotreported,struc
7、turesofwhichwerecorroboratedbyspectraofUV,IR,1H-NMR,and13C-NMR.Howtosynthesizeoneoftheactants3-phenylpentanoicacid,animportantmedicalstaplewasparticulardiscussed.III.DeterminationofantitumoractivityinvitroTheantitumoractivityoftargetcompoundswerede
