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Purity: ≥98%
Cyclosporin A (Cyclosporine A; CsA) is a naturally occuring cyclic polypeptide immunosuppressive agent and a calcineurin inhibitor, which binds to the cyclophilin and then inhibits calcineurin with IC50 of 7 nM in a cell-free assay. It is widely used in organ transplantation to prevent rejection. Cyclosporin A can also be used for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, and in organ transplants to prevent rejection. Cyclosporin A is responsible for the opening of the MPTP (mitochondrial permeability transition pore). When tested with retinal ganglion cells, Cyclosporin A showed a high selectivity for the expression of cyclophilin D and prolonged the cells survival. In human First-Trimester Trophoblast Cells, Cyclosporin A treatment promoted cells growth and invasiveness by inhibiting Ca2+/Calcineurin/NFAT signal. Cyclosporin A treatment promoted the apoptosis of T-cell by upregulating Fas/FasL and caspase activities
Targets |
Cyclophilin D; phosphatase activity of protein phosphatase 2B (PP2B/calcineurin)
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ln Vitro |
In T cells, cyclophilin and cyclosporin A can bind [1]. By creating the Cyclophilin-Cyclosporin A complex, cyclosporin A inhibits calcineurin [2]. With an IC50 value of 7 nM, cyclosporin A inhibits calcineurin in activated cells [3]. Cyclosporin A prevents NF-AT from moving to the nucleus [4]. With an IC50 of 39 nM, cyclosporin A inhibits mitochondrial MTP opening [5].
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ln Vivo |
When administered parenterally or orally to mice, rats, and guinea pigs, cyclosporine A exerts immunosuppressive effects [6]. In organ transplantation, cyclosporine A can be given to stop organ rejection [7].
The mouse model of pleurisy induced by carrageenan is characterized by a significant enhancement of cell migration due to neutrophils 4 h after pleurisy induction. Forty-eight hours after pleurisy induction, a significant increase in cell migration due to mononuclear cells occurs. Recently, studies in our laboratory have demonstrated that cyclosporine A (CsA) inhibits leukocyte migration in the pleural cavity and lungs in the mouse model of pleurisy induced by carrageenan. In the present work we evaluated whether CsA was able to downregulate CD11a/CD18 adhesion molecule in the lungs, as well as TNFalpha and IL-1 beta levels in the fluid leakage of the pleural cavity in this model. Our results showed that CsA significantly decreased CD11a/CD18 in the lungs, as well as TNFalpha and IL-1 beta levels in the fluid leakage of the pleural cavity 4 h and 48 h after pleurisy induction. It is our hypothesis that the inhibitory effect elicited by CsA upon these adhesion molecules may be also be attributed to the downregulation of TNFalpha and IL-1 beta cytokines[8]. |
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Enzyme Assay |
Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism[1].
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Cell Assay |
The immunosuppressive agents cyclosporin A (CsA) and FK 506 bind to distinct families of intracellular proteins (immunophilins) termed cyclophilins and FK 506-binding proteins (FKBPs). Recently, it has been shown that, in vitro, the complexes of CsA-cyclophilin and FK 506-FKBP-12 bind to and inhibit the activity of calcineurin, a calcium-dependent serine/threonine phosphatase. We have investigated the effects of drug treatment on phosphatase activity in T lymphocytes. Calcineurin is expressed in T cells, and its activity can be measured in cell lysates. Both CsA and FK 506 specifically inhibit cellular calcineurin at drug concentrations that inhibit interleukin 2 production in activated T cells. Rapamycin, which binds to FKBPs but exhibits different biological activities than FK 506, has no effect on calcineurin activity. Furthermore, excess concentrations of rapamycin prevent the effects of FK 506, apparently by displacing FK 506 from FKBPs. These results show that calcineurin is a target of drug-immunophilin complexes in vivo and establish a physiological role for calcineurin in T-cell activation[3].
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Animal Protocol |
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References |
[1]. Handschumacher RE, et al. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984 Nov 2;226(4674):544-7.
