PACLITAXEL DOCOSAHEXAENOIC ACID

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C69H81NO15
Molecular Weight	1164.3791
Optical Activity	UNSPECIFIED
Defined Stereocenters	11 / 11
E/Z Centers	6
Charge	0

SHOW SMILES / InChI

Structure of PACLITAXEL DOCOSAHEXAENOIC ACID

Structure Search

SMILES

[H][C@]12[C@H](OC(=O)C3=CC=CC=C3)[C@]4(O)C[C@H](OC(=O)[C@H](OC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC)[C@@H](NC(=O)C5=CC=CC=C5)C6=CC=CC=C6)C(C)=C([C@@H](OC(C)=O)C(=O)[C@]1(C)[C@@H](O)C[C@H]7OC[C@@]27OC(C)=O)C4(C)C

InChI

InChIKey=LRCZQSDQZJBHAF-PUBGEWHCSA-N

InChI=1S/C69H81NO15/c1-8-9-10-11-12-13-14-15-16-17-18-19-20-21-22-23-24-25-35-42-55(74)83-59(57(49-36-29-26-30-37-49)70-63(76)50-38-31-27-32-39-50)65(78)82-52-44-69(79)62(84-64(77)51-40-33-28-34-41-51)60-67(7,53(73)43-54-68(60,45-80-54)85-48(4)72)61(75)58(81-47(3)71)56(46(52)2)66(69,5)6/h9-10,12-13,15-16,18-19,21-22,24-34,36-41,52-54,57-60,62,73,79H,8,11,14,17,20,23,35,42-45H2,1-7H3,(H,70,76)/b10-9-,13-12-,16-15-,19-18-,22-21-,25-24-/t52-,53-,54+,57-,58+,59+,60-,62-,67+,68-,69+/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB01229
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf and https://www.ncbi.nlm.nih.gov/pubmed/18068131

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. When it was developed commercially by Bristol-Myers Squibb (BMS), the generic name was changed to paclitaxel and the BMS compound is sold under the trademark Taxol. In this formulation, paclitaxel is dissolved in Kolliphor EL and ethanol, as a delivery agent. Taxol is marketed for the treatment of Breast cancer; Gastric cancer; Kaposi's sarcoma; Non-small cell lung cancer; Ovarian cancer. A newer formulation, in which paclitaxel is bound to albumin, is sold under the trademark Abraxane. Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer. Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Used 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. Paclitaxel 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
HeLa cell growth 5 Target ID: HeLa cell growth Sources: https://www.ncbi.nlm.nih.gov/pubmed/27095936	Inhibitor 8297	7.08 µM [IC50]
SKOV3 breast cancer cell growth 5 Target ID: SKOV3 breast cancer cell growth Sources: https://www.ncbi.nlm.nih.gov/pubmed/27599579	Inhibitor 8297	38.7 nM [IC50]
microtubule polymerization 20 Target ID: GO:0046785 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8555181	Activator 1430	23.0 µM [EC50]
Tubulin beta-1 chain 9 Target ID: CHEMBL1915 Sources: http://www.drugbank.ca/drugs/DB01229	Inhibitor 8297
Apoptosis regulator Bcl-2 19 Target ID: CHEMBL4860 Sources: http://www.drugbank.ca/drugs/DB01229	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Advanced carcinoma of the ovary 5 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf	Primary	Approved 8429	TAXOL Approved Use TAXOL is indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary. Launch Date 1998
Breast cancer 434 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf	Primary	Approved 8429	TAXOL Approved Use TAXOL is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Launch Date 1998
Non-small cell lung cancer 206 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf	Primary	Approved 8429	TAXOL Approved Use TAXOL, in combination with cisplatin, is indicated for the first-line treatment of nonsmall cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy. Launch Date 1998

C_max

Value	Dose	Co-administered	Analyte	Population
6.92 μM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8664192	250 mg/m² steady-state, intravenous dose: 250 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		PACLITAXEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.5 μM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7799018	175 mg/m² steady-state, intravenous dose: 175 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		PACLITAXEL plasma	Homo sapiens population: UNKNOWN age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
27.07 μM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8664192	250 mg/m² steady-state, intravenous dose: 250 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		PACLITAXEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
14.8 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/7799018	175 mg/m² steady-state, intravenous dose: 175 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered:		PACLITAXEL plasma	Homo sapiens population: UNKNOWN age: ADULT sex: FEMALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
6.5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf			PACLITAXEL plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
135 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 135 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	Other AEs: Anaphylaxis, Dyspnea... Other AEs: Anaphylaxis (2%) Dyspnea (severe, 2%) Hypotension (severe, 2%) Generalized urticaria (severe, 2%) Angioedema (severe, 2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf

