T3DB: Vincristine

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (7)XML

Targets (7)

Record Information

Version

2.0

Creation Date

2014-08-29 04:49:14 UTC

Update Date

2014-12-24 20:26:35 UTC

Accession Number

T3D4016

Identification

Common Name

Vincristine

Class

Small Molecule

Description

Vincristine is only found in individuals that have used or taken this drug. It is an antitumor alkaloid isolated from Vinca Rosea. (Merck, 11th ed.) The antitumor activity of Vincristine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, Vincristine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca²⁺-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. Vincristine is indicated for the treatment of acute leukaemia, malignant lymphoma, Hodgkin's disease, acute erythraemia, and acute panmyelosis. Vincristine sulfate is often chosen as part of polychemotherapy because of lack of significant bone marrow suppression (at recommended doses) and of unique clinical toxicity (neuropathy).

Compound Type

Amide
Amine
Antineoplastic Agent, Phytogenic
Drug
Ester
Ether
Metabolite
Organic Compound
Synthetic Compound
Tubulin Modulator

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
22-Oxovincaleukoblastin
22-Oxovincaleukoblastine
Alcavixin
Alcrist
Citomid
Cytocristin
Indole alkaloid
LCR
Leurocristine
Marqibo
Oncocristin
Oncovin
Oncrivin
Sindovin
Tevacristin
VCR
VIN
Vinces
Vincrisin
Vincristin
Vincristina
Vincristinum
Vincrisul
Vincrstine
Vincrystine
Vinlon
Vinracine
Z-D-Val-Lys(Z)-OH

Chemical Formula

C₄₆H₅₆N₄O₁₀

Average Molecular Mass

824.958 g/mol

Monoisotopic Mass

824.400 g/mol

CAS Registry Number

57-22-7

IUPAC Name

methyl (1R,9R,10S,11R,12R,19R)-11-(acetyloxy)-12-ethyl-4-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0⁴,¹².0⁵,¹⁰]nonadeca-4(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-methoxy-8,16-diazapentacyclo[10.6.1.0¹,⁹.0²,⁷.0¹⁶,¹⁹]nonadeca-2,4,6,13-tetraene-10-carboxylate

Traditional Name

vincristine

SMILES

[H][C@@]12N3CC[C@@]11C4=CC(=C(OC)C=C4N(C=O)[C@@]1([H])[C@@](O)(C(=O)OC)[C@]([H])(OC(C)=O)[C@]2(CC)C=CC3)[C@]1(C[C@]2([H])CN(C[C@](O)(CC)C2)CCC2=C1NC1=CC=CC=C21)C(=O)OC

InChI Identifier

InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28)25-42)29-12-9-10-13-33(29)47-36)32-20-31-34(21-35(32)57-4)50(26-51)38-44(31)16-19-49-17-11-15-43(8-2,37(44)49)39(60-27(3)52)46(38,56)41(54)59-6/h9-13,15,20-21,26,28,37-39,47,55-56H,7-8,14,16-19,22-25H2,1-6H3/t28-,37+,38-,39-,42+,43-,44-,45+,46+/m1/s1

InChI Key

InChIKey=OGWKCGZFUXNPDA-XQKSVPLYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as dipeptides. These are organic compounds containing a sequence of exactly two alpha-amino acids joined by a peptide bond.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Dipeptides

Alternative Parents

Substituents

Alpha-dipeptide
Alpha-amino acid ester
Benzazepine
Alpha-amino acid or derivatives
Azepine
Fatty acid ester
Aralkylamine
Dicarboxylic acid or derivatives
Monocyclic benzene moiety
Fatty acyl
Benzenoid
Tertiary carboxylic acid amide
Carboxylic acid ester
Amino acid or derivatives
Amino acid
Lactam
Carboxamide group
Carboxylic acid
Secondary aliphatic amine
Azacycle
Secondary amine
Organoheterocyclic compound
Organic nitrogen compound
Organonitrogen compound
Carbonyl group
Organooxygen compound
Hydrocarbon derivative
Organic oxide
Organopnictogen compound
Amine
Organic oxygen compound
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

dicarboxylic acid monoester (CHEBI:3011 )
ethyl ester (CHEBI:3011 )
benzazepine (CHEBI:3011 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Name	SMPDB Link	KEGG Link
Vincristine Pathway	Not Available	Not Available

