Identification

Name
Vindesine
Accession Number
DB00309  (APRD00392)
Type
Small Molecule
Groups
Approved, Investigational
Description

Vinblastine derivative with antineoplastic activity against cancer. Major side effects are myelosuppression and neurotoxicity. Vindesine is used extensively in chemotherapy protocols (antineoplastic combined chemotherapy protocols). [PubChem]

Structure
Thumb
Synonyms
  • 3-(Aminocarbonyl)-O(4)-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine
  • 3-Carbamoyl-4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine
  • Desacetylvinblastine amide
  • Vindesina
Product Ingredients
IngredientUNIICASInChI Key
Vindesine SulfateCPH2U7DNDY59917-39-4COFJBSXICYYSKG-FJFFLIEUSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Eldisine Inj 5mg/2mlPowder, for solution5 mgIntravenousEli Lilly & Co. Ltd.1982-12-312000-08-03Canada
International/Other Brands
Eldesine / Eldisine
Categories
UNII
RSA8KO39WH
CAS number
53643-48-4
Weight
Average: 753.9261
Monoisotopic: 753.410149139
Chemical Formula
C43H55N5O7
InChI Key
HHJUWIANJFBDHT-KOTLKJBCSA-N
InChI
InChI=1S/C43H55N5O7/c1-6-39(52)21-25-22-42(38(51)55-5,33-27(13-17-47(23-25)24-39)26-11-8-9-12-30(26)45-33)29-19-28-31(20-32(29)54-4)46(3)35-41(28)15-18-48-16-10-14-40(7-2,34(41)48)36(49)43(35,53)37(44)50/h8-12,14,19-20,25,34-36,45,49,52-53H,6-7,13,15-18,21-24H2,1-5H3,(H2,44,50)/t25-,34+,35-,36-,39+,40-,41-,42+,43+/m1/s1
IUPAC Name
methyl (13S,15S,17S)-13-[(1R,9R,10S,11R,12R,19R)-10-carbamoyl-12-ethyl-10,11-dihydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.0¹,⁹.0²,⁷.0¹⁶,¹⁹]nonadeca-2,4,6,13-tetraen-4-yl]-17-ethyl-17-hydroxy-1,11-diazatetracyclo[13.3.1.0⁴,¹².0⁵,¹⁰]nonadeca-4(12),5,7,9-tetraene-13-carboxylate
SMILES
[H][C@@]12N3CC[C@@]11C4=CC(=C(OC)C=C4N(C)[C@@]1([H])[C@](O)([C@H](O)[C@]2(CC)C=CC3)C(N)=O)[C@]1(C[C@]2([H])CN(C[C@](O)(CC)C2)CCC2=C1NC1=CC=CC=C21)C(=O)OC

Pharmacology

Indication

For the treatment of acute leukaemia, malignant lymphoma, Hodgkin's disease, acute erythraemia and acute panmyelosis

Pharmacodynamics

Vindesine is indicated for the treatment of acute lymphocytic leukemia of childhood that is resistant to vincristine and non-oat cell lung cancer.Vindesine causes the arrest of cells in metaphase mitosis. It is three times more potent than vincristine and nearly 10 times more potent than vinblastine in causing mitotic arrest in in vitro studies at doses designed to arrest from 10 to 15% of the cells in mitosis. Vindesine and vincristine are approximately equipotent at dose levels that arrest 40 to 50% of the cells in mitosis. Unlike vinblastine, vindesine produces very few postmetaphase cells. Vindesine has demonstrated activity in patients who have relapsed while receiving multiple-agent treatment that included vincristine.

Mechanism of action

Vindesine acts by causing the arrest of cells in metaphase mitosis through its inhibition tubulin mitotic funcitoning. The drug is cell-cycle specific for the S phase.

TargetActionsOrganism
ATubulin beta-1 chain
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

65-75%

Metabolism

Hepatic

Route of elimination
Not Available
Half life

24 hours.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Vindesine Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Vindesine.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Vindesine.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Vindesine is combined with 2-Methoxyethanol.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Vindesine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Vindesine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Vindesine.
6-Deoxyerythronolide BThe serum concentration of Vindesine can be increased when it is combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Vindesine.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Vindesine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Vindesine is combined with Abatacept.
Food Interactions
Not Available

References

Synthesis Reference

Stanislaw Rolski, "Method of preparing vindesine sulfate." U.S. Patent US4259242, issued September, 1965.

