Cabazitaxelisasemi-syntheticderivativeofthenaturaltaxoid10-deacetylbaccatinIIIwithpotentialantineoplasticactivity.Cabazitaxelbindstoandstabilizestubulin,resultingintheinhibitionofmicrotubuledepolymerizationandcelldivision,cellcyclearrestintheG2/Mphase,andtheinhibitionoftumorcellproliferation.Unlikeothertaxanecompounds,thisagentisapoorsubstrateforthemembrane-associated,multidrugresistance(MDR),P-glycoprotein(P-gp)effluxpumpandmaybeusefulfortreatingmultidrug-resistanttumors.Inaddition,cabazitaxelpenetratestheblood-brainbarrier(BBB).

MedKooCat#:200585
Name:Cabazitaxel
CAS#:183133-96-2
ChemicalFormula:C45H57NO14
ExactMass:835.37791
MolecularWeight:835.93
ElementalAnalysis:C,64.66;H,6.87;N,1.68;O,26.80.


Synonym:XRP6258;XRP-6258;XRP6258;TXD258;TXD-258;TXD258;RPR116258A;axoidXRP6258;dimethoxydocetaxelUSbrandname:Jevtana.

IUPAC/ChemicalName:(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-3-phenylpropanoyl)oxy)-11-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-ylbenzoate.

InChiKey:BMQGVNUXMIRLCK-OAGWZNDDSA-N

InChiCode:InChI=1S/C45H57NO14/c1-24-28(57-39(51)33(48)32(26-17-13-11-14-18-26)46-40(52)60-41(3,4)5)22-45(53)37(58-38(50)27-19-15-12-16-20-27)35-43(8,36(49)34(55-10)31(24)42(45,6)7)29(54-9)21-30-44(35,23-56-30)59-25(2)47/h11-20,28-30,32-35,37,48,53H,21-23H2,1-10H3,(H,46,52)/t28-,29-,30+,32-,33+,34+,35-,37-,43+,44-,45+/m0/s1

SMILESCode:O=C(O[C@@H]([C@@]1([H])[C@@]2(C)[C@@H](OC)C[C@@]3([H])OC[C@]31OC(C)=O)[C@]4(O)C[C@H](OC([C@H](O)[C@@H](NC(OC(C)(C)C)=O)C5=CC=CC=C5)=O)C(C)=C(C4(C)C)[C@@H](OC)C2=O)C6=CC=CC=C6


TechnicalData

Appearance:
whitesolidpowder

Purity:
>98%(orrefertotheCertificateofAnalysis)

CertificateofAnalysis:
ViewcurrentbatchofCoA

QCData:
ViewNMR,ViewHPLC,ViewMS

SafetyDataSheet(MSDS):
ViewMaterialSafetyDataSheet(MSDS)

ShippingCondition:
Shippedunderambienttemperatureasnon-hazardouschemical.ThisproductisstableenoughforafewweeksduringordinaryshippingandtimespentinCustoms.

StorageCondition:
Dry,darkandat0-4Cforshortterm(daystoweeks)or-20Cforlongterm(monthstoyears).

Solubility:
SolubleinDMSO,notinwater

ShelfLife:
>2yearsifstoredproperly

DrugFormulation:
ThisdrugmaybeformulatedinDMSO

StockSolutionStorage:
0-4Cforshortterm(daystoweeks),or-20Cforlongterm(months).

HarmonizedSystemCode:
293490


AdditionalInformation

  
Chemicalstructureofcabazitaxel
Comparingtothechemicalstructureofdocetaxel,cabazitaxelhastwomoremethylgroups.Forthisreason,cabazitaxelisalsocalleddimethoxydocetaxel(seethefollowingchemicalstructures).
 
Scheme1:chemicalstructuresofcabazitaxelanddocetaxel
 
Cabazitaxel:DrugDescription
JEVTANA(cabazitaxel)isanantineoplasticagentbelongingtothetaxaneclass.Itispreparedbysemi-synthesiswithaprecursorextractedfromyewneedles.Thechemicalnameofcabazitaxelis(2α,5β;,7β;,10β;,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-ylbenzoate–propan-2-one(1:1).Cabazitaxelisawhitetooff-whitepowderwithamolecularformulaofC45H57NO14•C3H6Oandamolecularweightof894.01(fortheacetonesolvate)/835.93(forthesolventfree).Itislipophilic,practicallyinsolubleinwaterandsolubleinalcohol. JEVTANA(cabazitaxel)Injection60mg/1.5mLisasterile,non-pyrogenic,clearyellowtobrownish-yellowviscoussolutionandisavailableinsingle-usevialscontaining60mgcabazitaxel(anhydrousandsolventfree)and1.56gpolysorbate80.EachmLcontains40mgcabazitaxel(anhydrous)and1.04gpolysorbate80.DILUENTforJEVTANAisaclear,colorless,sterile,andnon-pyrogenicsolutioncontaining13%(w/w)ethanolinwaterforinjection,approximately5.7mL. JEVTANArequirestwodilutionspriortointravenousinfusion.JEVTANAinjectionshouldbedilutedonlywiththesuppliedDILUENTforJEVTANA,followedbydilutionineither0.9%sodiumchloridesolutionor5%dextrosesolution.
 
