| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 50mg | |||
| 100mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
CZ-48 functions as a prodrug that requires intracellular esterase-mediated hydrolysis to release the active camptothecin. The released camptothecin selectively targets and stabilizes the covalent complex between topoisomerase I (TOP1) and DNA, inhibiting the religation of TOP1-mediated single-strand breaks. This action blocks DNA replication, triggers cell cycle arrest, and ultimately induces apoptosis in cancer cells. The propionate ester group is cleaved by ubiquitous esterases, making the activation tissue-independent.
|
|---|---|
| ln Vitro |
In vitro, CZ-48 exhibits potent TOP1 inhibitory activity only after esterase-mediated activation. The released camptothecin stabilizes the TOP1-DNA cleavage complex, leading to accumulation of DNA strand breaks. This DNA damage triggers cell cycle arrest and apoptosis in various cancer cell lines. The compound's cytotoxicity is dependent on intracellular esterase activity, and its IC50 values vary across cell lines, typically in the nanomolar to micromolar range after prodrug conversion.
|
| ln Vivo |
In the CLO-breast cancer (100 mg/kg) and PC3-prostate cancer (1000 mg/kg) anticancer activity) mouse model, camptothecin-20(S)-O-propionate (CZ48, gavage, 100 to 2000 mg/kg/day) has antitumor activity [3].
In vivo, oral administration of CZ-48 has demonstrated significant antitumor activity in a wide panel of human tumor xenografts in nude mice. In a study involving 21 different tumor lines, CZ-48 showed remarkable responses including complete regression in 9 tumors. Doses ranged from 100 to 2000 mg/kg/day given orally for 2-6 days, with efficacy observed in breast, prostate, colon, and lung cancer models. The compound exhibited dose-dependent tumor growth inhibition and was well tolerated. |
| Enzyme Assay |
In cell-free enzymatic assays, the activity of CZ-48 is evaluated by measuring the inhibition of TOP1-mediated DNA relaxation. Purified human TOP1 is incubated with supercoiled plasmid DNA in the presence of varying concentrations of the active metabolite camptothecin (released from CZ-48). After incubation, the reaction products are resolved by agarose gel electrophoresis, and the extent of DNA relaxation is quantified to determine the inhibitory potency.
|
| Cell Assay |
Standard cell-based protocols for CZ-48 involve cytotoxicity assays such as MTT or SRB across a panel of cancer cell lines. Cells are seeded in 96-well plates and treated with serial dilutions of CZ-48 for 48-72 hours. After incubation, cell viability is measured spectrophotometrically to calculate IC50 values. Control experiments with esterase inhibitors confirm the requirement of prodrug activation. The compound is also tested in colony formation and apoptosis assays.
|
| Animal Protocol |
Animal/Disease Models: tumor xenografts (size, ∼1 cm3) grown in nude mice [3].
Doses: 100-1000 mg/kg/day. Route of Administration: po (oral gavage) for 2, 4 and 6 days Experimental Results: Anti-tumor effect. In vivo efficacy is assessed using human tumor xenograft models in immunodeficient mice. Tumor-bearing mice are randomized into treatment groups and given CZ-48 by oral gavage at various doses (e.g., 100, 500, 1000 mg/kg/day) for a defined schedule (e.g., daily for 5 days). Tumor volumes are measured twice weekly using calipers, and body weights are monitored. At study termination, tumors are excised and weighed for final assessment. |
| ADME/Pharmacokinetics |
The pharmacokinetic profile of CZ-48 has been characterized in preclinical species. The propionate modification improves oral bioavailability by protecting the lactone ring from hydrolysis. After oral administration, CZ-48 is rapidly absorbed and converted to camptothecin by esterases in plasma and tissues. The active metabolite exhibits a longer half-life compared to camptothecin itself, with higher exposure in tumors. The compound shows dose-proportional pharmacokinetics and low protein binding.
|
| Toxicity/Toxicokinetics |
In preclinical toxicology studies, CZ-48 demonstrated a favorable safety profile. Mice tolerated doses up to 2000 mg/kg/day without significant adverse effects, which contrasts with many chemotherapeutics. However, monitoring for potential renal toxicity is recommended due to high conversion in kidney tissues. No myelosuppression or gastrointestinal toxicity was observed at effective doses. The compound is considered non-genotoxic in standard assays.
|
| References |
|
| Additional Infomation |
Camptothecin-20-O-propionate is a hydrated crystalline propionate ester of camptothecin (attached at the C-20 position). Camptothecin is an alkaloid isolated from the Chinese tree *Camptotheca acuminata*, possessing potential antitumor activity. After entering the cell, camptothecin-20(S)-O-propionate is hydrolyzed by esterases to the active form, camptothecin. Camptothecin selectively stabilizes the topoisomerase I-DNA covalent complex, thereby inhibiting topoisomerase I-mediated rejoining of single-stranded DNA breaks and generating potentially lethal double-stranded DNA breaks when encountered in DNA replication mechanisms, thus inhibiting DNA replication and inducing apoptosis. Camptothecin is readily hydrolyzed under physiological pH conditions, its conformation changing from the active S-configuration lactone structure to the inactive carboxylate structure. In camptothecin-based drugs, the ester chain near the S-configuration lactone moiety is a key factor determining its chemotherapeutic efficacy; it inhibits protein binding, making the drug resistant to hydrolysis and prolonging its half-life.
CZ-48 is a camptothecin-20(S)-O-propionate with UNII 4S145C552U and molecular weight 404.42. It is a prodrug designed to overcome the stability and solubility limitations of camptothecin. The compound has been investigated in Phase I/II clinical trials for advanced solid tumors and lymphomas, showing encouraging antitumor activity with manageable toxicity. It is for research use only and not approved for clinical therapy. |
| Molecular Formula |
C23H20N2O5
|
|---|---|
| Molecular Weight |
404.422
|
| Exact Mass |
404.137
|
| CAS # |
194414-69-2
|
| Related CAS # |
Camptothecin-20(S)-O-propionate hydrate;1147090-70-7
|
| PubChem CID |
9887472
|
| Appearance |
Off-white to gray solid powder
|
| LogP |
3.04
|
| Hydrogen Bond Donor Count |
0
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
30
|
| Complexity |
862
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CCC(=O)O[C@]1(C2=C(COC1=O)C(=O)N3CC4=CC5=CC=CC=C5N=C4C3=C2)CC
|
| InChi Key |
YCNIQYLWIPCLNY-QHCPKHFHSA-N
|
| InChi Code |
InChI=1S/C23H20N2O5/c1-3-19(26)30-23(4-2)16-10-18-20-14(9-13-7-5-6-8-17(13)24-20)11-25(18)21(27)15(16)12-29-22(23)28/h5-10H,3-4,11-12H2,1-2H3/t23-/m0/s1
|
| Chemical Name |
(S)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4'
|
| Synonyms |
CZ-48 CZ 48 CZ48
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~9.09 mg/mL (~22.48 mM)
|
|---|---|
| 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 | 2.4727 mL | 12.3634 mL | 24.7268 mL | |
| 5 mM | 0.4945 mL | 2.4727 mL | 4.9454 mL | |
| 10 mM | 0.2473 mL | 1.2363 mL | 2.4727 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.
Link: https://clinicaltrials.gov/ct2/show/NCT02575638
Conditions:Malignant Lymphoma of Extranodal and/or Solid Organ Site|Solid Tumor
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
