MedKooCat#:200274
Name:Silatecan
CAS#:220913-32-6
ChemicalFormula:C26H30N2O5Si
ExactMass:478.1924
MolecularWeight:478.61
ElementalAnalysis:C,65.25;H,6.32;N,5.85;O,16.71;Si,5.87
Synonym:AR67;AR67;AR67;DB67;DB67;DB67;7tButyldimethylsilyl10hydroxycamptothecin;Silatecan.
IUPAC/ChemicalName:(S)-11-(tert-butyldimethylsilyl)-4-ethyl-4,9-dihydroxy-1H-pyrano[3",4":6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione
InChiKey:XUSKJHCMMWAAHV-SANMLTNESA-N
InChiCode:InChI=1S/C26H30N2O5Si/c1-7-26(32)18-11-20-21-16(12-28(20)23(30)17(18)13-33-24(26)31)22(34(5,6)25(2,3)4)15-10-14(29)8-9-19(15)27-21/h8-11,29,32H,7,12-13H2,1-6H3/t26-/m0/s1
SMILESCode:O=C1[C@](O)(CC)C2=C(CO1)C(N3CC4=C([Si](C)(C(C)(C)C)C)C5=CC(O)=CC=C5N=C4C3=C2)=O
TechnicalData
AdditionalInformation
AR-67(DB-67)isanovel,third-generationcamptothecinanaloguethathasdemonstratedhighpotencyinpreclinicalstudiesandimprovedpharmacokineticpropertiesinhumansascomparedwithfirstandsecond-generationproducts.ArnobelievesthatthisuniqueprofileandthepotentialfororaladmiNISTrationmaytranslateintosuperiorefficacyandpatientconvenienceinthetreatmentofbrain,lung,andothercancers.WebelievetheseadvantagescouldallowDB-67tobecomealeadingproductinthe$1.1billioncamptothecinmarket.Arnoiscurrentlyconductingasingleagent,ascendingdose,PhaseIclinicalstudyofDB-67inpatientswithadvancedsolidtumors.ThestudyisevaluatingthesafetyofDB-67,establishingthemaximumtolerateddose,andcharacterizingtheplasmaPKprofile.
References
1:ArnoldSM,RinehartJJ,TsakalozouE,EckardtJR,FieldsSZ,SheltonBJ,DeSimonePA,KeeBK,MoscowJA,LeggasM.AphaseIstudyof7-t-butyldimethylsilyl-10-hydroxycamptothecininadultpatientswithrefractoryormetastaticsolidmalignancies.ClinCancerRes.2010Jan15;16(2):673-80.Epub2010Jan12.PubMedPMID:20068096;PubMedCentralPMCID:PMC2831464.
2:YehTK,LiCM,ChenCP,ChuuJJ,HuangCL,WangHS,ShenCC,LeeTY,ChangCY,ChangCM,ChaoYS,LinCT,ChangJY,ChenCT.AntitumoractivitiesandpharmacokineticsofsilatecansDB-67andDB-91.PharmacolRes.2010Feb;61(2):108-15.Epub2009Jul28.PubMedPMID:19643180.
3:SivakWN,ZhangJ,PetoudS,BeckmanEJ.IncorporationofionicligandsacceleratesdrugreleasefromLDI-glycerolpolyurethanes.ActaBiomater.2010Jan;6(1):144-53.Epub2009Jun11.PubMedPMID:19524075.
4:SivakWN,ZhangJ,PetoudS,BeckmanEJ.Simultaneousdrugreleaseatdifferentratesfrombiodegradablepolyurethanefoams.ActaBiomater.2009Sep;5(7):2398-408.Epub2009Apr1.PubMedPMID:19398389.
5:KruszewskiS,ZiomkowskaB,CyrankiewiczM,WybranowskiT.ThecomparisonofbiophysicalpropertiesofDB-67anditsesterDB-67-4ABTFAdeterminedbyfluorescencespectroscopymethods.Biosystems.2008Dec;94(3):270-5.Epub2008Jul31.PubMedPMID:18718502.
6:JoguparthiV,AndersonBD.EffectofcyclodextrincomplexationontheliposomepermeabilityofamodelhydrophobicweakAcid.PharmRes.2008Nov;25(11):2505-15.Epub2008Jul19.PubMedPMID:18642063.
7:SivakWN,PollackIF,PetoudS,ZamboniWC,ZhangJ,BeckmanEJ.LDI-glycerolpolyurethaneimplantsexhibitcontrolledreleaseofDB-67andanti-tumoractivityinvitroagainstmalignantgliomas.ActaBiomater.2008Jul;4(4):852-62.Epub2007Nov17.PubMedPMID:18440882.
