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Record Information
Version2.0
Creation Date2009-07-30 17:58:49 UTC
Update Date2014-12-24 20:26:07 UTC
Accession NumberT3D3498
Identification
Common NameCyclosporin
ClassSmall Molecule
DescriptionA 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. Cyclosporine is produced as a metabolite by the fungus species Cordyceps militaris. (From Martindale, The Extra Pharmacopoeia, 30th ed).
Compound Type
  • Amide
  • Amine
  • Antifungal Agent
  • Antirheumatic Agent
  • Dermatologic Agent
  • Drug
  • Enzyme Inhibitor
  • Fungal Toxin
  • Immunomodulatory Agent
  • Immunosuppressive Agent
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Ciclosporin
CsA
CyA
Cyclosporin A
Gengraf
Neoral
Restasis
Sandimmune
Sangcya
Chemical FormulaC62H111N11O12
Average Molecular Mass1202.611 g/mol
Monoisotopic Mass1201.841 g/mol
CAS Registry Number59865-13-3
IUPAC Name30-ethyl-14,17,23,32-tetrahydroxy-33-[(4E)-1-hydroxy-2-methylhex-4-en-1-yl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-bis(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriaconta-13,16,22,31-tetraene-2,5,8,11,20,26,29-heptone
Traditional Name30-ethyl-14,17,23,32-tetrahydroxy-33-[(4E)-1-hydroxy-2-methylhex-4-en-1-yl]-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriaconta-13,16,22,31-tetraene-2,5,8,11,20,26,29-heptone
SMILES[H]\C(C)=C(\[H])CC(C)C(O)C1N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)N=C(O)C(C)N=C(O)C(CC(C)C)N(C)C(=O)C(N=C(O)C(CC(C)C)N(C)C(=O)CN(C)C(=O)C(CC)N=C1O)C(C)C
InChI IdentifierInChI=1/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+
InChI KeyInChIKey=PMATZTZNYRCHOR-IMVLJIQENA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as cyclosporins. These are cyclic depsipeptides containing the cyclosporin backbone.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassPeptidomimetics
Sub ClassPeptoid-peptide hybrids
Direct ParentCyclosporins
Alternative Parents
Substituents
  • Cyclosporin-backbone
  • Alpha-oligopeptide
  • Macrolactam
  • Alpha-amino acid or derivatives
  • Tertiary carboxylic acid amide
  • Carboxamide group
  • Lactam
  • Secondary alcohol
  • Secondary carboxylic acid amide
  • Carboxylic acid derivative
  • Azacycle
  • Organoheterocyclic compound
  • Organonitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Alcohol
  • Organic oxygen compound
  • Carbonyl group
  • Organooxygen compound
  • Organic nitrogen compound
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
  • Non-ribosomal peptide/polyketide hybrids (C05086 )
  • Non-ribosomal peptide/polyketide hybrids (LMPK14000003 )
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point148-151°C
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0058 g/LALOGPS
logP4.37ALOGPS
logP6.92ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.69ChemAxon
pKa (Strongest Basic)1.94ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count16ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area292.76 ŲChemAxon
Rotatable Bond Count15ChemAxon
Refractivity329.23 m³·mol⁻¹ChemAxon
Polarizability131.92 ųChemAxon
Number of Rings1ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
Toxicity Profile
Route of ExposureThe absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. The extent of absorption is dependent on the individual patient, the patient population, and the formulation. The absolute bioavailability of cyclosproine administered as Sandimmune™ is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The cyclosporine capsules and oral solution are bioequivalent. The time of peak blood concentrations (Tmax) following oral administration of cyclosporine [modified] ranged from 1.5 - 2.0 hours.
Mechanism of ToxicityCyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.
MetabolismHepatic, extensively metabolized by the cytochrome P450 3A enzyme system in the liver. It is also metabolized in the gastrointestinal tract and kidney to a lesser degree. The metabolites are significantly less potent than the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. Route of Elimination: Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Only 0.1% of the dose is excreted in the urine as unchanged drug. Half Life: Biphasic and variable, approximately 7 hours (range 7 to 19 hours) in children and approximately 19 hours (range 10 to 27 hours) in adults.
Toxicity ValuesThe oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)1, carcinogenic to humans. (6)
Uses/SourcesFor treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsThe oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00091
HMDB IDNot Available
PubChem Compound ID6435893
ChEMBL IDCHEMBL160
ChemSpider IDNot Available
KEGG IDC05086
UniProt IDNot Available
OMIM ID
ChEBI ID4031
BioCyc IDNot Available
CTD IDNot Available
Stitch IDCyclosporin
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkCyclosporine
References
Synthesis Reference

Hans Dietl, “Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and a process for its production.” U.S. Patent US5527537, issued October, 1990.

