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Purity: ≥98%
Chloroquine is reported to be highly effective in combating SARS-CoV-2 (COVID-19, CoronaVirus, or the COVID-19 pandemic) infections in vitro. It acts as a potent autophagy and toll-like receptors (TLRs) inhibitor, and a 4-aminoquinoline anti-malarial medication used to prevent and to treat malaria in areas where malaria is known to be sensitive to its effects. It is also an anti-rheumatoid agent, also acting as an ATM activator. Chloroquine diphosphate has been reported as an adjuvant for radiation and chemotherapy for inducing cell autophagy to anti-cancer cells proliferation or metastasis. The mechanism of chloroquine diphosphate inducing cells autophagy is arresting cells in G1, up-regulates the expression of p27 and p53 while down-regulates the expression of CDK2 and cyclin D1. Chloroquine is also a lysosomal inhibitor and is widely used for studying the mechanism of action for targeted protein degradation.
| Targets |
Antiviral; Plasmodium; SARS-COV-2; Malaria; TLRs; HIV-1
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| ln Vitro |
Activated human monocyte-derived Langerhans-like cells (MoLC) have a reduced Th1 priming capacity and are less able to release IL-12p70 when exposed to 20 μM of chloroquine (CHQ). Chloroquine (20 μM) simultaneously stimulates the release of IL-17A from CD4+ T cells and improves the IL-1-induced IL-23 in MoLC [1]. In parental MDA-MB-231 cells, MMP-9 mRNA expression is inhibited by 25 μM of chloroquine under both normoxic and hypoxic conditions. The effects of chloroquine on MMP-2, MMP-9, and MMP-13 mRNA are depending on cell expression, dosage, and hypoxia [2]. Significantly less HuH7 cell proliferation was observed in vitro when TLR7 and TLR9 were inhibited with IRS-954 or chloroquine [3]. At low micromolar doses (EC50=1.13 μM), chloroquine (0.01–100 μM; 48 hours) inhibits SARS-CoV-2 infection and efficiently blocks virus infection in vero E6 cells. By raising the endosomal pH needed for virus/cell fusion and interfering with the glycosylation of SARS-CoV cell acquisition, chloroquine causes viral infection [4].
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| ln Vivo |
In an orthotopic mouse model, chloroquine (80 mg/kg, ip) does not stop triple-negative MDA-MB-231 cells from growing, regardless of how much TLR9 is expressed [2]. The growth of tumor xenograft models was considerably decreased by IRS-954 or chloroquine-induced TLR7 and TLR9 inhibition. Additionally, in the DEN/NMOR tumor model, chloroquine greatly reduces the formation of HCC [3].
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| Enzyme Assay |
Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro.[2]
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| Cell Assay |
In this study, we investigated the effect of CHQ on human monocyte-derived Langerhans-like cells (MoLC) and dendritic cells (MoDC) in response to IL-1β. The presence of CHQ reduced IL-12p70 release in both subsets, but surprisingly increased IL-6 production in MoDC and IL-23 in MoLC. Importantly, CHQ-treated MoLC promoted IL-17A secretion by CD4(+) T cells and elevated RORC mRNA levels, whereas IFN-γ release was reduced. The dysregulation of IL-12 family cytokines in MoLC and MoDC occurred at the transcriptional level. Similar effects were obtained with other late autophagy inhibitors, whereas PI3K inhibitor 3-methyladenine failed to increase IL-23 secretion. The modulated cytokine release was dependent on IL-1 cytokine activation and abrogated by a specific IL-1R antagonist. CHQ elevated expression of TNFR-associated factor 6, a common intermediate in IL-1R and TLR-dependent signaling. Accordingly, treatment with Pam3CSK4 and CHQ enhanced IL-23 release in MoLC and MoDC. CHQ inhibited autophagic flux, confirmed by increased LC3-II and p62 expression, and activated ERK, p38, and JNK MAPK, but only inhibition of p38 abrogated IL-23 release by MoLC. Thus, our findings indicate that CHQ modulates cytokine release in a p38-dependent manner, suggesting an essential role of Langerhans cells and dendritic cells in CHQ-provoked psoriasis, possibly by promoting Th17 immunity.[1]
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| Animal Protocol |
