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Purity: ≥98%
Exatecan mesylate (DX-8951) is the methylate of Exatecan, which is a semisynthetic analog of camptothecin with improved water solubility. It has antineoplastic activity and is a potent inhibitor of DNA topoisomerase I, with an IC50 of 2.2 μM (0.975 μg/mL). By maintaining the cleavable complex between topoisomerase I and DNA and preventing the ligation of DNA breaks, exatecan mesylate inhibits topoisomerase I activity. This prevents DNA replication and causes apoptotic cell death. This substance is more potent than camptothecin and other camptothecin analogs and does not require enzymatic activation.
| Targets |
Topoisomerase I ( IC50 = 0.975 μg/mL )
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|---|---|
| ln Vitro |
Exatecan Mesylate exhibits potent inhibition of topoisomerase I along with potency against a battery of thirty-two malignant cell lines in vitro. Exatecan Mesylate exhibits anti-proliferative activity approximately 6 and 28 times higher than that of SN-38 or SK&F 10486-A, respectively. [1]
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| ln Vivo |
Three intravenous dosages of Exatecan Mesylate given at 4-day intervals have been shown to have more antitumor activity in mice than either CPT-11 or SK&F 10486-A when used against human gastric adenocarcinoma SC-6 xenografts. Additionally, it defeated P-glycoprotein-mediated multidrug resistance. These findings imply that Exatecan Mesylate is a promising therapeutic agent with strong antitumor activity.[1]
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| Enzyme Assay |
SDS buffer (10 mM HEPES, 2 mM orthovanadate, 10 mM NaF, 10 mM pyrophosphate, 1 mMPMSF, 10 µg/mL leupeptin, 10% 2-mercaptoethanol, 10% glycerol, 8% SDS, 42 mM Tris-HCl, 0.002% bromophenol blue, pH 7.4) is used to lyse cells (5×106). Protein from the lysates of the entire cell is separated using a 7.5% polyacrylamide gel and then blotted onto nitrocellulose membrane. First, horseradish peroxidase-conjugated protein A is applied to the membrane, followed by an anti-Topo I human antibody treatment. ECL reagents are used to detect the Topo I-specific band. In order to procure a nuclear extract, five hundred seventy-seven cells are cleaned using an ice-cold buffer (2 mM K2HPO4, 5 mM MgCl2, 150 mM NaCl, 1 mM EGTA, 0.1 mM dithiothreitol), reconstituted in a buffer that contains 0.35% Triton-X100 and PMSF, and subsequently placed on ice for ten minutes. The obtained lysates are centrifuged, and the precipitates are subsequently left to incubate for one hour at 4°C in a buffer containing 0.35 M NaCl. A protein assay kit is used to measure the protein concentration of the supernatant (nuclear extract) following centrifugation (18,000 g, 10 min). Western blotting analysis employing anti-Topo I antibody is used to analyze the same quantity of nuclear protein[3].
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| Cell Assay |
MTT assay is used to measure the number of viable cells at the end of the incubation period in growth inhibition experiments, which are carried out in 96-well flat-bottomed microplates. After plating and growing 500–20,000000 cells/well in 150 μL of medium for 24 hours (P388, CCRF–CEM, and K562 cells for 4 hours), the drug (such as Exatecan Mesylate in 150 μL of medium/well) or the medium alone (as a control) is added, and the cells are cultured for an extra 3 days. The plates are incubated for 4 hours and centrifuged at 800 g for 5 minutes after adding MTT (20 μL/well, 5 mg/mL in phosphate-buffered saline). The medium is then removed, and the blue dye that forms is dissolved in 150 μL of DMSO. A Microplate Reader model 3550 is used to measure the absorbance at 540 nm[1].
