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| Targets |
Exatecan Intermediate 1-d5 is a deuterium-labeled synthetic intermediate and does not directly target biological receptors. However, the parent compound Exatecan (which is synthesized from this intermediate) is a potent topoisomerase I inhibitor. Topoisomerase I is an enzyme that relieves torsional stress in DNA during replication and transcription. Exatecan binds to the topoisomerase I-DNA complex, preventing religation of the DNA strand and leading to the accumulation of single-strand and double-strand DNA breaks. This results in cell cycle arrest and apoptosis of cancer cells. Exatecan has shown potent antitumor activity in a variety of cancer cell lines and is being investigated as a payload in antibody-drug conjugates (ADCs) for targeted cancer therapy. The deuterated intermediate is used as an analytical standard and does not engage in biological interactions itself.
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| ln Vitro |
Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].
Exatecan Intermediate 1-d5 itself does not possess intrinsic in vitro biological activity as it is an analytical standard. However, the non-labeled Exatecan (the final drug product) exhibits potent in vitro activity against various cancer cell lines. In a typical cell viability assay, Exatecan shows IC50 values in the low nanomolar range (e.g., 0.1-10 nM) against a panel of cancer cell lines, including lung, colon, breast, and ovarian cancer cells. Exatecan's mechanism of action involves the inhibition of topoisomerase I, leading to DNA damage and apoptosis. The compound's activity is time- and concentration-dependent, with longer exposure times leading to increased cytotoxicity. Exatecan has also been used as a payload in antibody-drug conjugates, where it is linked to a tumor-targeting antibody to selectively deliver the drug to cancer cells. The deuterated intermediate is used for analytical purposes only. |
| ln Vivo |
Exatecan Intermediate 1-d5 does not exhibit in vivo biological activity because it is an analytical standard. However, the non-labeled Exatecan (the final drug product) has demonstrated in vivo antitumor activity in various xenograft mouse models. In a typical efficacy study, immunocompromised mice bearing subcutaneous human tumor xenografts (e.g., HT-29 colon cancer or A549 lung cancer) are treated with Exatecan administered intravenously at doses of 0.5-5 mg/kg. Exatecan treatment results in significant tumor growth inhibition and, in some models, tumor regression. The compound's mechanism of action involves the inhibition of topoisomerase I, leading to DNA damage and apoptosis of cancer cells. Exatecan is being investigated as a payload in antibody-drug conjugates (ADCs) for targeted cancer therapy. The deuterated intermediate is used as an analytical standard.
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| Enzyme Assay |
A typical non-cellular protocol for using Exatecan Intermediate 1-d5 as an internal standard involves its incorporation into the sample preparation workflow for LC-MS analysis. A stock solution of the internal standard (1 mg/mL) is prepared in methanol or DMSO. For monitoring the synthesis of Exatecan, reaction mixture samples (10 uL) are diluted with 90 uL of methanol. Then, 10 uL of the internal standard solution (diluted to a working concentration of 1 ug/mL) is added. The sample is vortexed and centrifuged at 10,000 rpm for 5 minutes. The supernatant (5-10 uL) is injected onto an LC-MS/MS system operated in positive ion mode with multiple reaction monitoring (MRM) for the specific transitions of the non-labeled Exatecan Intermediate 1 and the deuterated internal standard. Quantification is achieved by calculating the peak area ratio of the analyte to the internal standard against a calibration curve.
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| Cell Assay |
An in vitro cellular protocol for using Exatecan Intermediate 1-d5 is not directly applicable, as the intermediate is not used as an active compound in cell assays. However, a protocol can be described for quantifying the concentration of the non-labeled Exatecan (the final drug) in cell culture experiments using Exatecan Intermediate 1-d5 as an internal standard. Cancer cells (e.g., 1×10⁶ HT-29 cells) are seeded in 6-well plates and cultured overnight. Cells are treated with Exatecan (0.1-100 nM) for 24-72 hours. After treatment, cells are washed with PBS, harvested, and lysed. The cell lysate is spiked with Exatecan Intermediate 1-d5 internal standard (10 ng/mL). Proteins are precipitated with acetonitrile, and the supernatant is analyzed by LC-MS/MS. The concentration of Exatecan in the cells is quantified using a calibration curve prepared with the same internal standard. The internal standard corrects for extraction efficiency and matrix effects.