AEs

AE	Significance	Dose	Population
Anaphylaxis	2%	135 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 135 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf
Angioedema	severe, 2%	135 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 135 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf
Dyspnea	severe, 2%	135 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 135 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf
Generalized urticaria	severe, 2%	135 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 135 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf
Hypotension	severe, 2%	135 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 135 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 135 mg/m2, 1 times / 3 weeks Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020262s048lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461	CYP2C8 693 P-gp 1537 BCRP 561 MRP2 205 OATP1B3 350 OATP1B1 406 OATP1B2 7

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://www.jci.org/articles/view/15451 Page: -	no

Drug as victim

Target	Modality	Activity
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21660_ABRAXANE_biopharmr.PDF#page=20 Page: 20.0	major
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21660_ABRAXANE_biopharmr.PDF#page=20 Page: 20.0	minor
BCRP 561	substrate 3367 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.21013 Page: -	no
OATP1B3 350	substrate 3367 Sources: https://www.tandfonline.com/doi/abs/10.4161/cbt.4.8.1867 Page: -	yes [Km 6.79 uM]
MRP2 205	substrate 3367 Sources: https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.21013 Page: -	yes
OATP1B1 406	substrate 3367 Sources: https://www.nature.com/articles/tpj201013 Page: -	yes
OATP1B2 7	substrate 3367 Sources: https://www.jci.org/articles/view/96160 Page: -	yes
P-gp 1537	substrate 3367 Sources: https://clincancerres.aacrjournals.org/content/9/7/2849.short Page: -	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45863	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45863
ChemicalBook	CB3273425	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3273425
MolPort	MolPort-001-742-627	https://www.molport.com/shop/molecule-link/MolPort-001-742-627
ZINC	ZINC000096006020	http://zinc15.docking.org/substances/ZINC000096006020
eMolecules	29541201	https://www.emolecules.com/cgi-bin/more?vid=29541201
eMolecules	36754358	https://www.emolecules.com/cgi-bin/more?vid=36754358
eMolecules	506301	https://www.emolecules.com/cgi-bin/more?vid=506301

