Nolatrexed (AG-337)Non-classical thymidylate synthase inhibitor CAS# 152946-68-4 |
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Quality Control & MSDS
3D structure
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| Cas No. | 152946-68-4 | SDF | Download SDF |
| PubChem ID | 108188 | Appearance | Powder |
| Formula | C14H14Cl2N4OS | M.Wt | 357.26 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 41.67 mg/mL (116.64 mM; Need ultrasonic) | ||
| Chemical Name | 2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1H-quinazolin-4-one;dihydrochloride | ||
| SMILES | CC1=C(C2=C(C=C1)NC(=NC2=O)N)SC3=CC=NC=C3.Cl.Cl | ||
| Standard InChIKey | PJKVJJYMWOCLIJ-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C14H12N4OS.2ClH/c1-8-2-3-10-11(13(19)18-14(15)17-10)12(8)20-9-4-6-16-7-5-9;;/h2-7H,1H3,(H3,15,17,18,19);2*1H | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
Nolatrexed (AG-337) Dilution Calculator
Nolatrexed (AG-337) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.7991 mL | 13.9954 mL | 27.9908 mL | 55.9816 mL | 69.977 mL |
| 5 mM | 0.5598 mL | 2.7991 mL | 5.5982 mL | 11.1963 mL | 13.9954 mL |
| 10 mM | 0.2799 mL | 1.3995 mL | 2.7991 mL | 5.5982 mL | 6.9977 mL |
| 50 mM | 0.056 mL | 0.2799 mL | 0.5598 mL | 1.1196 mL | 1.3995 mL |
| 100 mM | 0.028 mL | 0.14 mL | 0.2799 mL | 0.5598 mL | 0.6998 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Description:
IC50: 1.0, 0.81 and 1.0 μM for L1210, CCRF-CEM and GC3/M TK- cell lines, respectively
Thymidylate synthase (TS) is a crucial enzyme in the synthesis of 2'-deoxythymidine-5'-monophosphate, an essential precursor for DNA biosynthesis. Thus, this enzyme is a critical target in cancer chemotherapy. Nolatrexed (AG-337) is a non-classical thymidylate synthase inhibitor.
In vitro: Nolatrexed was designed using X-ray crystallographic data from the TS molecular modeling and folate binding site. It is a non-classical TS inhibitor in that it lacks a terminal glutamate side chain and is uncharged at physiological pH. Nolatrexed does not require a specific transport mechanism to enter into cells and, once within the cell, is not a substrate for the enzyme folyl polyglutamate synthetase [1].
In vivo: When nolatrexed was administered to nude mice bearing Bu25TK- tumor xenografts, a time-dependent increase in antitumor activity was observed [1].
Clinical trial: Phase I clinical studies showed that Nolatrexed can be safely administered to cancer patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects [2].
Reference:
[1] Hughes AN, Rafi I, Griffin MJ, Calvert AH, Newell DR, Calvete JA, Johnston A, Clendeninn N, Boddy AV. Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days. Clin Cancer Res. 1999 Jan;5(1):111-8.
[2] Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH. Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol. 1998 Mar;16(3):1131-41.
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Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma.[Pubmed:16957834]
Invest New Drugs. 2007 Feb;25(1):85-94.
BACKGROUND: To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma. PATIENTS AND METHODS: Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced > or = grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method. RESULTS: Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1-12). The mean dose intensity was 700 mg/m(2)/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22-37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (C (max)) was 14.20 microg/mL (range 1.41 to 119 microg /mL) with no accumulation observed between cycles 1-6. CONCLUSION: This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.
