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Purity: ≥98%
LK-614 is a novel and potent iron chelator that is able to diminish the beneficial effects of novel modified HTK-1 solution in improving myocardial contractility and relaxation after heart transplantation.
LK-614 (3,4-dimethoxy-N-methyl-benzhydroxamic acid) is a newly developed lipophilic, membrane-permeable hydroxamic acid derivative that acts as an iron chelator. It was designed to penetrate cell membranes and chelate intracellular "chelatable iron," which becomes redox-active during cold storage and catalyzes the formation of highly reactive hydroxyl radicals via the Fenton reaction, contributing to cold-induced injury in organ preservation. In cultured rat hepatocytes, LK-614 (1 mM) effectively protected against histidine-induced cell injury and lipid peroxidation by chelating intracellular iron, demonstrating comparable efficacy to other membrane-permeable iron chelators such as 2,2′-dipyridyl. However, in a rat heterotopic heart transplantation model, the addition of LK-614 (0.02 mmol/L) combined with deferoxamine to histidine-tryptophan-ketoglutarate (HTK) preservation solution did not improve myocardial functional recovery after cold storage and reperfusion. [1,2]| Targets |
Intracellular chelatable iron (redox-active iron pool). LK-614 (3,4-dimethoxy-N-methyl-benzhydroxamic acid) is a newly developed lipophilic, membrane-permeable hydroxamic acid derivative that acts as an iron chelator. No specific binding affinity data (e.g., IC₅₀, Kᵢ) were reported in these studies. [1,2]
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| ln Vitro |
Protection against histidine-induced injury in hepatocytes: In cultured rat hepatocytes exposed to 100 mM L-histidine in modified Krebs-Henseleit buffer at 37°C under normoxic conditions, the addition of LK-614 (1 mM) provided significant protection against cell injury. LDH release was reduced from 63 ± 26% (histidine alone) to 15 ± 5% (with LK-614), and thiobarbituric acid-reactive substances (TBARS), a marker of lipid peroxidation, decreased from 13.2 ± 6.3 nmol/10⁶ cells to 0.8 ± 0.8 nmol/10⁶ cells. The protection was comparable to that provided by the membrane-permeable iron chelator 2,2′-dipyridyl. [1]
Mechanism of action: LK-614, like other membrane-permeable iron chelators (1,10-phenanthroline, 2,2′-dipyridyl, deferoxamine), protected cells from histidine-induced injury, whereas the membrane-impermeable chelator diethylenetriaminepentaacetic acid (DTPA) did not. This indicates that LK-614 acts by chelating intracellular iron, preventing the formation of redox-active iron complexes that catalyze the production of reactive oxygen species. [1] |
| ln Vivo |
Effect on myocardial function after heart transplantation: In a heterotopic rat heart transplantation model, donor hearts were preserved for 1 hour in modified HTK solution containing LK-614 (0.02 mmol/L) and deferoxamine (0.1 mmol/L) (HTK-2 group). After 1 hour of reperfusion, left ventricular systolic pressure (LVSP) was 60 ± 39 mmHg and minimum rate of pressure development (dP/dtmin) was 660 ± 446 mmHg/s in the HTK-2 group. In contrast, the HTK-1 group (containing N-α-acetyl-L-histidine but no iron chelators) showed significantly better functional recovery (LVSP: 106 ± 33 mmHg; dP/dtmin: 1388 ± 627 mmHg/s). The addition of LK-614 and deferoxamine did not improve myocardial contractility or relaxation compared to standard HTK solution. Energy charge potential was not significantly different between groups. [2]
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| Cell Assay |
Hepatocyte injury assessment: Rat hepatocytes were cultured and exposed to modified Krebs-Henseleit buffer containing 100 mM L-histidine or 198 mM L-histidine at 37°C under normoxic conditions for 4 hours. LK-614 was added at a concentration of 1 mM to test its protective effect. Cell injury was assessed by measuring lactate dehydrogenase (LDH) release and thiobarbituric acid-reactive substances (TBARS) as a marker of lipid peroxidation. [1]
Mechanistic studies: To confirm the intracellular site of action, the membrane-permeable iron chelator LK-614 was compared with the membrane-impermeable chelator DTPA (100 μM). Only the membrane-permeable chelators provided protection, indicating that LK-614 acts by chelating intracellular iron. [1] |
| Animal Protocol |
Heterotopic rat heart transplantation: Male Lewis rats (280-400 g) were used as donors and recipients. Donor hearts were arrested with 20 mL of cardioplegic solution (HTK, HTK-1, or HTK-2) and stored in cold (+4°C) preservation solution for 1 hour. Hearts were then transplanted heterotopically by anastomosing the donor aorta and pulmonary artery to the recipient abdominal aorta and vena cava, respectively. After 1 hour of reperfusion, hemodynamic functional assessment was performed using a Millar pressure catheter. The modified HTK-2 solution contained LK-614 at a concentration of 0.02 mmol/L and deferoxamine at 0.1 mmol/L. [2]