Applications

Not Available

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	220°C
Boiling Point	Not Available
Solubility	3.00e-02 g/L
LogP	2.82

Predicted Properties

Property	Value	Source
Water Solubility	0.03 g/L	ALOGPS
logP	3.36	ALOGPS
logP	3.13	ChemAxon
logS	-4.4	ALOGPS
pKa (Strongest Acidic)	10.85	ChemAxon
pKa (Strongest Basic)	8.66	ChemAxon
Physiological Charge	2	ChemAxon
Hydrogen Acceptor Count	9	ChemAxon
Hydrogen Donor Count	3	ChemAxon
Polar Surface Area	171.17 Å²	ChemAxon
Rotatable Bond Count	10	ChemAxon
Refractivity	221.48 m³·mol⁻¹	ChemAxon
Polarizability	88.59 Å³	ChemAxon
Number of Rings	9	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_3) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-004i-0000000090-ddde8bc651d70b277aa7	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Negative	splash10-00e9-0010001890-ec40da49423247b42f44	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-05r0-0000000960-3a843563d341d8bc8c67	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-05ot-0000000910-19f858ef585f6c37c067	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0537-1200000900-8774d71fd76cf13c57fe	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0c00-2005000950-4682841abaeccf6ff250	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-052r-1009000100-ce5fe6558a0993ae42c6	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0a4i-9002300800-16d21458a9981b9e680c	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-004i-0000000390-aa3de8e6a5248eff1e03	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-004j-0000000950-0e6c15ea67ad87695172	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0abc-9100112810-31f4dcec28eef9c1ce0c	2021-09-23	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0a4i-9000000420-c00fa346c22549393c80	2021-09-24	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0a4i-8000000900-54ffe3b7f7c10887482f	2021-09-24	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0002-4040000900-727e48a803b558914e66	2021-09-24	View Spectrum

Toxicity Profile

Route of Exposure

Not Available

Mechanism of Toxicity

The antitumor activity of Vincristine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, Vincristine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca²⁺-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis.

Metabolism

Hepatic. Cytochrome P450 isoenzymes of the CYP3A subfamily facilitate the metabolism of vincristine. Route of Elimination: The liver is the major excretory organ in humans and animals. 80% of an injected dose of vincristine sulfate is excreted via feces. 10 - 20% is excreted via urine. Half Life: When intravenously injected into cancer patients, a triphasic serum decay patten was observed. The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, 85 hours respectively. The range of the terminal half-life is humans is 19 - 155 hours.

Toxicity Values

IVN-RAT LD₅₀ 1300 mg/kg; IPR-MUS LD₅₀ 5.2 mg/kg.

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

Vincristine sulfate is not classifiable as to its carcinogenicity to humans (Group 3). Vincristine is part of MOPP, a combination chemotherapy regimen that is carcinogenic to humans (Group 1). (6)

Uses/Sources

Treatment of acute lymphocytic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphomas, Wilms' tumor, neuroblastoma, rhabdomyosarcoma. Liposomal vincristine is indicated for the treatment of relapsed Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL).

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

28445

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Vincristine

References

Synthesis Reference

Homer L. Pearce, “Method of preparing vincristine.” U.S. Patent US4303584, issued November, 1967.

MSDS

Link

General References

Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD: Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996 Apr 1;77(7):1356-62. [8608515 ]
Qweider M, Gilsbach JM, Rohde V: Inadvertent intrathecal vincristine administration: a neurosurgical emergency. Case report. J Neurosurg Spine. 2007 Mar;6(3):280-3. [17355029 ]
JOHNSON IS, ARMSTRONG JG, GORMAN M, BURNETT JP Jr: THE VINCA ALKALOIDS: A NEW CLASS OF ONCOLYTIC AGENTS. Cancer Res. 1963 Sep;23:1390-427. [14070392 ]
Gidding CE, Kellie SJ, Kamps WA, de Graaf SS: Vincristine revisited. Crit Rev Oncol Hematol. 1999 Feb;29(3):267-87. [10226730 ]
FDA label
International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Tubulin beta chain