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| Animal Protocol |
For therapeutic purposes, mice are randomized into five groups of five at three weeks following orthotopic implantation of BxPC-3-GFP and MIA-PaCa-2-GFP. Group 1 is the negative control, getting no medical attention. Exatecan Mesylate is administered to Groups 2 and 3 at a dose of 25 and 15 mg/kg, respectively. LY 188011 treatments are administered to groups 4 and 5, at doses of 300 and 150 mg/kg, respectively. Mice are randomized into three groups of twenty at six weeks following BxPC-3-GFP orthotopic implantation in order to provide treatment. Group 1 is the negative control, getting no medical attention. Group 3 is administered 300 mg/kg/dose of LY 188011, while Group 2 is treated with 25 mg/kg/dose of Exatecan Mesylate. The dosage for both medications is taken once a week for three weeks, stopped for two weeks, and then resumed for an additional three weeks. Weekly measurements are made of the primary tumor size and body weights in both early and late cancer models. The formula for calculating tumor volumes is a × b2 × 0.5, in which a and b stand for the larger and smaller diameters, respectively. When the research is over, mice are killed and examined. We record the final tumor weights and the primary tumor and metastases' direct GFP images for every mouse. TWt and TWc are the mean tumor weights of the treated and control groups, respectively, and the formula for calculating the tumor growth index (IR) is IR (%) = (1 − TWt/TWc) × 100[2].
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| References |
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| Additional Infomation |
Exatecan Mesylate Anhydrous is the anhydrous, mesylate salt form of exatecan, a semisynthetic, water-soluble derivative of camptothecin, with antineoplastic activity. Upon administration, exatecan mesylate inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA and inhibiting re-ligation of DNA breaks, thereby inhibiting DNA replication and triggering apoptotic cell death.
See also: Exatecan Mesylate (annotation moved to). |
| Molecular Formula |
C25H26FN3O7S
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|---|---|
| Molecular Weight |
531.553248882294
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| Exact Mass |
531.148
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| Elemental Analysis |
C, 56.49; H, 4.93; F, 3.57; N, 7.91; O, 21.07; S, 6.03
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| CAS # |
169869-90-3
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| Related CAS # |
197720-53-9 (mesylate dihydrate); 169869-90-3 (mesylate); 171335-80-1; 144008-87-7 (HCl); 171335-80-1; 169869-90-3 (mesylate); 197720-53-9 (mesylate dihydrate); 144008-87-7 (HCl)
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| PubChem CID |
6918249
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| Appearance |
Yellow solid powder
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| LogP |
3.758
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
37
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| Complexity |
1040
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| Defined Atom Stereocenter Count |
2
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| SMILES |
S(C)(=O)(=O)O.FC1C=C2C3=C(C=1C)CC[C@@H](C3=C1C(C3=CC4=C(COC([C@@]4(CC)O)=O)C(N3C1)=O)=N2)N([H])[H]
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| InChi Key |
BICYDYDJHSBMFS-GRGFAMGGSA-N
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| InChi Code |
InChI=1S/C24H22FN3O4.CH4O3S/c1-3-24(31)14-6-18-21-12(8-28(18)22(29)13(14)9-32-23(24)30)19-16(26)5-4-11-10(2)15(25)7-17(27-21)20(11)19;1-5(2,3)4/h6-7,16,31H,3-5,8-9,26H2,1-2H3;1H3,(H,2,3,4)/t16-,24-;/m0./s1
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| Chemical Name |
(1S,9S)-1-amino-9-ethyl-5-fluoro-9-hydroxy-4-methyl-1,2,3,9,12,15-hexahydro-10H,13H-benzo[de]pyrano[3',4'
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| Synonyms |
DX-8951; DX 8951; DX8951
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 11.8~12.5 mg/mL (22.1~23.5 mM)
Water: ~12.5 mg/mL |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8813 mL | 9.4065 mL | 18.8129 mL | |
| 5 mM | 0.3763 mL | 1.8813 mL | 3.7626 mL | |
| 10 mM | 0.1881 mL | 0.9406 mL | 1.8813 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00055939 | Completed | Drug: exatecan mesylate | Sarcoma | Daiichi Sankyo, Inc. | January 2003 | Phase 2 |
| NCT00055952 | Completed | Drug: exatecan mesylate | Sarcoma | Daiichi Sankyo, Inc. | January 2003 | Phase 2 |
| NCT00041236 | Completed | Drug: exatecan mesylate | Sarcoma | European Organisation for Research and Treatment of Cancer - EORTC |
May 2002 | Phase 2 |
| NCT00017212 | Completed | Drug: exatecan mesylate | Esophageal Cancer Gastric Cancer |
Daiichi Sankyo, Inc. | April 2001 | Phase 2 |
| NCT00004108 | Completed | Drug: exatecan mesylate | Liver Cancer | Daiichi Sankyo, Inc. | September 1999 | Phase 2 |
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