High-energy phosphate determination: After hemodynamic measurements, hearts were immediately frozen in liquid nitrogen. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) contents were assessed using an enzyme-kinetic assay, and energy charge potential was calculated. [2] |
| Toxicity/Toxicokinetics |
In the heart transplantation study, the addition of LK-614 and deferoxamine (HTK-2 group) did not improve functional outcomes and was associated with numerically lower myocardial function compared to the HTK-1 group, suggesting that the combination may not be beneficial in this model. No overt signs of toxicity were described. [2]
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| References |
[1]. Histidine-induced injury to cultured liver cells, effects of histidine derivatives and of iron chelators. Cellular and molecular life sciences. 2007 Jan;64(2):192-205.
[2]. Deferoxamine, the newly developed iron chelator LK-614 and N-alpha-acetyl-histidine in myocardial protection. Interact Cardiovasc Thorac Surg. 2010 Feb;10(2):181-4. |
| Additional Infomation |
Background and mechanism: LK-614 is a lipophilic, membrane-permeable hydroxamic acid derivative developed as an iron chelator. It was designed to penetrate cell membranes and chelate intracellular "chelatable iron," which becomes redox-active during cold storage and catalyzes the formation of hydroxyl radicals via the Fenton reaction. This process contributes to cold-induced injury in organ preservation. [1,2]
Chemical properties: LK-614 (3,4-dimethoxy-N-methyl-benzhydroxamic acid) is a lipophilic derivative of benzhydroxamic acid. Its membrane permeability allows it to access the intracellular pool of chelatable iron, unlike hydrophilic chelators such as deferoxamine (which has limited membrane permeability) or DTPA (which is impermeable). [1] Clinical context: LK-614 was tested as an additive to histidine-tryptophan-ketoglutarate (HTK) solution (Custodiol) to reduce cold ischemic injury in organ preservation. However, in the rat heart transplantation model, the combination of LK-614 and deferoxamine did not improve myocardial functional recovery after 1 hour of cold storage and reperfusion. In contrast, partial replacement of histidine with N-α-acetyl-L-histidine (HTK-1 solution) significantly improved functional outcomes. [2] Experimental context: In vitro studies in cultured rat hepatocytes demonstrated that LK-614 effectively protects against histidine-induced cell injury and lipid peroxidation, confirming its ability to chelate intracellular iron and prevent oxidative damage. This protective effect was observed at a concentration of 1 mM. [1] |
| Molecular Formula |
C10H13NO4
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|---|---|
| Molecular Weight |
211.21452
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| Exact Mass |
211.084
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| Elemental Analysis |
C, 56.87; H, 6.20; N, 6.63; O, 30.30
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| CAS # |
82461-57-2
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| PubChem CID |
22925579
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| Appearance |
Off-white to pink solid powder
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| LogP |
1.165
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
15
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| Complexity |
222
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ON(C)C(=O)C1C=CC(OC)=C(OC)C=1
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| InChi Key |
CFAMAWCPWJCAFR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C10H13NO4/c1-11(13)10(12)7-4-5-8(14-2)9(6-7)15-3/h4-6,13H,1-3H3
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| Chemical Name |
N-hydroxy-3,4-dimethoxy-N-methylbenzamide
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| Synonyms |
LK-614; LK 614; 82461-57-2; LK 614; Benzamide, N-hydroxy-3,4-dimethoxy-n-methyl-; UNII-83OI05F214; LK614
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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: ~175 mg/mL (828.6 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 | 4.7346 mL | 23.6731 mL | 47.3462 mL | |
| 5 mM | 0.9469 mL | 4.7346 mL | 9.4692 mL | |
| 10 mM | 0.4735 mL | 2.3673 mL | 4.7346 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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