Sirolimus (T3D2921)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (4)XML
Targets (4)
Record Information
Version2.0
Creation Date2009-07-21 20:27:53 UTC
Update Date2014-12-24 20:25:53 UTC
Accession NumberT3D2921
Identification
Common NameSirolimus
ClassSmall Molecule
DescriptionA macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [PubChem]
Compound Type
  • Amide
  • Amine
  • Anti-Bacterial Agent
  • Antibiotic, Antineoplastic
  • Antifungal Agent
  • Drug
  • Ester
  • Ether
  • Immunosuppressive Agent
  • Macrolide
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
(-)-Rapamycin
Rapamune
Rapamycin
Chemical FormulaC51H79NO13
Average Molecular Mass914.172 g/mol
Monoisotopic Mass913.555 g/mol
CAS Registry Number53123-88-9
IUPAC Name1,18-dihydroxy-12-[1-(4-hydroxy-3-methoxycyclohexyl)propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0⁴,⁹]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Traditional Namesirolimus
SMILESCOC1CC(CC(C)C2CC(=O)C(C)C=C(C)C(O)C(OC)C(=O)C(C)CC(C)C=CC=CC=C(C)C(CC3CCC(C)C(O)(O3)C(=O)C(=O)N3CCCCC3C(=O)O2)OC)CCC1O
InChI IdentifierInChI=1S/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,31-17-,35-25+
InChI KeyInChIKey=QFJCIRLUMZQUOT-LYULEKIKSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassMacrolide lactams
Sub ClassNot Available
Direct ParentMacrolide lactams
Alternative Parents
Substituents
  • Macrolide lactam
  • Alpha-amino acid ester
  • Macrolide
  • Alpha-amino acid or derivatives
  • Cyclohexanol
  • Oxane
  • Piperidine
  • Cyclic alcohol
  • Tertiary carboxylic acid amide
  • Cyclic ketone
  • Secondary alcohol
  • Carboxamide group
  • Carboxylic acid ester
  • Hemiacetal
  • Ketone
  • Lactam
  • Lactone
  • Organoheterocyclic compound
  • Azacycle
  • Carboxylic acid derivative
  • Oxacycle
  • Dialkyl ether
  • Ether
  • Monocarboxylic acid or derivatives
  • Organopnictogen compound
  • Alcohol
  • Organic oxygen compound
  • Carbonyl group
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Kidney
  • Liver
PathwaysNot Available
Applications
Biological Roles
Chemical Roles
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point183-185°C
Boiling PointNot Available
Solubility1.73e-03 g/L
LogP4.3
Predicted Properties
PropertyValueSource
Water Solubility0.0017 g/LALOGPS
logP4.85ALOGPS
logP7.45ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)9.96ChemAxon
pKa (Strongest Basic)-3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area195.43 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity250.66 m³·mol⁻¹ChemAxon
Polarizability100.33 ųChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03dj-0100000096-ee92635155740a3e55332019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01r2-1400000391-8099eb53cfe07137682c2019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0554-6200000290-a5517df584d3fbfaa9642019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0000000039-67b87ac814904521227d2019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03dj-0000000093-1ad01a0ea8fb27c83cc12019-02-23View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-014m-0000000090-06a0d2b6a142f1563e8c2019-02-23View Spectrum
Toxicity Profile
Route of ExposureOral
Mechanism of ToxicitySirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.
Metabolism Half Life: 57-63 hours
Toxicity ValuesLD50: >800 mg/kg (oral, rat) (7) LD50: >800 mg/kg (oral, mice) (7)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed to prevent rejection in organ transplantation; it is especially useful in kidney transplants. [Wikipedia]
Minimum Risk LevelNot Available
Health EffectsIncreased susceptibility to infection, lymphoma, and malignancy; bronchial anastomotic dehiscence in lung transplant patients; decline in renal function in long-term combination of cyclosporine with Rapamune; proteinuria. (7)
SymptomsThe most common ( ≥ 30%) adverse reactions observed with Rapamune in clinical studies are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. (7)
TreatmentGeneral supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. (8)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00877
HMDB IDHMDB15015
PubChem Compound ID46835353
ChEMBL IDCHEMBL413
ChemSpider ID21864757
KEGG IDC07909
UniProt IDNot Available
OMIM ID
ChEBI ID9168
BioCyc IDNot Available
CTD IDNot Available
Stitch IDSirolimus
PDB IDRAP
ACToR IDNot Available
Wikipedia LinkSirolimus
References
Synthesis Reference

Madhup K. Dhaon, Chi-nung Hsiao, Subhash R. Patel, Peter J. Bonk, Sanjay R. Chemburkar, Yong Y. Chen, “One pot synthesis of tetrazole derivatives of sirolimus.” U.S. Patent US20080167335, issued July 10, 2008.

