Methasquin
Methasquin is an antifolate dihydrofolate reductase inhibitor (antifolate dihydrofolate reductase) with an IC50 of 1.3 nM against dihydrofolate reductase derived from human leukemia cells. Methasquin binds to dihydrofolate reductase, depletes tetrahydrofolate derivatives, disrupts thymidylate synthesis and inhibits DNA synthesis. Methasquin can be used in leukemia-related research.
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- CAS No.: 18921-70-5
- Formule: C21H22N6O5
- Masse moléculaire:438.44
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Activité biologique
Description
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hDHFR 1.3 nM (IC50) |
In Vitro
L1210 leukemia cells take up Methasquin (0.45-2.25 μM; up to 60 min) in a biphasic manner, with a rapid initial cell-binding phase; at an external concentration of 0.45 μM, its carrier-mediated transport rate is 0.039 nmole/min/g dry weight[2].
For the carrier-mediated transport process of Methasquin mediated by L1210 leukemia cells, its Km value is 27.0 μM and Vmax value is 7.9×10-9 moles/min/g dry weight[2].
Methasquin (2.2 μM Methotrexate-3H; varying unlabeled concentrations) weakly competes with Methotrexate (HY-14519) for the shared carrier-mediated transport system in L1210 leukemia cells[2].
Methasquin (0.01-50.0 μg/mL; 3-day assay; 12-15 days of drug-free pre-assay growth) selects DC-3F Chinese hamster cell sublines with 5.9 to 6667-fold resistance to Methasquin. This resistance correlates with the long-term maintained concentration of Methasquin, and all sublines exhibit cross-resistance to Methotrexate[3].
The Methasquin-resistant DC-3F Chinese hamster cell subline (cultured in a 13- to 14-day drug-free pre-test) exhibits dihydrofolate reductase activity that is 2.9- to 165-fold higher than that of the drug-sensitive parental DC-3F cells, with the subline showing the strongest resistance having the greatest increase in enzyme activity[3].
Methasquin (143-161 ng/g intestinal wet weight; 5 min at 37°C, followed by 45 min incubation at 37°C after folate addition) potently inhibits dihydrofolate reductase in small intestinal supernatants from untreated male CD/1 mice, with efficacy comparable to that of methotrexate, and the titration endpoint is 161 ng/g intestinal wet weight[6].
Methasquin (122870) (2 min) inhibits dihydrofolate reductase derived from human leukemia cells, with an IC50 value of 1.3 nM[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Chinese hamster DC-3F parent cells and 11 methasquin-resistant DC-3F sublines
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Concentration:0.01-50.0 μg/mL (long-term maintenance); 0.012 μg/mL (parent cell ED50); 0.071-80 μg/mL (resistant subline ED50)
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Incubation Time:3 days (assay); 12-15 days (drug-free pre-assay growth)
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Result:Reached an ED50 of 0.012 μg/mL for drug-sensitive DC-3F parent cells.
Showed ED50 values ranging from 0.071 μg/mL (DC-3F/MQ2) to 80 μg/mL for methasquin-resistant sublines.
Exhibited resistance degrees ranging from 5.9-fold (DC-3F/MQ2) to 6667-fold (DC-3F/MQ39) compared to parent cells.
Confirmed cross-resistance to Methotrexate in all resistant sublines.
In Vivo
Methasquin (0.1-1 mg/kg; intravenous injection; single dose; 1 mg/kg; oral administration; single dose) is excreted in large quantities in dog urine after intravenous administration. After oral administration, gastrointestinal absorption is poor, renal clearance is about 0.6-0.7 times that of creatinine, and serum protein binding is about 53-58%[1].
Methasquin (0.75-30 mg/kg; intraperitoneal injection; single dose) exhibits dose-dependent uptake and retention characteristics in the small intestine of mice, with longer intracellular retention time at high doses and shorter retention time at the optimal antileukemic dose[4].
Methasquin (0.2-83 mg/kg; intravenous injection; single dose) is more potent than methotrexate in normal mouse intestinal tissue and has a longer duration of action. Its ID50 for maintaining an intestinal DNA synthesis inhibition rate of 50% for 18 hours is 0.4 mg/kg, and its median lethal dose is 83 mg/kg[6].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:CD rats (adult male, 230 to 420 g)[1]
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Dosage:1-100 mg/kg (i.v., single dose); 10-100 mg/kg (p.o., single dose)
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Administration:i.v.; single dose; p.o.; single dose
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Result:Recovered 31-35% of each i.v. dose in urine within 5 hours, with cumulative urinary recovery of 34-37% by 48 hours.
Reached 37-39% of the 100 mg/kg i.v. dose, 16-24% of the 10 mg/kg i.v. dose, and 16-24% of the 1 mg/kg i.v. dose in bile within 5 hours.
Achieved peak bile concentrations of 2475-2575 μg/mL 2-3 hours post-100 mg/kg i.v., 130-180 μg/mL 3-5 hours post-10 mg/kg i.v., and 14-27 μg/mL 3-5 hours post-1 mg/kg i.v.