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| Animal Protocol |
A typical in vivo animal protocol for using Exatecan Intermediate 1-d5 involves its use as an internal standard for the quantification of Exatecan (the final drug) in plasma and tissues. Male BALB/c nude mice bearing subcutaneous tumor xenografts (e.g., HT-29) are administered Exatecan via intravenous injection at a dose of 1-5 mg/kg. Blood samples (50-100 uL) are collected via the tail vein into EDTA-coated tubes at various time points (0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 hours) post-dose. Plasma is separated by centrifugation (2,000 g, 10 minutes, 4degC). For tissue analysis, mice are euthanized at the final time point, and tumors and other tissues (liver, kidney, lung) are harvested, weighed, and homogenized in PBS. For extraction, 50 uL of plasma or tissue homogenate is mixed with 10 uL of Exatecan Intermediate 1-d5 internal standard solution (1 ug/mL) and 150 uL of acetonitrile. After centrifugation, the supernatant is analyzed by LC-MS/MS. The internal standard corrects for variations in sample preparation and matrix effects.
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| ADME/Pharmacokinetics |
As an analytical internal standard, Exatecan Intermediate 1-d5 is not characterized by typical pharmacokinetic parameters. It is not intended to be administered as a test article for PK studies. However, the non-labeled Exatecan (the final drug) has been studied for its pharmacokinetic properties. In animal models, Exatecan has a short distribution half-life (t1/2alpha) of minutes and an elimination half-life (t1/2beta) of 1-3 hours. The compound is cleared primarily by the liver and excreted in the bile. Its active lactone form is in equilibrium with the inactive carboxylate form in a pH-dependent manner. When conjugated to antibodies in ADCs, the pharmacokinetic properties of Exatecan are altered, with a longer half-life due to the antibody carrier. The deuterated intermediate is used as an internal standard to accurately quantify Exatecan in biological samples.
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| Toxicity/Toxicokinetics |
Toxicity data specific to Exatecan Intermediate 1-d5 are not available, as this compound is an analytical standard and is not used as a therapeutic agent. The non-labeled Exatecan is a potent topoisomerase I inhibitor that can cause dose-limiting toxicities, including myelosuppression (neutropenia, thrombocytopenia), gastrointestinal toxicity (nausea, vomiting, diarrhea), and alopecia. Exatecan is not approved for clinical use as a single agent, but it is being investigated as a payload in antibody-drug conjugates (ADCs) to improve the therapeutic index. The deuterated intermediate should be handled with standard laboratory safety precautions, including the use of gloves, lab coats, and safety glasses. It is intended for research use only and should not be used in humans or animals for therapeutic or diagnostic purposes. The compound should be stored at -20degC, protected from light and moisture.
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| References | |
| Additional Infomation |
Exatecan Intermediate 1-d5 (CAS# 1346617-23-9) is a stable isotope-labeled compound with a molecular weight of 268.28. The molecular formula is C13H8D5NO5, and it is also known as Exatecan Intermediate-d5 and (S)-4-(Ethyl-d5)-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione. The isotopic purity is typically greater than 98%, and the chemical purity is ≥98%. The compound is a deuterated intermediate used in the synthesis of Exatecan, a potent topoisomerase I inhibitor and DNA damage agent. Exatecan is a camptothecin analog with potent antitumor activity and is being investigated as a payload in antibody-drug conjugates (ADCs). The deuterated intermediate serves as an analytical tool in drug development, ensuring precise measurements and a better understanding of drug behavior. This product is for research use only and is not approved for clinical applications.
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| Molecular Formula |
C13H13NO5
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| Molecular Weight |
268.276832342148
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| Exact Mass |
268.11
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| CAS # |
1346617-23-9
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| Related CAS # |
Exatecan Intermediate 1;110351-94-5
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| PubChem CID |
71316567
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| Appearance |
Brown to breen solid powder
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| LogP |
-0.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
19
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| Complexity |
574
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1(=O)C2N(C(=O)C3COC(=O)[C@](O)(C([2H])([2H])C([2H])([2H])[2H])C=3C=2)CC1
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| InChi Key |
IGKWOGMVAOYVSJ-LZEHPYLUSA-N
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| InChi Code |
InChI=1S/C13H13NO5/c1-2-13(18)8-5-9-10(15)3-4-14(9)11(16)7(8)6-19-12(13)17/h5,18H,2-4,6H2,1H3/t13-/m0/s1/i1D3,2D2
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| Chemical Name |
(4S)-4-hydroxy-4-(1,1,2,2,2-pentadeuterioethyl)-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10-trione
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 3.7274 mL | 18.6372 mL | 37.2745 mL | |
| 5 mM | 0.7455 mL | 3.7274 mL | 7.4549 mL | |
| 10 mM | 0.3727 mL | 1.8637 mL | 3.7274 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.
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