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| Targets |
alpha-Lapachone has several identified molecular targets. Its primary anticancer mechanism is through the inhibition of topoisomerase II (topo II). It acts as an "irreversible" inhibitor of topo II, preventing the enzyme from cutting and separating the two strands of DNA. This inhibition causes DNA damage that leads to cell death by necrosis or apoptosis. It has also been identified as a potent inhibitor of the malate dehydrogenase (MDH) of T. cruzi, a key enzyme in the parasite's energy metabolism, which explains its trypanocidal activity. alpha-Lapachone also has the ability to undergo redox cycling, generating reactive oxygen species (ROS), which contributes to its cytotoxic effects against both cancer cells and parasites.
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| ln Vitro |
In vitro, alpha-lapachone has demonstrated significant cytotoxicity against a variety of human cancer cell lines, with IC₅0 values typically in the low micromolar range (1-10 uM). It has been evaluated against breast, colon, lung, and leukemia cell lines. Its activity is mediated by topoisomerase II inhibition, leading to DNA double-strand breaks and cell cycle arrest. Against T. cruzi, alpha-lapachone shows trypanocidal activity with an IC₅0 in the range of 1-10 uM against the trypomastigote and amastigote forms of the parasite. It is more potent than its isomer beta-lapachone against T. cruzi. Its mechanism of action involves generating ROS, which damages the parasite's DNA and cellular structures.
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| ln Vivo |
In vivo, alpha-lapachone has demonstrated antitumor activity in several mouse xenograft models. In mice implanted with human breast cancer cells (MCF-7), treatment with alpha-lapachone (administered intraperitoneally at 20-50 mg/kg) resulted in significant tumor growth inhibition. It has also been tested in a mouse model of Chagas disease. In mice infected with T. cruzi, treatment with alpha-lapachone (10-20 mg/kg/day for 10 days) reduced parasitemia and extended survival compared to the untreated control group. However, the compound's clinical development has been hindered by its high hydrophobicity and systemic toxicity at higher doses. These in vivo studies highlight its potential as a lead for both cancer and anti-parasitic therapeutics.
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| Enzyme Assay |
A typical non-cellular topoisomerase II inhibition assay for alpha-lapachone uses purified human topo IIalpha. The reaction mixture (20 uL) contains 50 mM Tris-HCl (pH 8.0), 120 mM KCl, 10 mM MgCl2, 0.5 mM ATP, 1 mM DTT, 30 ug/mL BSA, 0.2 ug of relaxed pBR322 DNA, and 2 units of topo IIalpha. alpha-Lapachone is added at concentrations ranging from 0-100 uM. The reaction is incubated at 37degC for 30 min. It is then terminated by adding 1% SDS and proteinase K. The products are analyzed by agarose gel electrophoresis. Topo II activity is observed by the conversion of relaxed DNA to supercoiled DNA. The IC₅0 is the concentration of inhibitor required to prevent 50% of the decatenation or relaxation activity. For the MDH assay, the enzyme is incubated with its substrate (oxaloacetate) and NADH, and the rate of NADH oxidation is measured spectrophotometrically at 340 nm.
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| Cell Assay |
A typical in vitro cell-based assay for alpha-lapachone is the MTT assay using the human breast cancer cell line MCF-7. Cells are cultured in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin at 37degC in 5% CO2. Cells are seeded in 96-well plates at 5 × 103 cells/well and allowed to adhere overnight. The next day, the medium is replaced with fresh medium containing alpha-lapachone at concentrations ranging from 0.1 to 100 uM (serial dilutions). After 72 hours of incubation, 10 uL of MTT solution (5 mg/mL) is added to each well and incubated for 4 hours. The medium is then removed, and the formazan crystals are dissolved in 100 uL of DMSO. The absorbance is measured at 570 nm. The IC₅0 value is calculated by non-linear regression. For T. cruzi, a similar MTT or resazurin assay is used to assess the viability of the parasites.