PubMed

Title	Date	PubMed
Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis.	2000 Apr	10780927
Paclitaxel in advanced non-small cell lung cancer : an alternative high-dose weekly schedule.	2000 Apr	10777471
Schedule dependency of paclitaxel-induced neuropathy in mice: a morphological study.	2000 Aug	11022860
Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.	2000 Aug	10955861
Evidence for a schedule-dependent deleterious interaction between paclitaxel, vinblastine and cisplatin (PVC) in the treatment of advanced transitional cell carcinoma.	2000 Dec	11104554
Doxorubicin and paclitaxel in advanced breast carcinoma: importance of prior adjuvant anthracycline therapy.	2000 Dec 1	11147586
Paclitaxel-induced stomal neuropathy: a unique cause of pain in a patient with ileal conduit.	2000 Dec 20	11113764
Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein.	2000 Jan	10617675
Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol.	2000 Jan 28	10644670
Polymeric micellar paclitaxel phosphorylates Bcl-2 and induces apoptotic regression of androgen-independent LNCaP prostate tumors.	2000 Jul 1	10881025
Mechanism of paclitaxel activity in Kaposi's sarcoma.	2000 Jul 1	10861090
Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line.	2000 Mar 31	10704734
Second-line chemotherapy with paclitaxel, cisplatin and gemcitabine in pre-treated sensitive cisplatin-based patients with advanced non-small cell lung cancer.	2000 May-Jun	10928183
Cell cycle status and apoptosis of hematopoietic progenitor cells released into the peripheral blood after taxanes and granulocyte colony-stimulating factor in breast cancer patients.	2000 May-Jun	10767372
Bilateral blindness and lumbosacral myelopathy associated with high-dose carmustine and cisplatin therapy.	2000 Sep	11020424
Comparison of 2-methoxyestradiol-induced, docetaxel-induced, and paclitaxel-induced apoptosis in hepatoma cells and its correlation with reactive oxygen species.	2000 Sep 1	10964328
A paclitaxel-containing chemotherapy does not cause central nervous adverse effects: a prospective study in patients with ovarian cancer.	2000 Sep-Oct	11268500
Doxorubicin and paclitaxel in the treatment of advanced breast cancer: efficacy and cardiac considerations.	2001	11296620
The pharmacokinetics and pharmacodynamics of high-dose paclitaxel monotherapy (825 mg/m2 continuous infusion over 24 h) with hematopoietic support in women with metastatic breast cancer.	2001	11221961
Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene.	2001	11161223
In vivo metabolism of epothilone B in tumor-bearing nude mice: identification of three new epothilone B metabolites by capillary high-pressure liquid chromatography/mass spectrometry/tandem mass spectrometry.	2001	11135423
High affinity binding of paclitaxel to human serum albumin.	2001 Apr	11277943
Recurrent metastatic fallopian tube carcinoma in pregnancy.	2001 Apr	11277660
Connexin 43 (cx43) enhances chemotherapy-induced apoptosis in human glioblastoma cells.	2001 Apr 1	11279616
Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300.	2001 Apr 13	11278336
Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition.	2001 Apr 26	11275363
Isolation of cortical MTs from tobacco BY-2 cells.	2001 Feb	11230570
Changes in glycosylation during Drosophila development. The influence of ecdysone on hemomucin isoforms.	2001 Feb	11164341
Disruption of microtubular cytoskeleton induced by cryptogein, an elicitor of hypersensitive response in tobacco cells.	2001 Feb	11161014
Involvement of Asp-Glu-Val-Asp-directed, caspase-mediated mitogen-activated protein kinase kinase 1 Cleavage, c-Jun N-terminal kinase activation, and subsequent Bcl-2 phosphorylation for paclitaxel-induced apoptosis in HL-60 cells.	2001 Feb	11160861
Phase I study of paclitaxel (Taxol) plus vinorelbine (Navelbine) in patients with untreated stage IIIb and IV non-small cell lung cancer.	2001 Feb-Mar	11165410
Cisplatin and vinorelbine as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) resistant to taxol plus gemcitabine.	2001 Feb-Mar	11165406
Treatment of non-small-cell lung cancer in North America: the emerging role of irinotecan.	2001 Jan	11221017
Tumor cell-derived TGF-beta and IL-10 dysregulate paclitaxel-induced macrophage activation.	2001 Jan	11200057
Opposite effects of microtubule-stabilizing and microtubule-destabilizing drugs on biogenesis of mitochondria in mammalian cells.	2001 Jan	11148130
Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels.	2001 Jan 15	11212279
Taxane-antibody conjugates afford potent cytotoxicity, enhanced solubility, and tumor target selectivity.	2001 Jan 15	11212270
Antitumor synergy of CV787, a prostate cancer-specific adenovirus, and paclitaxel and docetaxel.	2001 Jan 15	11212244
Dispersion of cyclin B mRNA aggregation is coupled with translational activation of the mRNA during zebrafish oocyte maturation.	2001 Jan 15	11150242
Enhanced taxol production and release in Taxus chinensis cell suspension cultures with selected organic solvents and sucrose feeding.	2001 Jan-Feb	11170485
The role of actin filaments and microtubules in hepatocyte spheroid self-assembly.	2001 Mar	11223949
Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3.	2001 Mar 1	11222383
Paclitaxel sensitization of multidrug-resistant cells to chemotherapy is independent of the cell cycle.	2001 Mar 1	11170102
Paclitaxel restores radiation-induced apoptosis in a bcl-2-expressing, radiation-resistant lymphoma cell line.	2001 Mar 15	11240255
Regulation of ROMK1 channels by protein-tyrosine kinase and -tyrosine phosphatase.	2001 Mar 9	11114300
Insulin-like growth factor-I receptor antagonism results in increased cytotoxicity of breast cancer cells to doxorubicin and taxol.	2001 Mar-Apr	11182049
Inhibition of telomerase activity as a measure of tumor cell killing by cisplatin in squamous cell carcinoma cell line.	2001 Mar-Apr	11173816
P-glycoprotein efflux pump expression and activity in Calu-3 cells.	2001 May	11288109
Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2.	2001 May 11	11279118
Regulation of BRCA1 and BRCA2 transcript in response to cisplatin, adriamycin, taxol and ionising radiation is correlated to p53 functional status in ovarian cancer cell lines.	2001 May-Jun	11295099

Patents

Sample Use Guides

In Vivo Use Guide

For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. a.TAXOL (PACLITAXEL) administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or b.TAXOL (PACLITAXEL) administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2 2) In patients previously treated with chemotherapy for carcinoma of the ovary, the recommended regimen is TAXOL (PACLITAXEL) 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

Route of Administration: Intravenous

In Vitro Use Guide

Paclitaxel inhibited tubulin polymerization in the presence of MAPs in vitro with an IC50 value of 38.19 ± 3.33 uM in living cancer cells (Hela cells and human osteosarcoma U2OS cells).

Name

Type

Language

PACLITAXEL DOCOSAHEXAENOIC ACID

Common Name

English

PACLITAXEL 2'-(ALL-CIS-4,7,10,13,16,19-DOCOSAHEXAENOATE)

Common Name

English

PACLITAXEL-DHA

Common Name

English

DHA-PACLITAXEL

Common Name

English

PACLITAXEL DOCOSAHEXAENOIC ACID ESTER

Common Name

English

Dha paclitaxel [WHO-DD]

Common Name

English

DHA PACLITAXEL

Common Name

English

TAXOPREXIN

Brand Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

153301