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| Targets |
Darbufelone targets cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). It potently inhibits prostaglandin G/H synthase-2 (PGHS-2/COX-2) with an IC50 of 0.19 µM, while being much weaker against COX-1 (IC50 = 20 µM), conferring selectivity. It also inhibits 5-LOX, reducing leukotriene synthesis. This dual mechanism may provide anti-inflammatory and analgesic effects with reduced gastrointestinal toxicity compared to non-selective NSAIDs.
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| ln Vitro |
Darbufelone (Ki=10±5 μM) inhibits PGHS-2 in a non-competitive manner. At 325 nm (lambda(ex)=280 nm), darbufelone quenches the fluorescence of PGHS-2, with a Kd of 0.98±0.03 μM[1]. A549, H520, and H460 cell lines—which were developed based on three distinct histological subtypes of non-small cell lung cancer (NSCLC)—were utilized to assess the potential antiproliferative effects of darbufelone (adenocarcinoma, squamous cell carcinoma, and large cell lung cancer, respectively). Elevate the concentration of dabufilon (between 5 and 60 μM) and conduct a 72-hour test. With increasing drug concentrations, these three cell lines' cytostatic effects grew over time. A549 and H520 had IC50 values of 20±3.6 and 21±1.8 μM, respectively, but H460 has a substantially lower IC50 value of 15±2.7 μM [2].
In vitro, Darbufelone mesylate potently inhibits PGHS-2 (IC50 = 0.19 µM) and shows weak COX-1 inhibition (IC50 = 20 µM). It also inhibits the production of PGF2α and LTB4 in cellular assays. In lung cancer cell lines A549, H520, and H460, the compound induces growth inhibition with IC50 values of 20±3.6, 21±1.8, and 15±2.7 µM, respectively. It also induces apoptosis and cell cycle arrest at G0/G1 phase. |
| ln Vivo |
Darbufelone is a dual inhibitor of LTB4 and PGF2R synthesis in cells. In animal models of inflammation and arthritis, dabufilon is both orally active and non-ulcerogenic [1]. Tumor volume decreased in mice receiving dabufilone at a dose of 80 mg/kg/day in a time-dependent manner. Conversely, dabufilone at lesser dosages (20 or 40 mg/kg/day) did not significantly reduce the weight of tumors. Mice given dabufilon (80 mg/kg/day) at necropsy showed a 30.2% decrease in tumor weight as compared to controls [2].
In vivo, Darbufelone has demonstrated anti-inflammatory and analgesic activities in animal models. In carrageenan-induced paw edema in rats, it showed dose-dependent reduction. In a mouse xenograft model of lung cancer, oral administration at 80 mg/kg/day significantly reduced tumor volume and tumor weight by 30.2% compared to controls. It also decreased angiogenesis and proliferation markers. |
| Enzyme Assay |
In cell-free enzymatic assays, COX-2 activity is measured using a chromogenic assay with arachidonic acid as substrate and purified human COX-2 enzyme. Inhibition by Darbufelone is determined by the production of prostaglandin PGE2, quantified by ELISA. For 5-LOX, the enzyme is incubated with arachidonic acid, and leukotriene B4 production is measured by HPLC. IC50 values are calculated from concentration-response curves.
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| Cell Assay |
Cell-based assays for anti-inflammatory activity use LPS-stimulated RAW 264.7 macrophages or human whole blood. Cells are treated with Darbufelone for 1 hour before LPS stimulation, and PGE2 and LTB4 levels in supernatant are measured by ELISA. Cytotoxicity is assessed by MTT. For cancer cells, A549, H520, and H460 cells are treated with various concentrations for 48-72 hours, and cell viability is determined by SRB or MTT assays.
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| Animal Protocol |
In vivo animal protocols for anti-inflammatory efficacy: male Sprague-Dawley rats are given oral doses of Darbufelone (10-100 mg/kg) 1 hour before subplantar injection of carrageenan. Paw volume is measured plethysmometrically at 0, 1, 2, 3, 4, and 6 hours. For cancer xenograft, nude mice are implanted with A549 cells subcutaneously, and when tumors reach ~100 mm³, mice are treated orally with Darbufelone at 80 mg/kg/day for 14 days.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in rats show that Darbufelone is well absorbed after oral administration with a bioavailability of ~50%. Peak plasma concentrations occur within 2 hours, and the half-life is approximately 4-6 hours. The compound is extensively metabolized by CYP450 enzymes, primarily CYP2C9 and CYP3A4. It has moderate plasma protein binding (~90%). In humans, similar PK properties are expected.
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| Toxicity/Toxicokinetics |
Toxicology studies in preclinical species indicate that Darbufelone has a better gastrointestinal safety profile than non-selective NSAIDs due to its COX-2 selectivity. In chronic studies in rats and dogs, no significant gastrointestinal lesions were observed at therapeutic doses. However, as a COX-2 inhibitor, potential cardiovascular risks cannot be ruled out. The compound was not mutagenic in Ames test.
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| References |
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| Additional Infomation |
Darbufelone mesylate is a dual COX-2/5-LOX inhibitor with molecular formula C24H25NO4S·CH4O3S (mesylate salt) and molecular weight around 491.6. It was developed by Parke-Davis as CI-1004 but did not reach market. It is available for research use only. Its dual mechanism offers anti-inflammatory action with reduced GI toxicity. It also has anticancer properties in preclinical models.
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| Molecular Formula |
C18H24N2O2S.CH4O3S
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| Molecular Weight |
428.56602
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| Exact Mass |
428.144
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| Elemental Analysis |
C, 53.25; H, 6.59; N, 6.54; O, 18.67; S, 14.96
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| CAS # |
139340-56-0
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| Related CAS # |
Darbufelone;139226-28-1
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| PubChem CID |
6439420
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| Appearance |
White to light yellow solid powder
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| Boiling Point |
448.6ºC at 760mmHg
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| Flash Point |
225.1ºC
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| Vapour Pressure |
1.16E-08mmHg at 25°C
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| LogP |
5.139
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
609
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)(C)C1=CC(=CC(=C1O)C(C)(C)C)/C=C\2/C(=O)N=C(S2)N.CS(=O)(=O)O
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| InChi Key |
BAZGFSKJAVQJJI-CHHCPSLASA-N
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| InChi Code |
InChI=1S/C18H24N2O2S.CH4O3S/c1-17(2,3)11-7-10(8-12(14(11)21)18(4,5)6)9-13-15(22)20-16(19)23-13;1-5(2,3)4/h7-9,21H,1-6H3,(H2,19,20,22);1H3,(H,2,3,4)/b13-9-;
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| Chemical Name |
(5Z)-2-amino-5-[(3,5-ditert-butyl-4-hydroxyphenyl)methylidene]-1,3-thiazol-4-one;methanesulfonic acid
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| Synonyms |
Darbufelone mesylate; CI-1004; CI 1004; CI1004; Darbufelone mesilate; 139340-56-0; CI-1,004; PD-136095-0073; 5I2Y40C5PX;
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 : ~110 mg/mL (~256.7 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5.5 mg/mL (12.83 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 55.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3333 mL | 11.6667 mL | 23.3334 mL | |
| 5 mM | 0.4667 mL | 2.3333 mL | 4.6667 mL | |
| 10 mM | 0.2333 mL | 1.1667 mL | 2.3333 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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