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1、J.Nat.Prod.2007,70,461-477461NaturalProductsasSourcesofNewDrugsovertheLast25Years^DavidJ.Newman*andGordonM.CraggNaturalProductsBranch,DeVelopmentalTherapeuticsProgram,DiVisionofCancerTreatmentandDiagnosis,NationalCancerInstitute-Frederick,P.O.BoxB,Frederick
2、,Maryland21702ReceiVedOctober10,2006Thisreviewisanupdatedandexpandedversionoftwopriorreviewsthatwerepublishedinthisjournalin1997and2003.Inthecaseofallapprovedagentsthetimeframehasbeenextendedtoincludethe251/2yearsfrom01/1981to06/2006foralldiseasesworldwidea
3、ndfrom1950(earliestsofaridentified)to06/2006forallapprovedantitumordrugsworldwide.WehavecontinuedtoutilizeoursecondarysubdivisionofaªnaturalproductmimicºorªNMºtojointheoriginalprimarydivisions.Fromthedatapresented,theutilityofnaturalproductsassourcesofnovel
4、structures,butnotnecessarilythefinaldrugentity,isstillaliveandwell.Thus,intheareaofcancer,overthetimeframefromaroundthe1940stodate,ofthe155smallmolecules,73%areotherthanªSº(synthetic),with47%actuallybeingeithernaturalproductsordirectlyderivedtherefrom.Inoth
5、erareas,theinfluenceofnaturalproductstructuresisquitemarked,with,asexpectedfrompriorinformation,theantiinfectiveareabeingdependentonnaturalproductsandtheirstructures.Althoughcombinatorialchemistrytechniqueshavesucceededasmethodsofoptimizingstructuresandhave
6、,infact,beenusedintheoptimizationofmanyrecentlyapprovedagents,weareabletoidentifyonlyonedenoVocombinatorialcompoundapprovedasadruginthis25plusyeartimeframe.Wewishtodrawtheattentionofreaderstotherapidlyevolvingrecognitionthatasignificantnumberofnaturalproduc
7、tdrugs/leadsareactuallyproducedbymicrobesand/ormicrobialinteractionswiththeªhostfromwhenceitwasisolatedº,andthereforeweconsiderthatthisareaofnaturalproductresearchshouldbeexpandedsignificantly.Itisovernineyearssincethepublicationofourfirst,1andthreethatisre
8、cognizedbyanactivetransportsystemwhenconsideringyearssincethesecond,2analysisofthesourcesofnewandapprovedªdruggablechemicalentitiesº.8-10drugsforthetreatmentofhumandiseases,bothofwhichindicatedAlthough
