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Lificiguat, formerly known as YC-1, is a potent inhibitor of Hypoxia-inducible factor-1alpha (HIF-1alpha). YC-1 is being developed as a novel anticancer drug and is widely used as a potent HIF-1alpha inhibitor both in vitro and in vivo. Tumor invasion and metastasis are effectively inhibited by YC-1, suggesting that YC-1 deserves further development as a versatile anticancer medication.
| Targets |
sGC ( Kd = 0.6-1.1 μM )
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|---|---|
| ln Vitro |
YC-1 is a soluble guanylyl cyclase (sGC) allosteric activator. YC-1 sensitizes the enzyme to its gaseous activators, carbon monoxide or nitric oxide, and raises the enzyme's catalytic rate. While YC-1 by itself only activates the enzyme by a factor of ten, it increases the activation of sGC that is dependent on CO and NO, which can stimulate the highly purified enzyme by a factor of several hundred to several thousand [1]. In vitro, it suppresses HIF-1 activity, vascular contraction, and platelet aggregation. YC-1 entirely prevents HIF-1α expression at the post-transcriptional level, which in turn suppresses HIF-1 transcription factor activity in hepatoma cells cultured in hypoxic environments. This indicates that YC-1's effects are probably related to the oxygen-sensing pathway rather than the activation of soluble guanylyl cyclase[2].
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| ln Vivo |
When YC-1 is given to experimental animals, mean arterial pressure drops and platelet-rich thrombosis is inhibited, both of which are correlated with elevated cGMP levels [1]. YC-1 efficiently stops tumor growth in mice that are tumor-bearing. While YC-1's anti-platelet aggregation effect does not seem to affect tumor growth, the inhibition of HIF-1 activity in tumors from mice treated with the drug is linked to blocked angiogenesis and an inhibition of tumor growth[2].
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| Enzyme Assay |
The appearance of the CO-bound Soret absorption band is monitored while titrating CO from a saturated solution into sGC protein in order to determine CO dissociation constants. Excess dithionite is added to buffer that has been purged of Ar to prepare the Ms sGC β1(1-380) and Bt sGC β1(1-197) samples. CO binding experiments using a Cary 50 spectrophotometer with a modified sample holder are carried out in a 10 cm pathlength cuvette for Ms sGC-β1(1-380) and Ms sGC-NT21. A single site saturation ligand binding model in SigmaPlot is used to plot binding data in the presence and absence of 50 μM Lificiguat (YC-1).
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| Cell Assay |
The assay for measuring cell proliferation uses a Cell Counting Kit-8 (CCK-8). In a nutshell, 3×103/well of cells are cultured in 96-well plates, incubated for 24 hours, and then treated with Lificiguat (YC-1) or Sorafenib. Each well receives an addition of CCK-8 reagent following a 72-hour treatment. After 2.5 hours of incubation at 37°C, the absorbance is measured at 450 nm using an automated ELISA plate reader. Utilizing Microsoft Excel software, any synergistic effects arising from the combination of the compounds are measured in order to calculate the combination index values (CI>1: antagonistic effect, CI=1: additive effect, and CT<1: synergistic effect).
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| Animal Protocol |
Mice: The nu/nu mice used are fifty-eight females that are four weeks old. The mammary fat pads of naked mice are inoculated with MDA-MB-468 breast cancer cells (5×106 cells/mouse) suspended in 0.1 mL of Matrigel solution (50% v/v Matrigel in PBS). The tumor-bearing mice are randomly assigned to treatment groups after the tumor masses reach 100 mm3. These groups receive varying doses of Lificiguat (YC-1)/YC-1-S. A YC-1 injection (30 or 60 mg/kg) or a YC-1-S oral administration is given to the mice. Tumor volume (mm3) is computed using the formula length×(width)2×0.5. Tumor size and mouse body weight are measured once every three days. Tumor nodules are removed and weighed when the experiments are over and the mice are put down. Western blotting is used to examine tumor samples.
Rats: Male Wistar albino rats, ages 4 months (200-250 g) and 24 months (550-600 g), are utilized. Before use, ligiguat (YC-1) is prepared and administered intraperitoneally (i.p.) in a dose of 0.1 mL per 100 g of body weight. For two weeks, each rat was given 1 mg/kg/day of ligiguat (YC-1). Rats that are 4 months and 24 months old (n = 10, for each group) are given DMSO. All outcomes are measured, and doses are chosen to validate the chosen doses on locomotor activity. |
| References |
| Molecular Formula |
C19H16N2O2
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|---|---|
| Molecular Weight |
304.34
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| Exact Mass |
304.12
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| Elemental Analysis |
C, 74.98; H, 5.30; N, 9.20; O, 10.51
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| CAS # |
170632-47-0
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| Related CAS # |
170632-47-0
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| Appearance |
White solid powder
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| SMILES |
C1=CC=C(C=C1)CN2C3=CC=CC=C3C(=N2)C4=CC=C(O4)CO
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| InChi Key |
OQQVFCKUDYMWGV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H16N2O2/c22-13-15-10-11-18(23-15)19-16-8-4-5-9-17(16)21(20-19)12-14-6-2-1-3-7-14/h1-11,22H,12-13H2
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| Chemical Name |
[5-(1-benzylindazol-3-yl)furan-2-yl]methanol
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| Synonyms |
Lificiguat; YC1; YC 1; YC-1
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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: ~61 mg/mL (~200.43 mM)
Ethanol: ~31 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (8.21 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2858 mL | 16.4290 mL | 32.8580 mL | |
| 5 mM | 0.6572 mL | 3.2858 mL | 6.5716 mL | |
| 10 mM | 0.3286 mL | 1.6429 mL | 3.2858 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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