Tmic
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Record Information
Version2.0
Creation Date2014-08-29 04:49:18 UTC
Update Date2014-12-24 20:26:35 UTC
Accession NumberT3D4019
Identification
Common NamePaclitaxel
ClassSmall Molecule
DescriptionA cyclodecane isolated from the bark of the Pacific yew tree, TAXUS brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. ABI-007 (Abraxane) is the latest attempt to improve upon paclitaxel, one of the leading chemotherapy treatments. Both drugs contain the same active agent, but Abraxane is delivered by a nanoparticle technology that binds to albumin, a natural protein, rather than the toxic solvent known as Cremophor. It is thought that delivering paclitaxel with this technology will cause fewer hypersensitivity reactions and possibly lead to greater drug uptake in tumors. Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a US National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol. Later it was discovered that endophytic fungi in the bark synthesize paclitaxel.
Compound Type
  • Amine
  • Antineoplastic Agent, Phytogenic
  • Drug
  • Ester
  • Ether
  • Metabolite
  • Natural Compound
  • Organic Compound
  • Plant Toxin
  • Tubulin Modulator
Chemical Structure
Thumb
Synonyms
Synonym
5beta,20-Epoxy-1,2-alpha,4,7beta,10beta,13alpha-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine
7-Epi-Paclitaxel
7-Epi-Taxol
7-Epipaclitaxel
7-Epitaxol
ABI-007
Abraxane
Onxol
Paxceed
Paxene
Taxol
Taxol A
Chemical FormulaC47H51NO14
Average Molecular Mass853.906 g/mol
Monoisotopic Mass853.331 g/mol
CAS Registry Number33069-62-4
IUPAC Name(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-1,9-dihydroxy-15-{[(2R,3S)-2-hydroxy-3-phenyl-3-(phenylformamido)propanoyl]oxy}-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0³,¹⁰.0⁴,⁷]heptadec-13-en-2-yl benzoate
Traditional Namepaclitaxel
SMILES[H][C@](O)(C(=O)O[C@@]1([H])C[C@@]2(O)[C@@]([H])(OC(=O)C3=CC=CC=C3)[C@]3([H])[C@@]4(CO[C@]4([H])C[C@]([H])(O)[C@@]3(C)C(=O)[C@]([H])(OC(C)=O)C(=C1C)C2(C)C)OC(C)=O)[C@@]([H])(N=C(O)C1=CC=CC=C1)C1=CC=CC=C1
InChI IdentifierInChI=1S/C47H51NO14/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)5/h7-21,31-33,35-38,40,51-52,57H,22-24H2,1-6H3,(H,48,54)/t31-,32-,33+,35-,36+,37+,38-,40-,45+,46-,47+/m0/s1
InChI KeyInChIKey=RCINICONZNJXQF-MZXODVADSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as taxanes and derivatives. These are diterpenoids with a structure based either on the taxane skeleton, or a derivative thereof. In term of phytochemistry, several derivatives of the taxane skeleton exist: 2(3->20)-abeotaxane, 3,11-cyclotaxane, 11(15->1),11(10->9)-abeotaxane, 3,8-seco-taxane, and 11(15->1)-abeotaxane, among others. More complex skeletons have been found recently, which include the taxane-derived [3.3.3] propellane ring system.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassDiterpenoids
Direct ParentTaxanes and derivatives
Alternative Parents
Substituents
  • Taxane diterpenoid
  • Tetracarboxylic acid or derivatives
  • Benzoate ester
  • Benzoic acid or derivatives
  • Benzoyl
  • Fatty acid ester
  • Alpha-acyloxy ketone
  • Monocyclic benzene moiety
  • Fatty acyl
  • Benzenoid
  • Cyclic alcohol
  • Tertiary alcohol
  • Carboxylic acid ester
  • Ketone
  • Oxetane
  • Secondary alcohol
  • Carboximidic acid
  • Carboximidic acid derivative
  • Carboxylic acid derivative
  • Oxacycle
  • Dialkyl ether
  • Ether
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Organopnictogen compound
  • Organic oxide
  • Carbonyl group
  • Alcohol
  • Organonitrogen compound
  • Organooxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
Paclitaxel PathwayNot AvailableNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point216-217°C
Boiling PointNot Available
SolubilityInsoluble
LogP3
Predicted Properties
PropertyValueSource
Water Solubility0.0056 g/LALOGPS
logP3.2ALOGPS
logP3.54ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)10.36ChemAxon
pKa (Strongest Basic)-1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area221.29 ŲChemAxon
Rotatable Bond Count14ChemAxon
Refractivity218.29 m³·mol⁻¹ChemAxon
Polarizability87.17 ųChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-3971000000-2a76bfe38de6d5790a39View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-029i-0030050690-c48555dd5b3f5acd814bView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0900-0780090340-954315fc743a0eaf982fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a6r-1510290000-5903f2c1cdc9b5323c84View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0hgc-2240060490-3ffb6f7c9cb421bdaf33View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-069c-3120090220-f3e24aad4024a1fc8393View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4i-7621090000-c809e0c049a10dcb9b96View in MoNA
Toxicity Profile
Route of ExposureWhen a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng*h/mL.
Mechanism of ToxicityPaclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the 'building block' of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.
MetabolismHepatic. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6a, 3’-p-dihydroxypaclitaxel, by CYP3A4. Route of Elimination: In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Half Life: When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours.
