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| Targets |
G-quadruplex
Carboxy pyridostatin trifluoroacetate salt targets G-quadruplex (G4) structures in DNA and RNA. G4s are non-canonical secondary structures formed by guanine-rich nucleic acid sequences. By selectively binding and stabilizing G4 structures, the compound interferes with telomerase activity, transcription, and replication. This mechanism underlies its potential effects on tumor cell proliferation and gene expression. |
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| ln Vitro |
G-quadruplexes are pervasive nucleic acid secondary structures in mammalian genomes and transcriptomes that regulate gene expression and genome duplication. Small molecule ligands that modify the stability of G-quadruplexes are widely studied in cancer, but whether G-quadruplex ligands can also be used to manipulate cell function under normal development and homeostatic conditions is largely unexplored. Here we show that two related G-quadruplex ligands (pyridostatin and carboxypyridostatin) can reduce proliferation of adult neural stem cell and progenitor cells derived from the adult mouse subventricular zone both in vitro and in vivo. Studies with neurosphere cultures show that pyridostatin reduces proliferation by a mechanism associated with DNA damage and cell death. By contrast, selectively targeting RNA G-quadruplex stability with carboxypyridostatin diminishes proliferation through a mechanism that promotes cell cycle exit and the production of oligodendrocyte progenitors. The ability to generate oligodendrocyte progenitors by targeting RNA G-quadruplex stability, however, is dependent on the cellular environment. Together, these findings show that ligands that can selectively stabilize RNA G-quadruplexes are an important, new class of molecular tool for neural stem and progenitor cell engineering, whereas ligands that target DNA G-quadruplexes have limited utility due to their toxicity.[1]
In cell-free biochemical systems, Carboxy pyridostatin trifluoroacetate salt binds to G-quadruplex structures with high specificity. The compound's binding to G4s can be assessed using circular dichroism (CD) spectroscopy, UV melting assays, or fluorescence-based G4 binding assays. The compound displays high molecular specificity for RNA on DNA G4s. |
| ln Vivo |
In cell-based assays, Carboxy pyridostatin trifluoroacetate salt stabilizes G-quadruplex structures, leading to the inhibition of telomerase activity and modulation of gene expression. The compound's effects are evaluated in cancer cell lines by measuring telomerase activity, cell proliferation, and gene expression changes. By affecting tumor cell proliferation and gene expression, the compound has potential anticancer activity.
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| Enzyme Assay |
The pyridostatin (PDS) represents the lead compound of a family of G-quadruplex (G4) stabilizing synthetic small molecules based on a N,N'-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold. Its mechanism of action involves the induction of telomere dysfunction by competing for binding with telomere-associated proteins, such as human POT1. Recently, through a template-directed "in situ" click chemistry approach, a PDS derivative, the carboxypyridostatin (cPDS), was discovered. It has the peculiarity to exhibit high molecular specificity for RNA over DNA G4, while PDS is a good generic RNA and DNA G4-interacting small molecule. Structural data on the binding modes of these compounds are not available, and the selectivity mode of cPDS toward TERRA G4 is unknown too. Therefore, this work is aimed at rationalizing the selectivity of cPDS versus TERRA G4 by means of molecular dynamics and docking simulations, coupled to better understand the binding mode of these compounds to telomeric G4 structures. The comprehensive analysis of cPDS binding mode and its conformational behavior demonstrates the importance of the ligand conformation properties coupled with a remarkable solvation contribution. This work is expected to provide valuable clues for further rational design of novel and selective TERRA G4 binders.[2]
The cell-free assay for G4 binding involves incubating the compound with G-quadruplex-forming oligonucleotides. Binding is assessed using circular dichroism (CD) spectroscopy to monitor changes in the G4 structure, UV melting assays to measure thermal stability changes, or fluorescence-based assays using G4-specific fluorescent probes. The compound's selectivity for different G4 structures can be assessed by testing against various G4-forming sequences. |
| Cell Assay |
Cell-based assays for Carboxy pyridostatin trifluoroacetate salt involve culturing cancer cell lines and treating them with the compound at concentrations ranging from 0.1 to 100 μM. Telomerase activity is assessed using the TRAP assay. Cell proliferation is assessed using MTT or CCK-8 assays. Gene expression changes are evaluated by qRT-PCR or RNA-seq. The compound's effects on cell cycle progression and apoptosis are also assessed.
