Cyclosporin
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Basic Info
| Common Name | Cyclosporin (F04845) |
| 2D Structure | |
| Description | 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. Cyclosporine is produced as a metabolite by the fungus species Cordyceps militaris. (From Martindale, The Extra Pharmacopoeia, 30th ed). |
| FRCD ID | F04845 |
| CAS Number | 59865-13-3 |
| PubChem CID | 6435893 |
| Formula | C62H111N11O12 |
| IUPAC Name | 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 |
| InChI Key | PMATZTZNYRCHOR-KMSBSJHKSA-N |
| InChI | 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 |
| Canonical SMILES | CCC1C(=O)N(CC(=O)N(C(C(=O)NC(C(=O)N(C(C(=O)NC(C(=O)NC(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N1)C(C(C)CC=CC)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C |
| Isomeric SMILES | CCC1C(=O)N(CC(=O)N(C(C(=O)NC(C(=O)N(C(C(=O)NC(C(=O)NC(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N1)[C@@H]([C@H](C)C/C=C/C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C |
| Wikipedia | Cyclosporin |
| Synonyms |
SangCyA
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
cyclosporine
Cyclosporin
Restasis
Cyclosporine (Neoral)
Gengraf
Sandimmune
79217-60-0
Neoral
|
| Classifies |
Fungal Toxin
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Organic acids and derivatives |
| Class | Peptidomimetics |
| Subclass | Peptoid-peptide hybrids |
| Intermediate Tree Nodes | Not available |
| Direct Parent | Cyclosporins |
| Alternative Parents | |
| Molecular Framework | Aliphatic heteromonocyclic compounds |
| 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 |
| Description | This compound belongs to the class of organic compounds known as cyclosporins. These are cyclic depsipeptides containing the cyclosporin backbone. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 1202.635 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 12 |
| Rotatable Bond Count | 15 |
| Complexity | 2330 |
| Monoisotopic Mass | 1201.841 |
| Exact Mass | 1201.841 |
| XLogP | 7.5 |
| Formal Charge | 0 |
| Heavy Atom Count | 85 |
| Defined Atom Stereocenter Count | 2 |
| Undefined Atom Stereocenter Count | 10 |
| Defined Bond Stereocenter Count | 1 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB- | 0.9659 |
| Human Intestinal Absorption | HIA+ | 0.8727 |
| Caco-2 Permeability | Caco2- | 0.6994 |
| P-glycoprotein Substrate | Substrate | 0.8463 |
| P-glycoprotein Inhibitor | Inhibitor | 0.8685 |
| Non-inhibitor | 0.5992 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.9485 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.5714 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.8628 |
| CYP450 2D6 Substrate | Non-substrate | 0.8823 |
| CYP450 3A4 Substrate | Substrate | 0.6407 |
| CYP450 1A2 Inhibitor | Non-inhibitor | 0.9045 |
| CYP450 2C9 Inhibitor | Non-inhibitor | 0.9230 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9265 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.9026 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.6112 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.9968 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9815 |
| Non-inhibitor | 0.9214 | |
| AMES Toxicity | Non AMES toxic | 0.9133 |
| Carcinogens | Non-carcinogens | 0.8948 |
| Fish Toxicity | High FHMT | 0.5220 |
| Tetrahymena Pyriformis Toxicity | High TPT | 0.9670 |
| Honey Bee Toxicity | Low HBT | 0.6971 |
| Biodegradation | Not ready biodegradable | 0.9244 |
| Acute Oral Toxicity | III | 0.7726 |
| Carcinogenicity (Three-class) | Non-required | 0.5869 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -1.7659 | LogS |
| Caco-2 Permeability | 0.1822 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 2.8788 | LD50, mol/kg |
| Fish Toxicity | 1.8635 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | 0.2444 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Ochratoxin A-Induced Apoptosis of IPEC-J2 Cells through ROS-Mediated Mitochondrial Permeability Transition Pore Opening Pathway. | J Agric Food Chem | 2017 Dec 6 | 29136370 |
| Inhibitory effects of Cnidium monnieri fruit extract on pulmonary inflammation in mice induced by cigarette smoke condensate and lipopolysaccharide. | Chin J Nat Med | 2014 Sep | 25263974 |
| Transcellular transport of aconitine across human intestinal Caco-2 cells. | Food Chem Toxicol | 2013 Jul | 23562926 |
| Effect of biotherapeutics on cyclosporin-induced Clostridium difficile infection in mice. | J Gastroenterol Hepatol | 2010 Apr | 20074161 |
| An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells. | Int J Pharm | 2009 Jan 21 | 18840516 |
| Don't live in a town where there are no doctors: toxic epidermal necrolysis initially misdiagnosed as oral thrush. | BMJ Case Rep | 2009 | 22207871 |
| Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes. | Eur J Pharmacol | 2006 Jan 4 | 16325799 |
| Oxidative metabolism by P450 and function coupling to efflux systems: modulation of mycotoxin toxicity. | Food Addit Contam | 2005 Apr | 16019806 |
| Do calcium-mediated cellular signalling pathways, prostaglandin E2 (PGE2), estrogen or progesterone receptor antagonists, or bacterial endotoxins affect bovine placental function in vitro? | Prostaglandins Other Lipid Mediat | 2004 Apr | 15287156 |
| Immunosuppressive treatment affects cardiac and skeletal muscle mitochondria by the toxic effect of vehicle. | J Mol Cell Cardiol | 2000 Feb | 10722807 |
| Molecular mechanisms of butylated hydroxylanisole-induced toxicity: induction of apoptosis through direct release of cytochrome c. | Mol Pharmacol | 2000 Aug | 10908312 |
| Superinduction of IL-2 gene expression by vomitoxin (deoxynivalenol) involves increased mRNA stability. | Toxicol Appl Pharmacol | 1997 Dec | 9439728 |
| Modulation of immune cell proliferation by glycerol monolaurate. | Clin Diagn Lab Immunol | 1996 Jan | 8770497 |
| Adverse drug interactions clinically important for the dermatologist. | Arch Dermatol | 1995 Apr | 7726592 |
| Skeletal growth and bone density as sensitive parameters in experimental arthritis: effect of cyclosporin A. | Bone | 1994 Nov-Dec | 7873291 |
| Dose-response and concentration-response relationships: clinical and regulatory perspectives. | Ther Drug Monit | 1993 Dec | 8122284 |
| Therapeutic drug monitoring of cyclosporin. Practical applications and limitations. | Clin Pharmacokinet | 1989 Jan | 2650953 |
Targets
- General Function:
- Photoreceptor activity
- Uniprot ID:
- P93098
- Molecular Weight:
- 144705.43 Da
- Mechanism of Action:
- Cyclosporine binds to cyclophillin. 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.
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
- 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
- Mechanism of Action:
- Cyclosporine binds to cyclophillin. 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.
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
- 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
- Mechanism of Action:
- Cyclosporine binds to cyclophillin. 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.
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
- 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
- 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
References
- 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 ]
- 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
- Mechanism of Action:
- Cyclosporine binds to cyclophillin. 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.
References
- 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 ]
- 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
- Mechanism of Action:
- Cyclosporine binds to cyclophillin. 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.
References
- 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 ]