MSDST3D2921.pdf
General References
  1. Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [15896681 ]
  2. Shuchman M: Trading restenosis for thrombosis? New questions about drug-eluting stents. N Engl J Med. 2006 Nov 9;355(19):1949-52. [17093244 ]
  3. Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005 Aug 15;65(16):7052-8. [16103051 ]
  4. Chan S: Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004 Oct 18;91(8):1420-4. [15365568 ]
  5. Graziani EI: Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs. Nat Prod Rep. 2009 May;26(5):602-9. doi: 10.1039/b804602f. Epub 2009 Mar 5. [19387497 ]
  6. Drugs.com [Link]
  7. RxList. Rapamune [Link]
  8. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

Target Details
1. Serine/threonine-protein kinase mTOR
General Function:
Tfiiic-class transcription factor binding
Specific Function:
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity).
Gene Name:
MTOR
Uniprot ID:
P42345
Molecular Weight:
288889.05 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.0001 uMNot AvailableBindingDB 36609
IC500.00045 uMNot AvailableBindingDB 36609
IC500.0035 uMNot AvailableBindingDB 36609
References
  1. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N: Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 2010 Mar;1804(3):433-9. doi: 10.1016/j.bbapap.2009.12.001. Epub 2009 Dec 11. [20005306 ]
  2. Shuuin T, Karashima H: [Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma]. Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9. [19620795 ]
  3. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. [12742462 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  5. Edwards SR, Wandless TJ: The rapamycin-binding domain of the protein kinase mammalian target of rapamycin is a destabilizing domain. J Biol Chem. 2007 May 4;282(18):13395-401. Epub 2007 Mar 9. [17350953 ]
  6. Nicolaou KC: Joys of molecules. 2. Endeavors in chemical biology and medicinal chemistry. J Med Chem. 2005 Sep 8;48(18):5613-38. [16134928 ]
  7. Rabinowitz M, Seneci P, Rossi T, Dal Cin M, Deal M, Terstappen G: Solid-phase/solution-phase combinatorial synthesis of neuroimmunophilin ligands. Bioorg Med Chem Lett. 2000 May 15;10(10):1007-10. [10843203 ]
Target Details
2. Peptidyl-prolyl cis-trans isomerase FKBP1A
General Function:
Type i transforming growth factor beta receptor binding
Specific Function:
Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Gene Name:
FKBP1A
Uniprot ID:
P62942
Molecular Weight:
11950.665 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0002 uMNot AvailableBindingDB 36609
Inhibitory0.001 uMNot AvailableBindingDB 36609
IC500.00045 uMNot AvailableBindingDB 36609
IC500.0006 uMNot AvailableBindingDB 36609
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Nicolaou KC: Joys of molecules. 2. Endeavors in chemical biology and medicinal chemistry. J Med Chem. 2005 Sep 8;48(18):5613-38. [16134928 ]
  3. Sedrani R, Jones LH, Jutzi-Eme AM, Schuler W, Cottens S: Cleavage of the cyclohexyl-subunit of rapamycin results in loss of immunosuppressive activity. Bioorg Med Chem Lett. 1999 Feb 8;9(3):459-62. [10091702 ]
  4. Hamilton GS, Steiner JP: Immunophilins: beyond immunosuppression. J Med Chem. 1998 Dec 17;41(26):5119-43. [9857082 ]
  5. Luengo JI, Yamashita DS, Dunnington D, Beck AK, Rozamus LW, Yen HK, Bossard MJ, Levy MA, Hand A, Newman-Tarr T, et al.: Structure-activity studies of rapamycin analogs: evidence that the C-7 methoxy group is part of the effector domain and positioned at the FKBP12-FRAP interface. Chem Biol. 1995 Jul;2(7):471-81. [9383449 ]
  6. Chen YW, Smith ML, Sheets M, Ballaron S, Trevillyan JM, Burke SE, Rosenberg T, Henry C, Wagner R, Bauch J, Marsh K, Fey TA, Hsieh G, Gauvin D, Mollison KW, Carter GW, Djuric SW: Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol. 2007 Apr;49(4):228-35. [17438408 ]
Target Details
3. Eukaryotic translation initiation factor 4E
General Function:
Translation initiation factor activity
Specific Function:
Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap.
Gene Name:
EIF4E
Uniprot ID:
P06730
Molecular Weight:
25097.07 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Dissociation0.0005 uMNot AvailableBindingDB 36609
References
  1. Sadovski O, Jaikaran AS, Samanta S, Fabian MR, Dowling RJ, Sonenberg N, Woolley GA: A collection of caged compounds for probing roles of local translation in neurobiology. Bioorg Med Chem. 2010 Nov 15;18(22):7746-52. doi: 10.1016/j.bmc.2010.04.005. Epub 2010 Apr 7. [20427189 ]
Target Details
4. Fibroblast growth factor 2
General Function:
Ligand-dependent nuclear receptor transcription coactivator activity
Specific Function:
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro.
Gene Name:
FGF2
Uniprot ID:
P09038
Molecular Weight:
30769.715 Da
References
  1. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. [12742462 ]