Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemELometrexoldisodiumCat.No.:HY-14521ACASNo.:120408-07-3Synonyms:DDATHFdisodium分?式:C??H??N?Na?O?分?量:487.42作?靶點:Antifolate;Apoptosis;Caspase;Bcl-2Family作?通路:CellCycle/DNADamage;Apoptosis儲存?式:Powder-20°C3yearsInsolvent-80°C6months-20°C1monthBIOLOGICALACTIVITY?物活性Lometrexol(DDATHF)disodium?種抗嘌呤類抗葉酸(antifolate)藥，可抑制?氨酰胺核糖核苷酸甲酰轉移酶(GARFT)的活性，但不會引起可檢測?平的DNA鏈斷裂。Lometrexoldisodium可以進?步抑制嘌呤從頭合成，導致異常的細胞增殖，凋亡(apoptosis)和細胞周期停滯。Lometrexoldisodium具有抗癌活性。Lometrexoldisodium還?種有效的?絲氨酸羥甲轉移酶1/2(hSHMT1/2)抑制劑。體外研究Lometrexol(DDATHF)disodiumbindstightlytoGART,resultinginarapidandprolongeddepletionofintracellularpurineribonucleotides[3].Lometrexol(1-30μM;2-10hours)disodiuminducesrapidandcompletegrowthinhibitioninL1210cells[3].Lometrexol(1μM;2-24hours)disodiuminducescellcyclearrestinmurineleukemiaL1210cells[3].CellViabilityAssay[3]CellLine:MouseleukemiaL1210cellsConcentration:1,30μMIncubationTime:2,4,6,8,10hoursResult:Inducedrapidandcompletegrowthinhibition.CellCycleAnalysis[3]1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemECellLine:L1210cellsConcentration:1μMIncubationTime:2,4,8,12,24hoursResult:CausedarapidlossoftheG2/MphasepopulationofcellsandanearlySphaseaccumulationofcellsby8hours.By24h,theSphasepopulationappearedtobeslowlyshiftingtohigherDNAcontent,andhence,frommid-to-lateSphase.體內研究Lometrexol(DDATHF;i.p.;15-60mg/kg;ongestationday7.5)disodiuminducesneuraltubedefects(NTDs)bydisturbingpurinemetabolismandincreasestherateofembryonicresorptionandgrowthretardationinadose-dependentmanner[1].Lometrexol(i.p.;40mg/kg;ongestationday7.5)disodiumdecreasesglycinamideribonucleotideformyltransferase(GARFT)activityandChangesofATP,GTP,dATPanddGTPlevels[1].Lometrexol(i.p.;40mg/kg;ongestationday7.5)disodiuminducesabnormalproliferationandapoptosisexistinneuraltubedefects(NTDs)[1].AnimalModel:C57BL/6mice(7-8week,18-20g)[1]Dosage:15,30,35,40,45and60mg/kgAdministration:Intraperitonealinjection;ongestationday7.5Result:Increasedtherateofembryonicresorptionandgrowthretardationinadose-dependentmanner.AnimalModel:C57BL/6mice(7-8week,18-20g)[1]Dosage:40mg/kgAdministration:Intraperitonealinjection;ongestationday7.5,for0,6,24,48and96hoursResult:Inhibitedglycinamideribonucleotideformyltransferase(GARFT)activityandGARFTactivitywasmaximallyinhibitedafterat6hours.DecreasedthelevelsofATP,GTP,dATP,anddGTPofNTDsembryonicbraintissuesignificantlyat6hours.AnimalModel:C57BL/6mice(7-8week,18-20g)[1]Dosage:40mg/kgAdministration:Intraperitonealinjection;ongestationday7.5,for4daysResult:Decreasedtheexpressionofproliferation-relatedgenes(Pcna,Foxg1andPtch1)and2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEincreasedtheexpressionofapoptosis-relatedgenes(Bax,Casp8andCasp9)inNTDgroups.REFERENCES[1].XuL,et,al.Theeffectofinhibitingglycinamideribonucleotideformyltransferaseonthedevelopmentofneuraltubeinmice.NutrMetab(Lond).2016Aug23;13(1):56.[2].ScalettiE,et,al.StructuralbasisofinhibitionofthehumanserinehydroxymethyltransferaseSHMT2byantifolatedrugs.FEBSLett.2019Jul;593(14):1863-1873.[3].BronderJL,et,al.AntifolatestargetingpurinesynthesisallowentryoftumorcellsintoSphaseregardlessofp53function.CancerRes.2002Sep15;62(18):5236-41.McePdfHeightCaution:Product