AmsacrineTopoisomerase 2 inhibitor CAS# 51264-14-3 |
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Quality Control & MSDS
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Chemical structure
3D structure
| Cas No. | 51264-14-3 | SDF | Download SDF |
| PubChem ID | 2179 | Appearance | Powder |
| Formula | C21H19N3O3S | M.Wt | 393.46 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | AMSA; m-AMSA; CI-880; SN-11841; acridinyl anisidide | ||
| Solubility | DMSO : 9.3 mg/mL (23.64 mM; Need ultrasonic and warming) | ||
| Chemical Name | N-[4-(acridin-9-ylamino)-3-methoxyphenyl]methanesulfonamide | ||
| SMILES | COC1=C(C=CC(=C1)NS(=O)(=O)C)NC2=C3C=CC=CC3=NC4=CC=CC=C42 | ||
| Standard InChIKey | XCPGHVQEEXUHNC-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C21H19N3O3S/c1-27-20-13-14(24-28(2,25)26)11-12-19(20)23-21-15-7-3-5-9-17(15)22-18-10-6-4-8-16(18)21/h3-13,24H,1-2H3,(H,22,23) | ||
| 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. | ||
| Description | Amsacrine is an inhibitor of topoisomerase II, and acts as an antineoplastic agent which can intercalates into the DNA of tumor cells.In Vitro:Amsacrine blocks HERG currents in HEK 293 cells and Xenopus oocytes in a concentration-dependent manner, with IC50 values of 209.4 nm and 2.0 μM, respectively. Amsacrine causes a negative shift in the voltage dependence of both activation (−7.6 mV) and inactivation (−7.6 mV). HERG current block by amsacrine is not frequency dependent[1]. In vitro studies of normal human lymphocytes with various concentrations of m-AMSA, show both increased levels of chromosomal aberrations, ranging from 8% to 100%, and increase SCEs, ranging from 1.5 times the normal at the lowest concentration studied (0.005 μg/mL) to 12 times the normal (0.25 μg/mL)[3]. Amsacrine-induced apoptosis of U937 cells is characterized by caspase-9 and caspase-3 activation, increased intracellular Ca2+ concentration, mitochondrial depolarization, and MCL1 down-regulation. Amsacrine induces MCL1 down-regulation by decreasing its stability. Further, amsacrine-treated U937 cells show AKT degradation and Ca2+-mediated ERK inactivation[4].In Vivo:In animals treated with different doses of amsacrine (0.5-12 mg/kg), the frequencies of micronucleated polychromatic erythrocytes increase significantly after treatment with 9 and 12 mg/kg. Furthermore, the present study demonstrates for the first time that amsacrine has high incidences of clastogenicity and low incidences of aneugenicity whereas nocodazole has high incidences of aneugenicity and low incidences of clastogenicity during mitotic phases in vivo[2]. References: | |||||
Amsacrine Dilution Calculator
Amsacrine Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.5416 mL | 12.7078 mL | 25.4155 mL | 50.8311 mL | 63.5389 mL |
| 5 mM | 0.5083 mL | 2.5416 mL | 5.0831 mL | 10.1662 mL | 12.7078 mL |
| 10 mM | 0.2542 mL | 1.2708 mL | 2.5416 mL | 5.0831 mL | 6.3539 mL |
| 50 mM | 0.0508 mL | 0.2542 mL | 0.5083 mL | 1.0166 mL | 1.2708 mL |
| 100 mM | 0.0254 mL | 0.1271 mL | 0.2542 mL | 0.5083 mL | 0.6354 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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Amsacrine (Amsidine, m-AMSA) is an inhibitor of topoisomerase 2 [1].
Amsacrine is a chemotherapy drug of antineoplastic, used to treat some types of lymphoma and acute leukaemia. In addition, Amsacrine has shown the sensitivities to the cancer cell lines with the IC50 values of 190.2±27.4ng/ml, 46.1±3.9ng/ml,22.6±3.1ng/ml, 11.8±2.0ng/ml, 5.0±0.4ng/ml, and 11.7±1.5ng/ml for three bladder cancer cell lines (HT1376,RT112, RT4) and three testis cancer cell lines(833K, Susa, GH), respectively. And it has been found that the testis tumor cell lines are more sensitive to inhibiting by Amsacrine than the bladder cell lines [1].
References:
[1] Nelson EM, Tewey KM, Liu LF. Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1361-5.
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Amsacrine-induced apoptosis of human leukemia U937 cells is mediated by the inhibition of AKT- and ERK-induced stabilization of MCL1.[Pubmed:27757735]
Apoptosis. 2017 Mar;22(3):406-420.