MSDST3D3498.pdf
General References
  1. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994 Jun 30;330(26):1841-5. [8196726 ]
  2. Husi H, Schorgendorfer K, Stempfer G, Taylor P, Walkinshaw MD: Prediction of substrate-specific pockets in cyclosporin synthetase. FEBS Lett. 1997 Sep 15;414(3):532-6. [9323029 ]
  3. Drugs.com [Link]
  4. Patent Genius (2006). Cyclosporin with improved activity profile. [Link]
  5. Pubmed [Link]
  6. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
References
  1. Grenier J, Fradette C, Morelli G, Merritt GJ, Vranderick M, Ducharme MP: Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharmacol Ther. 2006 Mar;79(3):255-62. Epub 2006 Feb 7. [16513449 ]
  2. Bachmakov I, Werner U, Endress B, Auge D, Fromm MF: Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol. 2006 Jun;20(3):273-82. [16671962 ]
  3. Kotrych K, Masiuk M, Domanski L, Rozanski J, Drozdzik M: Peripheral blood lymphocytes P-glycoprotein (P-gp, gp-170) expression in allogenic kidney transplant patients. Nephrology (Carlton). 2006 Jun;11(3):257-60. [16756642 ]
  4. Thuerauf N, Fromm MF: The role of the transporter P-glycoprotein for disposition and effects of centrally acting drugs and for the pathogenesis of CNS diseases. Eur Arch Psychiatry Clin Neurosci. 2006 Aug;256(5):281-6. [16783494 ]
  5. Nagira M, Tomita M, Mizuno S, Kumata M, Ayabe T, Hayashi M: Ischemia/reperfusion injury in the monolayers of human intestinal epithelial cell line caco-2 and its recovery by antioxidants. Drug Metab Pharmacokinet. 2006 Jun;21(3):230-7. [16858127 ]
General Function:
Virion binding
Specific Function:
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Gene Name:
PPIA
Uniprot ID:
P62937
Molecular Weight:
18012.42 Da
References
  1. Keckesova Z, Ylinen LM, Towers GJ: Cyclophilin A renders human immunodeficiency virus type 1 sensitive to Old World monkey but not human TRIM5 alpha antiviral activity. J Virol. 2006 May;80(10):4683-90. [16641261 ]
  2. Patwardhan AM, Jeske NA, Price TJ, Gamper N, Akopian AN, Hargreaves KM: The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11393-8. Epub 2006 Jul 18. [16849427 ]
  3. Redell JB, Zhao J, Dash PK: Acutely increased cyclophilin a expression after brain injury: a role in blood-brain barrier function and tissue preservation. J Neurosci Res. 2007 Jul;85(9):1980-8. [17461417 ]
  4. Schaller T, Ylinen LM, Webb BL, Singh S, Towers GJ: Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses. J Virol. 2007 Sep;81(18):10055-63. Epub 2007 Jul 3. [17609268 ]
General Function:
Photoreceptor activity
Specific Function:
Not Available
Gene Name:
Not Available
Uniprot ID:
P93098
Molecular Weight:
144705.43 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Wang S, Lu B, Wood P, Lund RD: Grafting of ARPE-19 and Schwann cells to the subretinal space in RCS rats. Invest Ophthalmol Vis Sci. 2005 Jul;46(7):2552-60. [15980247 ]
General Function:
Calcium ion binding
Specific Function:
Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity (By similarity).
Gene Name:
PPP3R2
Uniprot ID:
Q96LZ3
Molecular Weight:
19533.065 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
General Function:
Not Available
Specific Function:
Likely involved in the mobilization of calcium as a result of the TCR/CD3 complex interaction. Binds to cyclophilin B.
Gene Name:
CAMLG
Uniprot ID:
P49069
Molecular Weight:
32952.255 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
General Function:
Peptidyl-prolyl cis-trans isomerase activity
Specific Function:
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probability of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.
Gene Name:
PPIF
Uniprot ID:
P30405
Molecular Weight:
22040.09 Da
References
  1. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW: Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984 Nov 2;226(4674):544-7. [6238408 ]
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP). Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:
SLCO1B3
Uniprot ID:
Q9NPD5
Molecular Weight:
77402.175 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory1.2 uMNot AvailableBindingDB 86672
References
  1. Letschert K, Komatsu M, Hummel-Eisenbeiss J, Keppler D: Vectorial transport of the peptide CCK-8 by double-transfected MDCKII cells stably expressing the organic anion transporter OATP1B3 (OATP8) and the export pump ABCC2. J Pharmacol Exp Ther. 2005 May;313(2):549-56. Epub 2005 Jan 21. [15665139 ]