Toxicity ValuesRat (ipr) LD50=32530 µg/kg.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. Abraxane™ is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01229
HMDB IDHMDB15360
PubChem Compound ID36314
ChEMBL IDCHEMBL428647
ChemSpider ID33395
KEGG IDC07394
UniProt IDNot Available
OMIM ID
ChEBI ID7887
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDTA1
ACToR IDNot Available
Wikipedia LinkPaclitaxel
References
Synthesis Reference

Hendricus B. A. de Bont, Ruben G. G. Leenders, Johan W. Scheeren, Hidde J. Haisma, Dick de Vos, “Paclitaxel prodrugs, method for preparation as well as their use in selective chemotherapy.” U.S. Patent US5760072, issued September, 1989.

MSDSLink
General References
  1. Wall ME, Wani MC: Camptothecin and taxol: discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Res. 1995 Feb 15;55(4):753-60. [7850785 ]
  2. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT: Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971 May 5;93(9):2325-7. [5553076 ]
  3. Fuchs DA, Johnson RK: Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep. 1978 Aug;62(8):1219-22. [688258 ]
  4. Saville MW, Lietzau J, Pluda JM, Feuerstein I, Odom J, Wilson WH, Humphrey RW, Feigal E, Steinberg SM, Broder S, et al.: Treatment of HIV-associated Kaposi's sarcoma with paclitaxel. Lancet. 1995 Jul 1;346(8966):26-8. [7603142 ]
  5. ABI 007. Drugs R D. 2004;5(3):155-9. [15139776 ]
  6. Gaitanis A, Staal S: Liposomal doxorubicin and nab-paclitaxel: nanoparticle cancer chemotherapy in current clinical use. Methods Mol Biol. 2010;624:385-92. doi: 10.1007/978-1-60761-609-2_26. [20217610 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Ubiquitin protein ligase binding
Specific Function:
Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785).
Gene Name:
BCL2
Uniprot ID:
P10415
Molecular Weight:
26265.66 Da
References
  1. Gan Y, Wientjes MG, Au JL: Expression of basic fibroblast growth factor correlates with resistance to paclitaxel in human patient tumors. Pharm Res. 2006 Jun;23(6):1324-31. Epub 2006 Jun 8. [16741658 ]
  2. Thomadaki H, Talieri M, Scorilas A: Treatment of MCF-7 cells with taxol and etoposide induces distinct alterations in the expression of apoptosis-related genes BCL2, BCL2L12, BAX, CASPASE-9 and FAS. Biol Chem. 2006 Aug;387(8):1081-6. [16895478 ]
  3. Yoshino T, Shiina H, Urakami S, Kikuno N, Yoneda T, Shigeno K, Igawa M: Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6116-24. [17062688 ]
  4. Matsuyoshi S, Shimada K, Nakamura M, Ishida E, Konishi N: Bcl-2 phosphorylation has pathological significance in human breast cancer. Pathobiology. 2006;73(4):205-12. [17119350 ]
  5. Zhang X, Wang Q, Ling MT, Wong YC, Leung SC, Wang X: Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells. Int J Cancer. 2007 May 1;120(9):1891-8. [17230521 ]
General Function:
Structural constituent of cytoskeleton
Specific Function:
Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain (By similarity).
Gene Name:
TUBB1
Uniprot ID:
Q9H4B7
Molecular Weight:
50326.56 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. Cheung CH, Chen HH, Kuo CC, Chang CY, Coumar MS, Hsieh HP, Chang JY: Survivin counteracts the therapeutic effect of microtubule de-stabilizers by stabilizing tubulin polymers. Mol Cancer. 2009 Jul 3;8:43. doi: 10.1186/1476-4598-8-43. [19575780 ]
  4. Horwitz SB: Mechanism of action of taxol. Trends Pharmacol Sci. 1992 Apr;13(4):134-6. [1350385 ]
  5. Kovacs P, Csaba G, Pallinger E, Czaker R: Effects of taxol treatment on the microtubular system and mitochondria of Tetrahymena. Cell Biol Int. 2007 Jul;31(7):724-32. Epub 2007 Jan 14. [17314054 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
References
  1. Harmsen S, Meijerman I, Beijnen JH, Schellens JH: Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43. doi: 10.1007/s00280-008-0842-3. Epub 2008 Oct 7. [18839173 ]
  2. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. [14977870 ]
  3. Lim YP, Liu CH, Shyu LJ, Huang JD: Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects. Pharmacogenet Genomics. 2005 May;15(5):337-41. [15864135 ]
General Function:
Structural molecule activity
Specific Function:
The exact function of MAP2 is unknown but MAPs may stabilize the microtubules against depolymerization. They also seem to have a stiffening effect on microtubules.
Gene Name:
MAP2
Uniprot ID:
P11137
Molecular Weight:
199524.51 Da
References
  1. McGrogan BT, Gilmartin B, Carney DN, McCann A: Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta. 2008 Apr;1785(2):96-132. Epub 2007 Nov 12. [18068131 ]
General Function:
Structural molecule activity
Specific Function:
Non-neuronal microtubule-associated protein. Promotes microtubule assembly.
Gene Name:
MAP4
Uniprot ID:
P27816
Molecular Weight:
121003.805 Da
References
  1. McGrogan BT, Gilmartin B, Carney DN, McCann A: Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta. 2008 Apr;1785(2):96-132. Epub 2007 Nov 12. [18068131 ]
General Function:
Structural constituent of cytoskeleton
Specific Function:
Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization.
Gene Name:
MAPT
Uniprot ID:
P10636
Molecular Weight:
78927.025 Da
References
  1. McGrogan BT, Gilmartin B, Carney DN, McCann A: Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta. 2008 Apr;1785(2):96-132. Epub 2007 Nov 12. [18068131 ]