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| Targets |
pre-mRNA splicing
Madrasin targets the spliceosome, the complex machinery responsible for removing introns from pre-mRNA transcripts. It specifically interferes with the early stages of spliceosome assembly, stalling the process at the A complex. The A complex is an early intermediate in spliceosome formation where the U2 snRNP associates with the branch point sequence. By blocking assembly at this stage, Madrasin prevents the formation of a functional spliceosome, thereby inhibiting pre-mRNA splicing. This inhibition leads to the accumulation of unspliced pre-mRNA and the disruption of normal gene expression. |
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| ln Vitro |
Madrasin (10-30 μM; 4-24 hours; HeLa cells) treatment prevents each of the pre-mRNAs for RIOK3, BRD2, Hsp40, MCL1, CCNA2, AURKA, and p27 from being spliced in both HeLa and HEK293 cells[1].
Madrasin (10-30 μM; 4-24 hours; HeLa and HEK293 cells) treatment inhibits the progression of the cell cycle in a dose- and time-dependent manner[1]. In vitro, Madrasin is a potent inhibitor of pre-mRNA splicing in cell-based assays. It induces cell cycle arrest in treated cells and promotes a specific reorganization of subnuclear protein localization. Studies have shown that Madrasin affects pre-RNA species in both HeLa and HEK293 cells. Its activity is characterized by its ability to stall spliceosome assembly at the A complex, which is a key step in the splicing pathway. The compound is considered toxic to cells at higher concentrations, but at its minimal concentration, it is known to induce subnuclear protein localization and cause cell cycle arrest. |
| ln Vivo |
In vivo studies for Madrasin are not extensively documented in the available literature. As a research compound primarily used for studying splicing mechanisms, its in vivo applications are limited to cell culture models. However, the compound's ability to penetrate cells and inhibit splicing makes it a valuable tool for studying the role of splicing in various biological processes. Its use in animal models would be a logical next step for understanding the systemic effects of splicing inhibition. Currently, specific in vivo efficacy data are not available in the public domain.
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| Enzyme Assay |
In vitro enzyme/receptor binding studies are not applicable to Madrasin, as it is a splicing inhibitor that acts by disrupting a macromolecular complex (the spliceosome) rather than binding to a specific enzyme or receptor. Its activity is assessed by measuring its effects on splicing in cell-based assays. These assays typically involve treating cells with the compound and then analyzing the splicing of specific pre-mRNA transcripts using RT-PCR or Northern blotting. The inhibition of splicing is confirmed by the accumulation of unspliced pre-mRNA and the reduction of mature mRNA.
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| Cell Assay |
After being sown in 6-well plates, HeLa cells are given a madrasin treatment. Following harvesting, the cells are left in ice-cold 70% ethanol for 4 hours, 8 hours, and 24 hours. After that, they are twice washed with PBS and fixed at room temperature for half an hour. Flow cytometry analysis is performed on fixed cells.
In vitro cellular assays for Madrasin are the primary method for evaluating its activity. In these experiments, cell lines such as HeLa or HEK293 are treated with the compound. The inhibition of splicing is assessed by measuring the levels of spliced and unspliced mRNA for specific genes. Additionally, the effects on cell cycle progression are analyzed by flow cytometry. The reorganization of subnuclear protein localization can be visualized by immunofluorescence microscopy. These assays confirm the compound's mechanism of action and its effects on cellular processes. |
| Animal Protocol |
In vivo animal studies for Madrasin are not detailed in the provided sources. As a tool for studying splicing, its use in animal models would be important for understanding its effects on development and disease. Such studies could involve administering the compound to model organisms and analyzing the effects on splicing, gene expression, and phenotype. However, specific protocols and data are not available. The compound is considered toxic to cells at higher concentrations, which could limit its in vivo utility.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Madrasin include its molecular weight of 311.34 g/mol. It is reported to be soluble in DMSO at 1 mg/mL (3.21 mM) and in ethanol at 3 mg/mL. It is insoluble in water. For in vivo administration, it can be formulated as a homogeneous suspension in CMC-Na at ≥5 mg/mL, or as a clear solution in 5% DMSO, 40% PEG300, 5% Tween 80, and 50% ddH2O for injection. These formulations are important for its use in animal studies. Specific data on its half-life and bioavailability are not detailed.
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| Toxicity/Toxicokinetics |
Toxicological data for Madrasin are limited, as it is a research compound. It is considered toxic to cells at higher concentrations. At its minimal concentration, it induces subnuclear protein localization and causes cell cycle arrest. These effects are a consequence of its mechanism of action as a splicing inhibitor. Comprehensive toxicological studies have not been reported, and its use is strictly confined to non-clinical research settings. As with all research chemicals, it should be handled with appropriate laboratory safety precautions.
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| References | |
| Additional Infomation |
2-[(7-methoxy-4-methyl-2-quinazolinyl)amino]-5,6-dimethyl-1H-pyrimidin-4-one is a member of the quinazolinoid class of compounds.
Madrasin is a research-use-only compound that acts as a potent and cell-penetrant pre-mRNA splicing inhibitor. Its CAS number is 374913-63-0. It is also known as DDD00107587. It interferes with the early stages of spliceosome assembly and stalls it at the A complex, making it a valuable tool for studying the role of splicing in gene expression and disease. It is not an approved drug and is intended for non-clinical research applications. |
| Molecular Formula |
C16H17N5O2
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|---|---|
| Molecular Weight |
311.345
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| Exact Mass |
311.138
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| Elemental Analysis |
C, 61.72; H, 5.50; N, 22.49; O, 10.28
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| CAS # |
374913-63-0
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| Related CAS # |
374913-63-0
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| PubChem CID |
135444382
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
567.2±42.0 °C at 760 mmHg
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| Flash Point |
296.9±27.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.671
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| LogP |
1.91
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
23
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| Complexity |
545
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C([H])([H])[H])C1C([H])=C([H])C2=C(C([H])([H])[H])N=C(N=C2C=1[H])N([H])C1=NC(C([H])([H])[H])=C(C([H])([H])[H])C(N1[H])=O
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| InChi Key |
QQJIYKXTEMDJFM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H17N5O2/c1-8-9(2)17-16(20-14(8)22)21-15-18-10(3)12-6-5-11(23-4)7-13(12)19-15/h5-7H,1-4H3,(H2,17,18,19,20,21,22)
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| Chemical Name |
2-[(7-methoxy-4-methylquinazolin-2-yl)amino]-4,5-dimethyl-1H-pyrimidin-6-one
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| Synonyms |
RNA splicing inhibitor; DDD00107587; Madrasin
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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: 1~2 mg/mL (3.2~6.4 mM)
H2O: < 0.1 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 | 3.2118 mL | 16.0591 mL | 32.1182 mL | |
| 5 mM | 0.6424 mL | 3.2118 mL | 6.4236 mL | |
| 10 mM | 0.3212 mL | 1.6059 mL | 3.2118 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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