Dropped serum levels to 20-25% of initial 10-minute levels within the first hour, then declined by one-third to one-half each subsequent hour for i.v. doses.
Recovered less than 0.7% of each p.o. dose in urine by 48 hours, with less than 0.2% recovered within the first 5 hours.
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Animal Model:mongrel dogs (adult, female; additional adult female and male)[1]
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Dosage:0.1-1 mg/kg (i.v., single dose); 1 mg/kg (p.o., single dose)
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Administration:i.v.; single dose; p.o.; single dose
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Result:Recovered 41-50% of the 1 mg/kg i.v. dose in urine within 5 hours, with cumulative urinary recovery of 61-80% by 24 hours.
Fell serum levels to 50% of initial 10-minute levels within the first hour, with measurable levels still present at 24 and 48 hours for the 1 mg/kg i.v. dose.
Achieved cumulative urinary recovery of 0.24-5.7% by 48 hours, with less than 0.5% recovered within the first 5 hours for the 1 mg/kg p.o. dose.
Showed undetectable or very low (≤0.01 μg/mL) serum levels for the first 4 hours in most dogs for the 1 mg/kg p.o. dose.
Fell serum levels to 50% of initial 10-minute levels within the first hour, with levels below assay sensitivity by 24 hours for the 0.1 mg/kg i.v. dose.
Recovered 14-26% of the 0.1 mg/kg i.v. dose in urine within 70 minutes.
Exhibited serum protein binding of 53.2-57.5% at 1 μg/mL.
Ranged renal clearance to creatinine clearance ratio from 0.60 to 0.71.
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Animal Model:BDF1 (C57BL/6 × DBA2) male[4]
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Dosage:0.75 mg/kg; 3 mg/kg; 30 mg/kg
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Administration:i.p.; single dose
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Result:Reached maximum accumulation in small intestine at 2 hours, reaching 4- to 5-fold the dihydrofolate reductase content (1×102 ng/g wet wt) after 3 mg/kg dose; free reagent persisted intracellularly for about 16 hours.
Reached maximum accumulation in small intestine within 1 hour, reaching nearly 70-fold the dihydrofolate reductase content after 30 mg/kg dose; tissue concentration fell to the dihydrofolate reductase level by 50 hours.
Reached maximum accumulation in small intestine within 1 hour, not reaching 2-fold the dihydrofolate reductase content after 0.75 mg/kg dose; tissue concentration fell to the dihydrofolate reductase level by about 4 hours.
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Animal Model:CD/1 Swiss (male, 5 to 6 weeks old, 24 to 30 g)[6]
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Dosage:0.2 mg/kg; 0.4 mg/kg; 1.2 mg/kg; 4 mg/kg; 83 mg/kg
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Administration:i.v.; single dose
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Result:Determined median lethal dose as 83 mg/kg.
Reported ID50 for inhibition of UdR-3H incorporation into intestinal DNA as 0.2 mg/kg at 1 hour, 0.15 mg/kg at 6 hours, and 0.4 mg/kg at 18 hours post-injection.
Reduced intestinal DNA content to 28.0 μmol, 26.5 μmol, and 24.4 μmol deoxyribose per intestine at 18 hours post-injection for doses of 0.4 mg/kg, 1.2 mg/kg, and 4 mg/kg, respectively (control mean is 32.1 μmol).
Disappeared from serum more slowly than methotrexate and aminopterin after doses of 1 mg/kg and 10 mg/kg.
Reached maximal intestinal uptake within 15 to 30 minutes after 0.2 mg/kg dose, stayed constant between 2 and 6 hours at approximately half the intestinal folate reductase content, and showed an average loss of 17 ng/g between 4 and 24 hours.
Left free intestinal dihydrofolate reductase activity at 30 to 40% of control levels at 1 hour post-0.2 mg/kg dose, with a smaller increase (to 28% above initial levels) between 4 and 24 hours compared to methotrexate or aminopterin.
Chemical Information
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CAS No. 18921-70-5
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Masse moléculaire 438.44
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Formule C21H22N6O5
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SMILES
CC1=C(CNC2=CC=C(C=C2)C(N[C@H](C(O)=O)CC(O)=O)=O)C=CC3=C1C(N)=NC(N)=N3
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Methasquin Related Classifications
HY-187636 Related Classifications
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Keywords
- Methasquin
- 18921-70-5
- Antifolate
- Dihydrofolate reductase (DHFR)
- DC-3F Chinese hamster cells
- thymidylate synthesis
- human acute myelocytic leukemia cells
- DNA synthesis
- dihydrofolate reductase
- mouse small intestinal crypt epithelium
- human myelomonocytic leukemia cells
- human leukemia cell
- L1210 leukemia cells
- tetrahydrofolate derivatives
- Inhibitor
- inhibitor
- inhibit