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| Targets |
Cystic fibrosis transmembrane regulator (CFTR); α-Sarcoglycan (α-SG). CFTR corrector 12 (compound C17) is a 4'-methyl-4,5'-bithiazole derivative previously identified as a cystic fibrosis transmembrane regulator (CFTR) corrector. In the context of this study, it was evaluated for its ability to recover folding-defective mutants of α-sarcoglycan. [1]
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| ln Vitro |
In primary myogenic cells derived from a LGMDR3 subject (compound heterozygote for the V247M and L31P mutations in the α-sarcoglycan protein), treatment with C17 at 20 μM and 15 μM for 72 hours elicited the maximum effect, doubling the content of the mutated α-sarcoglycan expressed by myotubes, as determined by Western blot analysis. The effect was significantly higher than vehicle control (1% DMSO). [1]
In L31P/V247M α-SG mutant cells, CFTR corrector 12 (compound 17C) (15 μM; 72 h) may replenish α-sarcoglycan content [1]. |
| ln Vivo |
The article mentions that in a humanized mouse model expressing the R98H-α-sarcoglycan, recovery of the defective protein corresponded to improvement in muscle strength (citing previous work), but no new in vivo experiments are presented. [1]
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| Cell Assay |
Cell Culture and Treatment: Primary myogenic cells from a LGMDR3 subject (compound heterozygote for V247M and L31P mutations in α-sarcoglycan) were grown in proliferation medium (DMEM with 30% FBS, 10 μg/mL insulin, 25 ng/mL FGF, 10 ng/mL EGF). Myotube differentiation was induced by replacing medium with differentiation medium (DMEM with 2% horse serum, 10 μg/mL insulin, 100 μg/mL transferrin) for 7 days. C17 was added during the last 72 hours of differentiation at final concentrations of 20 μM and 15 μM (dissolved in DMSO, final DMSO concentration 1‰). Vehicle control was 1% DMSO. [1]
Western Blot Analysis: After treatment, cells were lysed with RIPA buffer containing protease inhibitors. Protein concentration was determined by BCA assay. Equal amounts of total proteins were separated by SDS-PAGE, transferred to nitrocellulose membranes, and probed with rabbit monoclonal anti-α-sarcoglycan antibody and mouse monoclonal anti-β-actin antibody. Secondary antibodies were HRP-conjugated. Blots were developed with ECL substrate, and chemiluminescent signals were acquired. Densitometry was performed using ImageJ software. The intensities of α-sarcoglycan bands were normalized to Ponceau Red staining of total protein and to β-actin signal. C17 at both 20 and 15 μM doubled the α-sarcoglycan content compared to vehicle control. [1] |
| References | |
| Additional Infomation |
Compound C17 is a 4'-methyl-4,5'-bithiazole derivative that was previously identified as a CFTR corrector, able to correct folding-defective mutants of the CFTR channel. It has also been shown to recover folding-defective mutants of other proteins, including the I661T mutant of ATP8B1 and α-sarcoglycan mutants associated with limb girdle muscular dystrophy R3 (LGMDR3). In this study, C17 was used as a reference compound to compare the activity of newly synthesized bithiazole derivatives. The results showed that C17 elicited maximum recovery of α-sarcoglycan expression in LGMDR3 myotubes at 20 and 15 μM, doubling the protein content. The new derivatives maintained partial activity, but were less effective than C17, indicating that both substituted moieties on the bithiazole scaffold are important for full activity. [1]
4'-Methyl-4,5'-bithiazole compounds have previously been identified as cystic fibrosis transmembrane regulator (CFTR) correctors, capable of correcting channel folding defect mutants and thereby regulating chloride ion transmembrane transport. Furthermore, the bithiazole derivative C17 has been reported to restore α-inosinic sugar expression in vitro and in vivo. This paper reports the synthesis of two novel C17 derivatives in which both sides of the bithiazole backbone are modified. We tested the synthesized compounds and their corresponding precursors using myogenic cells to evaluate α-inosinic sugar expression. The results showed that both substituents on the bithiazole backbone are crucial for maximally restoring α-inosinic sugar mutants. Nevertheless, partial activity retention was observed. Therefore, this paves the way for further derivatization/optimization and targeted capture studies, which were initially conducted in this study as proof of concept to investigate the molecular mechanisms leading to α-inosinic sugar correction. |
| Molecular Formula |
C19H21CLN4O2S2
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|---|---|
| Molecular Weight |
436.978640317917
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| Exact Mass |
436.079
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| CAS # |
958941-60-1
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| PubChem CID |
11958611
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| Appearance |
White to off-white solid powder
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| LogP |
5.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
551
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC(=C(C=1)NC1=NC(=CS1)C1=C(C)N=C(NC(C(C)(C)C)=O)S1)OC
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| InChi Key |
XERLNCVIGMCAMO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H21ClN4O2S2/c1-10-15(28-18(21-10)24-16(25)19(2,3)4)13-9-27-17(23-13)22-12-8-11(20)6-7-14(12)26-5/h6-9H,1-5H3,(H,22,23)(H,21,24,25)
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| Chemical Name |
N-[5-[2-(5-chloro-2-methoxyanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]-2,2-dimethylpropanamide
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| Synonyms |
CFTR corrector 12; C17; 958941-60-1; SMR000156108; MLS000561583; corr15jf; CHEMBL262627; orb2277839; SCHEMBL3800272;
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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 | 2.2884 mL | 11.4422 mL | 22.8843 mL | |
| 5 mM | 0.4577 mL | 2.2884 mL | 4.5769 mL | |
| 10 mM | 0.2288 mL | 1.1442 mL | 2.2884 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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