Paclitaxel
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Basic Info
| Common Name | Paclitaxel(F05187) |
| 2D Structure | |
| Description | A 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. |
| FRCD ID | F05187 |
| CAS Number | 33069-62-4 |
| PubChem CID | 36314 |
| Formula | C47H51NO14 |
| IUPAC Name | None |
| InChI Key | RCINICONZNJXQF-MZXODVADSA-N |
| InChI | InChI=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 |
| Canonical SMILES | CC1=C2C(C(=O)C3(C(CC4C(C3C(C(C2(C)C)(CC1OC(=O)C(C(C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C |
| Isomeric SMILES | CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C |
| Wikipedia | Paclitaxel |
| Synonyms |
Taxol A
paclitaxel
TAXOL
33069-62-4
Abraxane
Paxene
Paxceed
Plaxicel
Yewtaxan
Onxol
|
| Classifies |
Plant Toxin
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Lipids and lipid-like molecules |
| Class | Prenol lipids |
| Subclass | Diterpenoids |
| Intermediate Tree Nodes | Not available |
| Direct Parent | Taxanes and derivatives |
| Alternative Parents |
|
| Molecular Framework | Aromatic heteropolycyclic compounds |
| 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 |
| Description | This compound 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. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 853.918 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 14 |
| Rotatable Bond Count | 14 |
| Complexity | 1790 |
| Monoisotopic Mass | 853.331 |
| Exact Mass | 853.331 |
| XLogP | 2.5 |
| Formal Charge | 0 |
| Heavy Atom Count | 62 |
| Defined Atom Stereocenter Count | 11 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB- | 0.9748 |
| Human Intestinal Absorption | HIA+ | 0.9140 |
| Caco-2 Permeability | Caco2- | 0.8957 |
| P-glycoprotein Substrate | Substrate | 0.8345 |
| P-glycoprotein Inhibitor | Inhibitor | 0.5509 |
| Non-inhibitor | 0.7309 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.9349 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.6557 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.8370 |
| CYP450 2D6 Substrate | Non-substrate | 0.9116 |
| CYP450 3A4 Substrate | Substrate | 0.7278 |
| CYP450 1A2 Inhibitor | Non-inhibitor | 0.9045 |
| CYP450 2C9 Inhibitor | Non-inhibitor | 0.9071 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9231 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.9025 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.8309 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.8937 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9978 |
| Non-inhibitor | 0.7982 | |
| AMES Toxicity | Non AMES toxic | 0.9132 |
| Carcinogens | Non-carcinogens | 0.9158 |
| Fish Toxicity | High FHMT | 0.9854 |
| Tetrahymena Pyriformis Toxicity | High TPT | 0.9986 |
| Honey Bee Toxicity | High HBT | 0.6004 |
| Biodegradation | Not ready biodegradable | 0.9491 |
| Acute Oral Toxicity | III | 0.5918 |
| Carcinogenicity (Three-class) | Non-required | 0.4813 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -3.8728 | LogS |
| Caco-2 Permeability | 0.4145 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 2.4391 | LD50, mol/kg |
| Fish Toxicity | 0.6419 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | 0.6557 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application. | Int J Mol Sci | 2018 Jan 16 | 29337925 |
| Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). | Lancet | 2017 Oct 7 | 28756902 |
| Novel paclitaxel formulations solubilized by parenteral nutrition nanoemulsions for application against glioma cell lines. | Int J Pharm | 2016 Jun 15 | 27107899 |
| Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells. | Toxicol Appl Pharmacol | 2015 Nov 1 | 26341291 |
| Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, andsuppresses lung metastasis and tumor growth in combination with taxol in tumorxenografted C57BL/6 mice. | J Nutr Biochem | 2015 Jun | 25736483 |
| Plant diterpene synthases: exploring modularity and metabolic diversity forbioengineering. | Trends Biotechnol | 2015 Jul | 26003209 |
| Enhancing Activity of Anticancer Drugs in Multidrug Resistant Tumors byModulating P-Glycoprotein through Dietary Nutraceuticals. | Asian Pac J Cancer Prev | 2015 | 26514453 |
| Improvement of hairy root cultures and plants by changing biosynthetic pathways leading to pharmaceutical metabolites: strategies and applications. | Biotechnol Adv | 2014 Nov 1 | 24699436 |
| Novel action modality of the diterpenoid anisomelic acid causes depletion of E6and E7 viral oncoproteins in HPV-transformed cervical carcinoma cells. | Biochem Pharmacol | 2014 May 15 | 24565908 |
| Systemic toxicity induced by paclitaxel in vivo is associated with the solvent cremophor EL through oxidative stress-driven mechanisms. | Food Chem Toxicol | 2014 Jun | 24657178 |
| The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone. | Food Chem Toxicol | 2013 Jan | 23085095 |
| Clinical application of drug delivery systems in cancer chemotherapy: review of the efficacy and side effects of approved drugs. | Biol Pharm Bull | 2013 | 23649331 |
| Ascorbic acid alleviates toxicity of paclitaxel without interfering with the anticancer efficacy in mice. | Nutr Res | 2012 Nov | 23176798 |
| New anti-cancer characteristics of jatrophane diterpenes from Euphorbia dendroides. | Food Chem Toxicol | 2011 Dec | 21996302 |
| The flavonoid quercetin transiently inhibits the activity of taxol and nocodazolethrough interference with the cell cycle. | Nutr Cancer | 2010 | 21058190 |
| IL-13 cytotoxin has potent antitumor activity and synergizes with paclitaxel in a mouse model of oral squamous cell carcinoma. | Int J Cancer | 2009 Mar 15 | 19065664 |
| Intestinal absorption of the acetamiprid neonicotinoid by Caco-2 cells:transepithelial transport, cellular uptake and efflux. | J Environ Sci Health B | 2008 Mar-Apr | 18368547 |
| Nanoparticle albumin-bound paclitaxel for treatment of metastatic breast cancer. | Drugs Today (Barc) | 2006 Sep | 17028669 |
| Pilot study of accelerated radiotherapy with concurrent chemotherapy for stage III non-small cell lung cancer. | Semin Oncol | 2005 Apr | 16015530 |
| Campylobacter fetus adheres to and enters INT 407 cells. | Can J Microbiol | 2002 Nov | 12556127 |
Targets
- 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
- 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
- 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
- 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:
- 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
- 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 ]
- 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
- 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:
- 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
- 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 ]