Control and TLR9 siRNA MDA-MB-231 cells (5×105 cells in 100 μl) were inoculated into the mammary fat pads of four-week-old, immune-deficient mice (athymic nude/nu Foxn1; Harlan Sprague Dawley, Inc., Indianapolis, IN, USA). Treatments were started seven days after tumor cell inoculation. The mice were treated daily either with intraperitoneal (i.p.) chloroquine (80 mg/kg) or vehicle (PBS). The animals were monitored daily for clinical signs. Tumor measurements were performed twice a week and tumor volume was calculated according to the formula V = (π / 6) (d1 × d2)3/2, where d1 and d2 are perpendicular tumor diameters (9). The tumors were allowed to grow for 22 days, at which point the mice were sacrificed and the tumors were dissected for a final measurement. Throughout the experiments, the animals were maintained under controlled pathogen-free environmental conditions (20–21ºC, 30–60% relative humidity and a 12-h lighting cycle). The mice were fed with small-animal food pellets (Harlan Sprague Dawley) and supplied with sterile water ad libitum. The experimental procedures were reviewed and approved by the University of Alabama at Birmingham Institutional Animal Care and Use Committee.[2]
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| References |
[1]. Said A, et al. Chloroquine promotes IL-17 production by CD4+ T cells via p38-dependent IL-23 release by monocyte-derived Langerhans-like cells. J Immunol. 2014 Dec 15;193(12):6135-43.
[2]. Tuomela J, et al. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer. Oncol Lett. 2013 Dec;6(6):1665-1672. [3]. Mohamed FE, et al. Effect of toll-like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma. Liver Int. 2014 Jul 2. doi: 10.1111/liv.12626. [4]. Colson P, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020;55(4):105932. [5]. Savarino A, et al. The anti-HIV-1 activity of chloroquine. J Clin Virol. 2001;20(3):131-135. |
| Additional Infomation |
Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia.[2]
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| Molecular Formula |
C18H26CLN3
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|---|---|
| Molecular Weight |
319.87
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| Exact Mass |
319.1815
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| Elemental Analysis |
C, 67.59; H, 8.19; Cl, 11.08; N, 13.14
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| CAS # |
54-05-7
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| Related CAS # |
Chloroquine phosphate;50-63-5;Chloroquine-d5;1854126-41-2;Chloroquine dihydrochloride;3545-67-3;Chloroquine-d5 diphosphate; 132-73-0 (sulfate); 1854126-42-3; 54-05-7 ;151-69-9 (acetate) ; 1446-17-9 (phosphate); 3545-67-3 (HCl) ; 50-63-5 (diphosphate) ;
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| PubChem CID |
2719
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| Appearance |
Typically exists as white to light yellow solids at room temperature
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
460.6±40.0 °C at 760 mmHg
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| Melting Point |
87ºC
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| Flash Point |
232.3±27.3 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.592
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| LogP |
4.7
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| tPSA |
28.16
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| SMILES |
CC(NC1=CC=NC2=CC(Cl)=CC=C12)CCCN(CC)CC
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| InChi Key |
WHTVZRBIWZFKQO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H26ClN3/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21)
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| Chemical Name |
N4-(7-chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine
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| Synonyms |
RP 3377; RP-3377; RP3377;Imagon; NSC 187208; NSC-187208; NSC187208;
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
Ethanol : ~100 mg/mL (~312.63 mM)
DMSO : ~50 mg/mL (~156.31 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.82 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 (7.82 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (7.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (31.26 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; Need ultrasonic and warming and heat to 44°C. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1263 mL | 15.6314 mL | 31.2627 mL | |
| 5 mM | 0.6253 mL | 3.1263 mL | 6.2525 mL | |
| 10 mM | 0.3126 mL | 1.5631 mL | 3.1263 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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