[2]. Liu J, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [3]. Fruman DA, et al. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3686-90. [4]. Flanagan WM, et al. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature. 1991 Aug 29;352(6338):803-7. [5]. Nicolli A, et al. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem. 1996 Jan 26;271(4):2185-92. [6]. Borel JF, et al. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977 Jun;32(6):1017-25. [7]. Williams, R, et al. Randomised trial comparing FK506 and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet, 1994, 344(8920), 423-428. [8]. Dalmarco EM, et al. Cyclosporin A inhibits CD11a/CD18 adhesion molecules due to inhibition of TNFalpha and IL-1 beta levels in the mouse model of pleurisy induced by carrageenan. Cell Adh Migr. 2008 Oct-Dec;2(4):231-5 |
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Additional Infomation |
Cyclosporin a appears as white prismatic needles (from acetone) or white powder. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Cyclosporin A is a cyclic nonribosomal peptide of eleven amino acids; an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system, and therefore the risk of organ rejection. Also causes reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. It has a role as an antifungal agent, an antirheumatic drug, a dermatologic drug, an immunosuppressive agent, a metabolite, a carcinogenic agent, an anti-asthmatic drug, an EC 3.1.3.16 (phosphoprotein phosphatase) inhibitor, an anticoronaviral agent and a geroprotector. Cyclosporine is a calcineurin inhibitor known for its immunomodulatory properties that prevent organ transplant rejection and treat various inflammatory and autoimmune conditions. It is isolated from the fungus Beauveria nivea. Initially manufactured by Sandoz and approved for use by the FDA in 1983, cyclosporine is now available in various products by Novartis (previously known as Sandoz). Cyclosporine is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of cyclosporine is as a Calcineurin Inhibitor, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor. Cyclosporine is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after solid organ transplantation. Cyclosporine therapy can be associated with mild elevations in serum bilirubin and transient serum enzyme elevations, and to rare instances of clinically apparent cholestatic liver injury. Ciclosporin is a natural product found in Trichoderma polysporum and Tolypocladium inflatum with data available. Cyclosporine is a natural cyclic polypeptide immunosuppressant isolated from the fungus Beauveria nivea. The exact mechanism of action of cyclosporine is not known but may involve binding to the cellular protein cytophilin, resulting in inhibition of the enzyme calcineurin. This agent appears to specifically and reversibly inhibit immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited with T-helper cells as the primary target. Cyclosporine also inhibits lymphokine production and release. (NCI04) Ciclosporin (Cyclosporin A; Cyclosporine) can cause cancer according to The World Health Organization's International Agency for Research on Cancer (IARC). The CA Office of Environmental Health Hazard Assessment (OEHHA) A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed). |
Molecular Formula |
C62H111N11O12
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Molecular Weight |
1202.61
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Exact Mass |
1201.84130
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Elemental Analysis |
C, 61.92; H, 9.30; N, 12.81; O, 15.96
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CAS # |
59865-13-3
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Related CAS # |
Cyclosporin A acetate-d4;Cyclosporin A-13C2,d4;Cyclosporin A-d4;Cyclosporin A-d3;222295-76-3
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PubChem CID |
5284373
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Appearance |
Typically exists as white to off-white solids at room temperature
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Density |
1.0±0.1 g/cm3
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Boiling Point |
1293.8±65.0 °C at 760 mmHg
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Melting Point |
148-151°C
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Flash Point |
736.3±34.3 °C
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Vapour Pressure |
0.0±0.6 mmHg at 25°C
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Index of Refraction |
1.468
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LogP |
3.35
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tPSA |
278.8
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SMILES |
O([H])[C@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])/C(/[H])=C(\[H])/C([H])([H])[H])[C@@]1([H])C(N([H])[C@]([H])(C(N(C([H])([H])[H])C([H])([H])C(N(C([H])([H])[H])[C@]([H])(C(N([H])[C@]([H])(C(N(C([H])([H])[H])[C@]([H])(C(N([H])[C@@]([H])(C([H])([H])[H])C(N([H])[C@]([H])(C([H])([H])[H])C(N(C([H])([H])[H])[C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])C(N(C([H])([H])[H])[C@]([H])(C(N(C([H])([H])[H])[C@]([H])(C(N1C([H])([H])[H])=O)C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)=O)=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)=O)C([H])([H])C([H])([H])[H])=O
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InChi Key |
PMATZTZNYRCHOR-CGLBZJNRSA-N
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InChi Code |
InChI=1S/C62H111N11O12/c1-25-27-28-40(15)52(75)51-56(79)65-43(26-2)58(81)67(18)33-48(74)68(19)44(29-34(3)4)55(78)66-49(38(11)12)61(84)69(20)45(30-35(5)6)54(77)63-41(16)53(76)64-42(17)57(80)70(21)46(31-36(7)8)59(82)71(22)47(32-37(9)10)60(83)72(23)50(39(13)14)62(85)73(51)24/h25,27,34-47,49-52,75H,26,28-33H2,1-24H3,(H,63,77)(H,64,76)(H,65,79)(H,66,78)/b27-25+/t40-,41+,42-,43+,44+,45+,46+,47+,49+,50+,51+,52-/m1/s1
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Chemical Name |
(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
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Synonyms |
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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. |
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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) |
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Solubility (In Vivo) |
Solubility in Formulation 1: 2.62 mg/mL (2.18 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (1.73 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 20.8 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. View More
Solubility in Formulation 3: 2.08 mg/mL (1.73 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. Solubility in Formulation 4: ≥ 2.08 mg/mL (1.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. Solubility in Formulation 5: 2% DMSO +30%PEG 300 +5% Tween 80 +ddH2O: 5mg/mL Solubility in Formulation 6: 20 mg/mL (16.63 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 0.8315 mL | 4.1576 mL | 8.3152 mL | |
5 mM | 0.1663 mL | 0.8315 mL | 1.6630 mL | |
10 mM | 0.0832 mL | 0.4158 mL | 0.8315 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.