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| Animal Protocol |
An in vivo animal study for alpha-lapachone typically uses a mouse xenograft model of breast cancer. Female BALB/c nude mice (6-8 weeks old) are injected subcutaneously in the flank with 5 × 10⁶ MCF-7 cells. When tumors reach an average volume of 100 mm3, the mice are randomized into groups (n=8). alpha-Lapachone is dissolved in a suitable vehicle, such as DMSO: polyethylene glycol 400: saline (10:40:50). The compound is administered intraperitoneally (IP) at a dose of 20 mg/kg daily for 14 days. Control groups receive the vehicle alone. Tumor volume is measured with calipers every 3 days. Body weight is also monitored. At the end of the study (day 14), the mice are euthanized, and the tumors are excised, weighed, and fixed for histopathological analysis (H&E and Ki-67 staining). Tumor growth inhibition (TGI) is calculated. Pharmacodynamic markers like cleaved caspase-3 are measured.
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| ADME/Pharmacokinetics |
The pharmacokinetic (PK) properties of alpha-lapachone have been studied in rodents. It exhibits poor aqueous solubility and is typically formulated in DMSO or other organic solvents for injection. Following intravenous (IV) administration, it has a short elimination half-life (t1/2 of ~1-2 hours) and a high volume of distribution, indicating extensive tissue binding. It is highly plasma protein bound (>90%). Oral bioavailability is low due to poor solubility and extensive first-pass metabolism. It is primarily metabolized by liver cytochrome P450 (CYP) enzymes, specifically CYP1A1 and CYP1A2, to reduced metabolites. Its metabolites are eliminated in the bile and urine. These PK properties make it a challenging candidate for further development.
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| Toxicity/Toxicokinetics |
Toxicological data for alpha-lapachone is limited, but it is considered to have a narrow therapeutic window. In animal studies, dose-limiting toxicities are observed at levels only slightly above the efficacious dose. Reported toxicities include weight loss, gastrointestinal disturbances (diarrhea), and hepatotoxicity (increased liver enzymes). In vitro, it is cytotoxic to rapidly dividing cells, which explains its mechanism-based toxicity. It is a quinone, which can generate reactive oxygen species and cause oxidative stress in normal tissues. Standard safety precautions should be used when handling this compound. It is not suitable for human consumption outside of a controlled clinical trial.
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| References | |
| Additional Infomation |
α-Lapadone is an organic heterocyclic tricyclic compound and an organic oxygen compound. It has been reported to exist in Catalpa ovata, Ekmaniana longiflora, and other organisms with relevant data.
alpha-Lapachone is not an approved drug. It is a natural product lead compound studied for its anticancer and antiparasitic activities. Its mechanism of action involves topoisomerase II inhibition and the generation of reactive oxygen species (ROS). It has been investigated in preclinical studies for Chagas disease and various cancers. Due to toxicity and poor pharmacokinetics, it has not advanced to clinical trials as a single agent, but its analogs are of continued research interest. No clinical trials have been registered for alpha-lapachone as a drug. For research use only; not for human therapeutic or diagnostic use. |
| Molecular Formula |
C15H14O3
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|---|---|
| Molecular Weight |
242.27
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| Exact Mass |
242.094
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| CAS # |
4707-33-9
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| PubChem CID |
72732
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| Appearance |
Light brown to brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
372.9±42.0 °C at 760 mmHg
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| Flash Point |
165.5±27.9 °C
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| Vapour Pressure |
0.0±0.8 mmHg at 25°C
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| Index of Refraction |
1.595
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| LogP |
3.13
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
18
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| Complexity |
445
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1(CCC2=C(O1)C(=O)C3=CC=CC=C3C2=O)C
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| InChi Key |
PJWHOPKRRBUSDH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H14O3/c1-15(2)8-7-11-12(16)9-5-3-4-6-10(9)13(17)14(11)18-15/h3-6H,7-8H2,1-2H3
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| Chemical Name |
2,2-dimethyl-3,4-dihydrobenzo[g]chromene-5,10-dione
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 100 mg/mL (412.76 mM)
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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 | 4.1276 mL | 20.6381 mL | 41.2763 mL | |
| 5 mM | 0.8255 mL | 4.1276 mL | 8.2553 mL | |
| 10 mM | 0.4128 mL | 2.0638 mL | 4.1276 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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