8:ZamboniWC,JungLL,StrychorS,JosephE,ZamboniBA,FettermanSA,SidoneBJ,BurkeTG,CurranDP,EisemanJL.Plasmaandtissuedispositionofnon-LiposomalDB-67andliposomalDB-67inC.B-17SCIDmice.InvestNewDrugs.2008Oct;26(5):399-406.Epub2008Feb2.PubMedPMID:18246299.
9:JoguparthiV,FengS,AndersonBD.DeterminationofintraliposomalpHanditseffectonmembranepartitioningandpassiveloadingofahydrophobiccamptothecin,DB-67.IntJPharm.2008Mar20;352(1-2):17-28.Epub2007Oct12.PubMedPMID:18065174;PubMedCentralPMCID:PMC2277365.
10:JoguparthiV,XiangTX,AndersonBD.Liposometransportofhydrophobicdrugs:gelphaselipidbilayerpermeabilityandpartitioningofthelactoneformofahydrophobiccamptothecin,DB-67.JPharmSci.2008Jan;97(1):400-20.PubMedPMID:17879989.
11:XiangTX,JiangZQ,SongL,AndersonBD.Moleculardynamicssimulationsandexperimentalstudiesofbindingandmobilityof7-tert-butyldimethylsilyl-10-hydroxycamptothecinandits20(S)-4-aminobutyrateesterinDMPCmembranes.MolPharm.2006Sep-Oct;3(5):589-600.PubMedPMID:17009858.
12:HornJ,JordanSL,SongL,RobertsMJ,AndersonBD,LeggasM.ValidationofanHPLCmethodforanalysisofDB-67anditswatersolubleprodruginmouseplasma.JChromatogrBAnalytTechnolBiomedLifeSci.2006Nov21;844(1):15-22.Epub2006Jul21.PubMedPMID:16860004.
13:ChenAY,ShihSJ,GarriquesLN,RothenbergML,HsiaoM,CurranDP.SilatecanDB-67isanovelDNAtopoisomeraseI-targetedradiationsensitizer.MolCancerTher.2005Feb;4(2):317-24.PubMedPMID:15713902.
14:Lopez-BarconsLA,ZhangJ,SiriwitayawanG,BurkeTG,Perez-SolerR.ThenovelhighlylipophilictopoisomeraseIinhibitorDB67iseffectiveinthetreatmentoflivermetastasesofmurineCT-26coloncarcinoma.Neoplasia.2004Sep-Oct;6(5):457-67.PubMedPMID:15548354;PubMedCentralPMCID:PMC1531650.
15:BenceAK,MattinglyCA,BurkeTG,AdamsVR.TheeffectofDB-67,alipophiliccamptothecinderivative,ontopoisomeraseIlevelsinnon-small-celllungcancercells.CancerChemotherPharmacol.2004Oct;54(4):354-60.Epub2004Jun12.PubMedPMID:15197485.
16:LansiauxA,BaillyC.[Asymphonyforthecamptothecins].BullCancer.2003Mar;90(3):239-45.French.PubMedPMID:12801826.
17:DuW,KaskarB,BlumbergsP,SubramanianPK,CurranDP.SemisynthesisofDB-67andothersilatecansfromcamptothecinbythiol-promotedadditionofsilylradicals.BioorgMedChem.2003Feb6;11(3):451-8.PubMedPMID:12517440.
18:XiangTX,AndersonBD.Stablesupersaturatedaqueoussolutionsofsilatecan7-t-butyldimethylsilyl-10-hydroxycamptothecinviachemicalconversioninthepresenceofachemicallymodifiedbeta-cyclodextrin.PharmRes.2002Aug;19(8):1215-22.PubMedPMID:12240949.
19:BomD,CurranDP,ZhangJ,ZimmerSG,BevinsR,KruszewskiS,HoweJN,BingcangA,LatusLJ,BurkeTG.ThehighlylipophilicDNAtopoisomeraseIinhibitorDB-67displayselevatedlactonelevelsinhumanbloodandpotentanticanceractivity.JControlRelease.2001Jul6;74(1-3):325-33.PubMedPMID:11489514.
20:BomD,CurranDP,KruszewskiS,ZimmerSG,ThompsonStrodeJ,KohlhagenG,DuW,ChavanAJ,FraleyKA,BingcangAL,LatusLJ,PommierY,BurkeTG.Thenovelsilatecan7-tert-butyldimethylsilyl-10-hydroxycamptothecindisplayshighlipophilicity,improvedhumanbloodstability,andpotentanticanceractivity.JMedChem.2000Oct19;43(21):3970-80.PubMedPMID:11052802.
