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Clofarabine DNA/RNA Synthesis remmer

Name: Clofarabine
Brand: Selleck Chemicals
SKU: S1218
Rating: 5 (23 reviews)

Cat.Nr.S1218

Clofarabine (Clolar) remt de enzymatische activiteiten van ribonucleotide reductase (RNR) (IC50 = 65 nM) en DNA-polymerase. Deze verbinding induceert autophagy en apoptosis.

Clofarabine DNA/RNA Synthesis remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 303.68

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Kwaliteitscontrole

Batch: Zuiverheid: 99.90%

99.90

Gerelateerde doelwitten	HDAC PARP ATM/ATR DNA-PK WRN Topoisomerase PPAR Sirtuin Casein Kinase eIF
Overige DNA/RNA Synthesis Inhibitoren	CX-5461 (Pidnarulex) B02 SCR7 Favipiravir (T-705) EED226 RK-33 BMH-21 Triapine (3-AP) Carmofur YK-4-279

Celkweek, behandeling & werkconcentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Activiteitsbeschrijving	PMID
K562 cell	Cytotoxicity assay			Compound was tested for cytotoxicity against K562 cell lines, IC50=0.003 μM	1732556
HEp-2 cell	Cytotoxicity assay			Compound was tested for cytotoxicity against HEp-2 cell lines, IC50=0.012 μM	1732556
CCRF-CEM cell lines	Cytotoxicity assay			Compound was tested for cytotoxicity against CCRF-CEM cell lines, IC50=0.05 μM	1732556
L1210 cell	Cytotoxicity assay			Compound was tested for cytotoxicity against L1210 cell lines, IC50=2.3 μM	1732556
NCI-H23	Cytotoxicity assay		5 days	Cytotoxicity against human NCI-H23 cells after 5 days by SRB assay, GI50=0.04μM	19929004
PC3	Cytotoxicity assay		5 days	Cytotoxicity against human PC3 cells after 5 days by SRB assay, GI50=0.063μM	19929004
BT549	Cytotoxicity assay		5 days	Cytotoxicity against human BT549 cells after 5 days by SRB assay, GI50=0.065μM	19929004
HCT15	Cytotoxicity assay		5 days	Cytotoxicity against human HCT15 cells after 5 days by SRB assay, GI50=0.18μM	19929004
NCI-H23	Cytostatic assay		5 days	Cytostatic activity against human NCI-H23 cells after 5 days by SRB assay, GI50=0.04μM	21711054
MT4	Cytostatic assay		5 days	Cytostatic activity against human MT4 cells after 5 days by SRB assay, GI50=0.051μM	21711054
PC3	Cytostatic assay		5 days	Cytostatic activity against human PC3 cells after 5 days by SRB assay, GI50=0.063μM	21711054
BT549	Cytostatic assay		5 days	Cytostatic activity against human BT549 cells after 5 days by SRB assay, GI50=0.065μM	21711054
A549	Cytostatic assay		5 days	Cytostatic activity against human A549 cells after 5 days by SRB assay, GI50=0.086μM	21711054
HCT116	Cytostatic assay		5 days	Cytostatic activity against human HCT116 cells after 5 days by SRB assay, GI50=0.106μM	21711054
DU145	Cytostatic assay		5 days	Cytostatic activity against human DU145 cells after 5 days by SRB assay, GI50=0.125μM	21711054
HCT15	Cytostatic assay		5 days	Cytostatic activity against human HCT15 cells after 5 days by SRB assay, GI50=0.18μM	21711054
Hs578	Cytostatic assay		5 days	Cytostatic activity against human Hs578 cells after 5 days by SRB assay, GI50=1.241μM	21711054
HL60	Cytostatic assay		48 hrs	Cytostatic activity against human HL60 cells after 48 hrs by MTT assay, IC50=0.1μM	23820572
A549	Cytostatic assay		48 hrs	Cytostatic activity against human A549 cells after 48 hrs by MTT assay, IC50=8μM	23820572
U373-MAGI	Function assay	50 nM	2 hrs	Potentiation of 5-Aza-C-induced antiviral activity against VSV-G pseudotyped HIV-1 NL4-3 infected in human U373-MAGI cells assessed as 5-Aza-C EC50 at 50 nM preincubated for 2 hrs followed by 5-Aza-C addition for 2 hrs and subsequent viral infection measu, EC50=30.4μM	27117260
U373-MAGI	Antiviral assay	50 nM	4 hrs	Antiviral activity against VSV-G pseudotyped HIV-1 NL4-3 infected in human U373-MAGI cells assessed as reduction in viral infectivity at 50 nM incubated for 4 hrs prior to viral infection measured at 72 hrs post infection by flow cytometric analysis	27117260
U373-MAGI	Function assay	200 nM	6 hrs	Reduction in dGTP level in human U373-MAGI cells at 200 nM after 6 hrs by LC-MS/MS analysis	27117260
U373-MAGI	Function assay	200 nM	6 hrs	Reduction in dCTP level in human U373-MAGI cells at 200 nM after 6 hrs by LC-MS/MS analysis	27117260
U373-MAGI	Function assay	200 nM	6 hrs	Reduction in dATP level in human U373-MAGI cells at 200 nM after 6 hrs by LC-MS/MS analysis	27117260