Cabazitaxel:MechanismofAction
Thetaxanesactbybindingtomicrotubules,cytoskeletalpolymerscomposedofα-tubulinandβ-tubulinheterodimers.ThebindingoftaxanestotubulinpromotesthestabilizationofGDP-boundtubulininthemicrotubuleresultingininhibitionofdisassemblyandpreventionofsubsequentmitosisandcelldivision. Derivedfromthebarkofyewtrees,in1992,paclitaxelwasthefirsttaxaneapprovedbytheFoodandDrugAdministration(FDA)asananti-neoplasticagent.Docetaxel,asemisyntheticanalogwithincreasedpotency,wasapprovedbytheFDAin1996forthetreatmentadvancedbreastcancerandlaterin2004forthetreatmentofmetastaticCRPC.TheseearliergenerationtaxaneshavehighsubstrateaffinityfortheATP-dependentdrugeffluxpumpP-glycoprotein1(P-gp1).Therefore,P-gp1isthoughttoaccountfor,atleastinpart,bothinherentandacquiredresistancetotheseagents.
 
Cabazitaxel,alsoknownasXRP6258,isasemi-synthetictaxanefromasinglediastereoisomerof10-deacetylbaccatinIII,andderivedfromtheneedlesofvariousTaxusspecies.Bybindingtotubulin,cabazitaxelinhibitsmicrotubuledepolymerizationandcelldivision,resultingincellcyclearrest.ThiscompoundwasselectedforclinicaltestingduetoitspooraffinityforATP-dependentdrugeffluxpumpP-gp1,anditsgreaterblood-brainbarrierpenetrationcomparedtopaclitaxelanddocetaxel.Cabazitaxelhasalsodemonstratedsuperiorinvitrocytotoxicitycomparedtodocetaxelinseveralmurineandhumancancercelllines.(source:ClinicalDevelopmentofCabazitaxelfortheTreatmentofCastration-ResistantProstateCancer.Che-KaiTsao,SoniaSeng,WilliamK.Oh,andMatthewD.GalskyDivisionofHematologyandMedicalOncology,TischCancerInstitute,MountSinaiSchoolofMedicine,NewYork,NY10029,USA,http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117627/).
   


References

1:AbidiA.Cabazitaxel:Anoveltaxaneformetastaticcastration-resistantprostatecancer-currentimplicationsandfutureprospects.JPharmacolPharmacother.2013Oct;4(4):230-237.Review.PubMedPMID:24250198;PubMedCentralPMCID:PMC3825997.

2:KearnsB,LloydJonesM,StevensonM,LittlewoodC.Cabazitaxelforthesecond-linetreatmentofmetastatichormone-refractoryprostatecancer:aNICEsingletechnologyappraisal.Pharmacoeconomics.2013Jun;31(6):479-88.doi:10.1007/s40273-013-0050-9.Review.PubMedPMID:23580356.

3:KeatingGM.Cabazitaxel:aguidetoitsuseinhormone-refractorymetastaticprostatecancer.DrugsAging.2013May;30(5):359-65.doi:10.1007/s40266-013-0078-8.Review.PubMedPMID:23532557.

4:CheethamP,PetrylakDP.Tubulin-targetedagentsincludingdocetaxelandcabazitaxel.CancerJ.2013Jan-Feb;19(1):59-65.doi:10.1097/PPO.0b013e3182828d38.Review.PubMedPMID:23337758.

5:YapTA,PezaroCJ,deBonoJS.Cabazitaxelinmetastaticcastration-resistantprostatecancer.ExpertRevAnticancerTher.2012Sep;12(9):1129-36.doi:10.1586/era.12.88.Review.PubMedPMID:23098113.

6:MalhotraM,DhingraR,SharmaT,DeepA,NarasimhanB,PhogatP,SharmaPC.Cabazitaxel:anoveldrugforhormone-refractoryprostatecancer.MiniRevMedChem.2013May1;13(6):915-20.Review.PubMedPMID:22950608.

7:Doyle-LindrudS.Managingsideeffectsofthenoveltaxanecabazitaxelincastrate-resistantprostatecancer.ClinJOncolNurs.2012Jun1;16(3):286-91.doi:10.1188/12.CJON.286-291.Review.PubMedPMID:22641321.

8:PeanE,DemolisP,MoreauA,HemmingsRJ,O'ConnorD,BrownD,ShepardT,AbadieE,PignattiF.TheEuropeanMedicinesAgencyreviewofcabazitaxel(Jevtana®)forthetreatmentofhormone-refractorymetastaticprostatecancer:summaryofthescientificassessmentofthecommitteeformedicinalproductsforhumanuse.Oncologist.2012;17(4):543-9.doi:10.1634/theoncologist.2011-0364.Epub2012Apr3.Review.PubMedPMID:22477727;PubMedCentralPMCID:PMC3336839.

9:VillanuevaC,BazanF,KimS,DemarchiM,ChaigneauL,Thiery-VuilleminA,NguyenT,CalsL,DobiE,PivotX.Cabazitaxel:anovelmicrotubuleinhibitor.Drugs.2011Jul9;71(10):1251-8.doi:10.2165/11591390-000000000-00000.Review.Erratumin:Drugs.2011Sep10;71(13):1720.PubMedPMID:21770474.

10:PallerCJ,AntonarakisES.Cabazitaxel:anovelsecond-linetreatmentformetastaticcastration-resistantprostatecancer.DrugDesDevelTher.2011Mar10;5:117-24.doi:10.2147/DDDT.S13029.Review.Erratumin:DrugDesDevelTher.2011;5:183.PubMedPMID:21448449;PubMedCentralPMCID:PMC3063116.