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| Animal Protocol |
There is no established animal experimental protocol for Carboxy pyridostatin trifluoroacetate salt specifically. As a G-quadruplex stabilizer with potential anticancer activity, the compound could potentially be evaluated in animal models of cancer. Typical studies involve administration of the compound to tumor-bearing mice via intraperitoneal or intravenous routes. Tumor growth, telomerase activity, and gene expression changes would be assessed.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Carboxy pyridostatin trifluoroacetate salt have not been extensively reported. As a large molecule with a molecular weight of 820.73 g/mol, the compound would be expected to have limited oral bioavailability and may require parenteral administration. The compound is soluble in water at 60 mg/mL and is typically stored at -20°C, dry and sealed. Further pharmacokinetic studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
Carboxy pyridostatin trifluoroacetate salt is intended for research use only and lacks established toxicity profiles for therapeutic applications. Standard laboratory safety precautions should be observed when handling this compound. As a G-quadruplex stabilizer, it may have effects on normal cells as well as cancer cells. Standard toxicity studies in rodents would be required to determine the maximum tolerated dose and safety profile.
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| References | |
| Additional Infomation |
Carboxy pyridostatin trifluoroacetate salt is a research-grade compound supplied for G-quadruplex and cancer research. It is not an approved pharmaceutical and has no clinical trial history. The compound is a G-quadruplex stabilizer that selectively binds G4 structures in DNA or RNA. This product is intended for research use only.
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| Molecular Formula |
C37H35F3N10O9
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| Molecular Weight |
820.7306
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| Exact Mass |
706.26119
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| CAS # |
2444713-88-4
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| PubChem CID |
134828255
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
-1.1
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
19
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
59
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| Complexity |
1190
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C1=CC(NC(C2=CC(OCC3N=NN(CCC(=O)O)C=3)=CC(C(=O)NC3C=C(OCCN)C4C=CC=CC=4N=3)=N2)=O)=NC2C=CC=CC1=2)CCN.O=C(C(F)(F)F)O
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| InChi Key |
WTHDBHUUPVHFQX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C35H34N10O7.C2HF3O2/c36-10-13-50-29-17-31(39-25-7-3-1-5-23(25)29)41-34(48)27-15-22(52-20-21-19-45(44-43-21)12-9-33(46)47)16-28(38-27)35(49)42-32-18-30(51-14-11-37)24-6-2-4-8-26(24)40-32;3-2(4,5)1(6)7/h1-8,15-19H,9-14,20,36-37H2,(H,46,47)(H,39,41,48)(H,40,42,49);(H,6,7)
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| Chemical Name |
3-[4-[[2,6-bis[[4-(2-aminoethoxy)quinolin-2-yl]carbamoyl]pyridin-4-yl]oxymethyl]triazol-1-yl]propanoic acid;2,2,2-trifluoroacetic acid
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| Synonyms |
Carboxy pyridostatin trifluoroacetate salt; 2444713-88-4; Carboxy pyridostatin (trifluoroacetate salt);3-(4-(((2,6-Bis((4-(2-aminoethoxy)quinolin-2-yl)carbamoyl)pyridin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)propanoic acid;
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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: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 (121.84 mM)
H2O : 60 mg/mL (73.11 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 | 1.2184 mL | 6.0921 mL | 12.1843 mL | |
| 5 mM | 0.2437 mL | 1.2184 mL | 2.4369 mL | |
| 10 mM | 0.1218 mL | 0.6092 mL | 1.2184 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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