U373-MAGI	Function assay	50 nM	2 hrs	Reduction in dCTP level in human U373-MAGI cells at 50 nM preincubated for 2 hrs followed by 5-aza-C addition measured after 4 hrs by LC-MS/MS analysis	27117260
U373-MAGI	Function assay	200 nM	2 hrs	Reduction in dCTP level in human U373-MAGI cells at 200 nM preincubated for 2 hrs followed by 5-aza-C addition measured after 4 hrs by LC-MS/MS analysis relative to 5-aza-C	27117260
U373-MAGI	Function assay	50 nM	2 hrs	Increase in 5-aza-dCTP/dCTP ratio in human U373-MAGI cells at 50 nM preincubated for 2 hrs followed by 5-aza-dC addition measured after 4 hrs by LC-MS/MS analysis relative to 5-aza-dC	27117260
U373-MAGI	Function assay	200 nM	2 hrs	Increase in 5-aza-dCTP/dCTP ratio in human U373-MAGI cells at 200 nM preincubated for 2 hrs followed by 5-aza-dC addition measured after 4 hrs by LC-MS/MS analysis relative to 5-aza-dC	27117260
U373-MAGI	Function assay	200 nM	2 hrs	Reduction in dRGU-TP level in human U373-MAGI cells at 200 nM preincubated for 2 hrs followed by 5-aza-C addition measured after 4 hrs by LC-MS/MS analysis	27117260
U373-MAGI	Function assay	200 nM	2 hrs	Reduction in 5-aza-dCTP level in human U373-MAGI cells at 200 nM preincubated for 2 hrs followed by 5-aza-C addition measured after 4 hrs by LC-MS/MS analysis	27117260
U373-MAGI	Function assay	200 nM	2 hrs	Reduction in dCTP level in human U373-MAGI cells at 200 nM preincubated for 2 hrs followed by 5-aza-dC addition measured after 4 hrs by LC-MS/MS analysis relative to 5-aza-dC	27117260
U373-MAGI	Function assay	50 nM	2 hrs	Reduction in dCTP level in human U373-MAGI cells at 50 nM preincubated for 2 hrs followed by 5-aza-dC addition measured after 4 hrs by LC-MS/MS analysis relative to 5-aza-dC	27117260
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells	29435139
DAOY	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells	29435139
SJ-GBM2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells	29435139
A673	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells	29435139
SK-N-MC	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells	29435139
BT-37	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells	29435139
NB-EBc1	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
LAN-5	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells	29435139
OHS-50	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
MG 63 (6-TG R)	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells	29435139
NB1643	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells	29435139
A673	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells)	29435139
SK-N-MC	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells	29435139
LAN-5	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for LAN-5 cells	29435139
SJ-GBM2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells	29435139
BT-37	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells	29435139
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells	29435139
MG 63 (6-TG R)	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells	29435139
Rh30	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells	29435139
Saos-2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells	29435139
SJ-GBM2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for SJ-GBM2 cells	29435139
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for TC32 cells	29435139
MG 63 (6-TG R)	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for MG 63 (6-TG R) cells	29435139
Granta	Cytotoxicity assay		72 hrs	Cytotoxicity against human Granta cells assessed as decrease in cell viability after 72 hrs by MTT assay, IC50=0.017μM	30176535
HL60	Cytotoxicity assay		72 hrs	Cytotoxicity against human HL60 cells assessed as decrease in cell viability after 72 hrs by MTT assay, IC50=0.04μM	30176535
CCRF-CEM	Cytotoxicity assay		72 hrs	Cytotoxicity against human CCRF-CEM cells assessed as decrease in cell viability after 72 hrs by MTT assay, IC50=0.044μM	30176535
RL	Cytotoxicity assay		72 hrs	Cytotoxicity against human RL cells assessed as decrease in cell viability after 72 hrs by MTT assay, IC50=0.38μM	30176535
Klik om meer experimentele gegevens over de cellijn te bekijken

Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht	303.68	Formule	C₁₀H₁₁ClFN₅O₃	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	123318-82-1	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	Clolar			Smiles	C1=NC2=C(N=C(N=C2N1C3C(C(C(O3)CO)O)F)Cl)N

Oplosbaarheid

In vitro
Batch:

DMSO : 60 mg/mL (197.57 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Targets/IC₅₀/Ki	Ribonucleotide reductase (Cell-free assay) 65 nM
In vitro	Clofarabine wordt efficiënt in cellen getransporteerd via twee faciliterende of equilibrerende nucleosidetransporters, hENT1 en hENT2, en een concentratieve nucleosidetransporter, hCNT253. Deze verbinding wordt stapsgewijs gefosforyleerd door cytosolische kinases tot de nucleotideanalogen clofarabine 5′-mono-, di- en trifosfaat na binnenkomst in cellen, waarbij Clofarabine trifosfaat de actieve vorm is. Clofarabine 5′-mono-, di- en trifosfaat zijn geen substraten voor nucleosidetransporters en moeten enzymatisch door 5′-nucleotidase worden omgezet naar hun gedephosphoryleerde nucleosidevorm voor transport uit de cel. Dit verbindingstrifosfaat is een potente remmer van ribonucleotide reductase (IC50 = 65 nM), vermoedelijk door binding aan de allosterische site op de regulerende subeenheid. Er is ook aangetoond dat het direct op mitochondria inwerkt door het transmembraanpotentiaal te wijzigen met vrijgave van cytochroom c, apoptose-inducerende factor (AIF), apoptosis protease-activating factor 1 (APAF1) en caspase 9 in het cytosol. Deze chemische stof vertoont een sterke in vitro groeiremming en cytotoxische activiteit (IC50-waarden = 0,028–0,29 μM) in een breed scala aan leukemie- en solide tumorcellijnen. Het is aangetoond dat het de activiteit van dCK in HL60-cellen verhoogt en de vorming van de mono-, di- en trifosfaten van ara-C in K562-cellen verhoogt36. Deze verbinding (10 μM) remt de reparatie geïnitieerd door 4-hydroperoxycyclofosfamide (4-HC), met een maximale remming bij intracellulaire concentraties van 5 μM in chronische lymfatische leukemie (CLL) lymfocyten. Het (10 μM) gecombineerd met 4-hydroperoxycyclofosfamide (4-HC) produceert meer dan additieve apoptotische celdood dan de som van elk afzonderlijk. Deze chemische stof (1 μM) gecombineerd met ara-C (10 μM) resulteert in een biochemische modulatie van ara-CTP en synergetische celdoding in K562-cellen.
In vivo	Clofarabine, intraperitoneaal toegediend, heeft significante activiteit tegen een breed scala aan menselijke tumorxenografts die subcutaan zijn geïmplanteerd in athymische naakte of ernstig gecombineerde immuundeficiëntie muizen.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/17016426/ [2] https://pubmed.ncbi.nlm.nih.gov/11705880/ [3] https://pubmed.ncbi.nlm.nih.gov/15723262/

Informatie klinische proef

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT05917405	Recruiting	Acute Myeloid Leukemia in Remission	Nantes University Hospital	September 14 2023	Phase 2
NCT03609814	Completed	Hematologic Malignancies\|Nonmalignant Diseases\|Immunodeficiencies\|Hemoglobinopathies\|Genetic Inborn Errors of Metabolism\|Fanconi''s Anemia\|Thalassemia\|Sickle Cell Disease	University of California San Francisco	January 26 2016	--

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