Previous studies have attributed the anticancer activity of Amsacrine to its inhibitory effect on topoisomerase II. However, 9-aminoacridine derivatives, which have the same structural scaffold as Amsacrine, induce cancer cell apoptosis by altering the expression of BCL2 family proteins. Therefore, in the present study, we assessed whether BCL2 family proteins mediated the cytotoxic effects of Amsacrine on human leukemia U937 cells. Amsacrine-induced apoptosis of U937 cells was characterized by caspase-9 and caspase-3 activation, increased intracellular Ca(2+) concentration, mitochondrial depolarization, and MCL1 down-regulation. Amsacrine induced MCL1 down-regulation by decreasing its stability. Further, Amsacrine-treated U937 cells showed AKT degradation and Ca(2+)-mediated ERK inactivation. Blockade of ERK-mediated phosphorylation of MCL1 inhibited the effect of Pin1 on the stabilization of MCL1, and AKT degradation promoted GSK3beta-mediated degradation of MCL1. Restoration of ERK phosphorylation and AKT expression abrogated Amsacrine-induced MCL1 down-regulation. Moreover, MCL1 over-expression inhibited Amsacrine-induced depolarization of mitochondria membrane and increased the viability of Amsacrine-treated cells. Taken together, our data indicate that Amsacrine abolishes ERK- and Pin1-mediated stabilization of MCL1 and promotes GSK3beta-mediated degradation of MCL1, leading to activate mitochondria-mediated apoptosis pathway in U937 cells.
Studies on Non-synonymous Polymorphisms Altering Human DNA Topoisomerase II-Alpha Interaction with Amsacrine and Mitoxantrone: An In Silico Approach.[Pubmed:27834128]
Curr Cancer Drug Targets. 2017;17(7):657-668.
BACKGROUND: DNA topoisomerase II-alpha (Top2-alpha), an essential enzyme for the management of DNA during replication, transcription, recombination, and chromatin remodeling, is one of the most important anticancer targets. Numerous molecules have been designed as Top2-alpha inhibitors. However, several studies have shown that polymorphisms and mutations in Top2 have conferred resistance to most of these anticancer drugs. The aim of this study was to computationally examine the mechanisms by which genomic variations in Top2-alpha could affect its resistance to Amsacrine and Mitoxantrone as important inhibitors of the enzyme. RESULTS: The results showed that variants K529E, R568H, R568G and T530M could affect Top2-alpha inhibition by Amsacrine causing possible drug-resistant. Moreover, R487K, and Y481C variants could change the response of the enzyme to Mitoxantrone. CONCLUSION: These results could facilitate the prediction and development of more effective drugs for Top2-alpha variants, making the cancer chemotherapy more effectiv.
Computational analysis of Amsacrine resistance in human topoisomerase II alpha mutants (R487K and E571K) using homology modeling, docking and all-atom molecular dynamics simulation in explicit solvent.[Pubmed:28110185]
J Mol Graph Model. 2017 Mar;72:209-219.
Amsacrine is an effective topoisomerase II enzyme inhibitor in acute lymphatic leukemia. Previous experimental studies have successfully identified two important mutations (R487K and E571K) conferring 100 and 25 fold resistance to Amsacrine respectively. Although the reduction of the cleavage ligand-DNA-protein ternary complex has been well thought as the major cause of drug resistance, the detailed energetic, structural and dynamic mechanisms remain to be elusive. In this study, we constructed human topoisomerase II alpha (hTop2alpha) homology model docked with Amsacrine based on crystal structure of human Top2beta in complex with etoposide. This wild type complex was used to build the ternary complex with R487K and E571K mutants. Three 500ns molecular dynamics simulations were performed on complex systems of wild type and two mutants. The detailed energetic, structural and dynamic analysis were performed on the simulation data. Our binding data indicated a significant impairment of Amsacrine binding energy in the two mutants compared with the wild type. The order of weakening (R487K>E571K) was in agreement with the order of experimental drug resistance fold (R489K>E571K). Our binding energy decomposition further indicated that weakening of the ligand-protein interaction rather than the ligand-DNA interaction was the major contributor of the binding energy difference between R487K and E571K. In addition, key residues contributing to the binding energy (DeltaG) or the decrease of the binding energy (DeltaDeltaG) were identified through the energy decomposition analysis. The change in ligand binding pose, dynamics of protein, DNA and ligand upon the mutations were thoroughly analyzed and discussed. Deciphering the molecular basis of drug resistance is crucial to overcome drug resistance using rational drug design.
A comparative spectroscopic and calorimetric investigation of the interaction of amsacrine with heme proteins, hemoglobin and myoglobin.[Pubmed:27064820]
J Biomol Struct Dyn. 2017 May;35(6):1260-1271.
The binding of the anilido aminoacridine derivative Amsacrine with the heme proteins, hemoglobin, and myoglobin, was characterized by various spectroscopic and calorimetric methods. The binding affinity to hemoglobin was (1.21 +/- .05) x 10(5) M(-1), while that to myoglobin was three times higher (3.59 +/- .15) x 10(5) M(-1). The temperature-dependent fluorescence study confirmed the formation of ground-state complexes with both the proteins. The stronger binding to myoglobin was confirmed from both spectroscopic and calorimetric studies. The binding was exothermic in both cases at the three temperatures studied, and was favored by both enthalpy and entropy changes. Circular dichroism results, three-dimensional (3D) and synchronous fluorescence studies confirmed that the binding of Amsacrine significantly changed the secondary structure of hemoglobin, while the change in the secondary structure of myoglobin was much less. New insights, in terms of structural and energetic aspects of the interaction of Amsacrine with the heme proteins, presented here may help in understanding the structure-activity relationship, therapeutic efficacy, and drug design aspects of acridines.