General Function:: Ubiquitin protein ligase binding
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.
Gene Name:: TUBB
Uniprot ID:: P07437
Molecular Weight:: 49670.515 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 ]
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 ]
Kurtzberg LS, Roth SD, Bagley RG, Rouleau C, Yao M, Crawford JL, Krumbholz RD, Schmid SM, Teicher BA: Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents. Cancer Chemother Pharmacol. 2009 Oct;64(5):1029-38. doi: 10.1007/s00280-009-0959-z. Epub 2009 Mar 10. [19277662 ]
Gan PP, McCarroll JA, Po'uha ST, Kamath K, Jordan MA, Kavallaris M: Microtubule dynamics, mitotic arrest, and apoptosis: drug-induced differential effects of betaIII-tubulin. Mol Cancer Ther. 2010 May;9(5):1339-48. doi: 10.1158/1535-7163.MCT-09-0679. Epub 2010 May 4. [20442307 ]

Target Details

2. Tubulin alpha-4A chain

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.
Gene Name:: TUBA4A
Uniprot ID:: P68366
Molecular Weight:: 49923.995 Da

References

Yasui M, Koyama N, Koizumi T, Senda-Murata K, Takashima Y, Hayashi M, Sugimoto K, Honma M: Live cell imaging of micronucleus formation and development. Mutat Res. 2010 Oct 13;692(1-2):12-8. doi: 10.1016/j.mrfmmm.2010.07.009. Epub 2010 Aug 5. [20691709 ]
Gan PP, McCarroll JA, Po'uha ST, Kamath K, Jordan MA, Kavallaris M: Microtubule dynamics, mitotic arrest, and apoptosis: drug-induced differential effects of betaIII-tubulin. Mol Cancer Ther. 2010 May;9(5):1339-48. doi: 10.1158/1535-7163.MCT-09-0679. Epub 2010 May 4. [20442307 ]
Vilpo JA, Koski T, Vilpo LM: Selective toxicity of vincristine against chronic lymphocytic leukemia cells in vitro. Eur J Haematol. 2000 Dec;65(6):370-8. [11168494 ]

Target Details

3. Canalicular multispecific organic anion transporter 1

General Function:: Organic anion transmembrane transporter activity
Specific Function:: Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name:: ABCC2
Uniprot ID:: Q92887
Molecular Weight:: 174205.64 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	802 uM	Not Available	BindingDB 50139772

References

Tang F, Horie K, Borchardt RT: Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res. 2002 Jun;19(6):773-9. [12134946 ]

Target Details

4. Multidrug resistance protein 1

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

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	213 uM	Not Available	BindingDB 50139772

References

Tang F, Horie K, Borchardt RT: Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res. 2002 Jun;19(6):765-72. [12134945 ]

Target Details

5. Multidrug resistance-associated protein 1

General Function:: Transporter activity
Specific Function:: Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs. Hydrolyzes ATP with low efficiency.
Gene Name:: ABCC1
Uniprot ID:: P33527
Molecular Weight:: 171589.5 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
IC50	70 uM	Not Available	BindingDB 50139772

References

Loe DW, Almquist KC, Cole SP, Deeley RG: ATP-dependent 17 beta-estradiol 17-(beta-D-glucuronide) transport by multidrug resistance protein (MRP). Inhibition by cholestatic steroids. J Biol Chem. 1996 Apr 19;271(16):9683-9. [8621644 ]

Target Details

6. Solute carrier organic anion transporter family member 1B1

General Function:: Sodium-independent organic anion transmembrane transporter activity
Specific Function:: Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
Gene Name:: SLCO1B1
Uniprot ID:: Q9Y6L6
Molecular Weight:: 76447.99 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	42 uM	Not Available	BindingDB 50139772
IC50	44 uM	Not Available	BindingDB 50139772

References

Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]

Target Details

7. Solute carrier organic anion transporter family member 1B3

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

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	9.8 uM	Not Available	BindingDB 50139772
IC50	11 uM	Not Available	BindingDB 50139772

References

Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [22541068 ]

Vincristine (T3D4016)

Structure for T3D4016: Vincristine

Targets

References

References

Binding/Activity Constants

References

Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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