US4259242
General References
Not Available
External Links
Human Metabolome Database
HMDB0014454
KEGG Drug
D01769
PubChem Compound
40839
PubChem Substance
46504548
ChemSpider
37302
ChEBI
36373
ChEMBL
CHEMBL219146
Therapeutic Targets Database
DAP000949
PharmGKB
PA10232
RxList
RxList Drug Page
Wikipedia
Vindesine
ATC Codes
L01CA03 — Vindesine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Unknown StatusTreatmentLung Cancers1
1, 2RecruitingTreatmentT Cell Non-Hodgkin's Lymphoma1
2CompletedTreatmentNeuroblastomas1
2CompletedTreatmentPeripheral T-Cell Lymphoma (PTCL)1
2Unknown StatusTreatmentLeukemias2
2, 3RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
2, 3RecruitingTreatmentLymphoma, Lymphoblastic1
3Active Not RecruitingTreatmentLeukemias1
3CompletedTreatmentCervical Cancers1
3CompletedTreatmentLeukemias2
3CompletedTreatmentLung Cancers1
3CompletedTreatmentNeuroblastomas2
3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Lymphoma, Lymphoblastic1
3RecruitingTreatmentAcute Lymphoblastic Leukemia, Pediatric1
3RecruitingTreatmentLymphoma, Large B-Cell, Diffuse (DLBCL)1
3RecruitingTreatmentMature B-cell Non-Hodgkin Lymphoma1
3TerminatedTreatmentLymphoma, Large-Cell, Diffuse1
3TerminatedTreatmentMalignant Lymphomas1
3Unknown StatusTreatmentLeukemias1
3Unknown StatusTreatmentLeukemias / Malignant Lymphomas1
3Unknown StatusTreatmentLung Cancers1
3Unknown StatusTreatmentNeuroblastomas1
4CompletedTreatmentAdult Acute Lymphocytic Leukemia2
4CompletedTreatmentBurkitt's Lymphoma / Large Cell Anaplastic Lymphoma / Lymphoma, Lymphoblastic / Mediastinal Neoplasms1
4CompletedTreatmentLymphoma, Lymphoblastic1
4Unknown StatusTreatmentAdult Acute Lymphocytic Leukemia1
4Unknown StatusTreatmentMetastatic Melanoma1
Not AvailableActive Not RecruitingTreatmentMalignant Lymphomas1
Not AvailableCompletedTreatmentLeukemias1
Not AvailableRecruitingTreatmentNeuroblastomas1
Not AvailableUnknown StatusTreatmentMalignant Lymphomas1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Powder, for solutionIntravenous5 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)230-232 °CNot Available
logP2.9Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.07 mg/mLALOGPS
logP3.53ALOGPS
logP2.79ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)11.34ChemAxon
pKa (Strongest Basic)8.68ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area164.82 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity210.32 m3·mol-1ChemAxon
Polarizability82.58 Å3ChemAxon
Number of Rings9ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9027
Blood Brain Barrier-0.9821
Caco-2 permeable-0.5154
P-glycoprotein substrateSubstrate0.9164
P-glycoprotein inhibitor INon-inhibitor0.5717
P-glycoprotein inhibitor IINon-inhibitor0.6577
Renal organic cation transporterNon-inhibitor0.8851
CYP450 2C9 substrateNon-substrate0.8468
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7597
CYP450 1A2 substrateNon-inhibitor0.8766
CYP450 2C9 inhibitorNon-inhibitor0.8798
CYP450 2D6 inhibitorNon-inhibitor0.8911
CYP450 2C19 inhibitorNon-inhibitor0.8814
CYP450 3A4 inhibitorNon-inhibitor0.811
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.933
Ames testNon AMES toxic0.8682
CarcinogenicityNon-carcinogens0.8976
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.9430 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9892
hERG inhibition (predictor II)Inhibitor0.6584
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as vinca alkaloids. These are alkaloids with a dimeric chemical structure composed of an indole nucleus (catharanthine), and a dihydroindole nucleus (vindoline), joined together.
Kingdom
Organic compounds
Super Class
Alkaloids and derivatives
Class
Vinca alkaloids
Sub Class
Not Available
Direct Parent
Vinca alkaloids
Alternative Parents
Carbazoles / Quinoline carboxamides / 3-alkylindoles / Anisoles / Dialkylarylamines / Aralkylamines / Alkyl aryl ethers / N-alkylpyrrolidines / Piperidines / Methyl esters
show 15 more
Substituents
Vinca alkaloid skeleton / Carbazole / Quinoline-6-carboxamide / 3-alkylindole / Indole / Indole or derivatives / Anisole / Dialkylarylamine / Tertiary aliphatic/aromatic amine / Alkyl aryl ether
show 34 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary alcohol, tertiary amino compound, organic heterotetracyclic compound, organic heteropentacyclic compound, methyl ester, carboxamide, vinca alkaloid (CHEBI:36373)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
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
Uniprot Name
Tubulin beta-1 chain
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. [PubMed: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. [PubMed:17016423]
  3. Natsume T, Watanabe J, Tamaoki S, Fujio N, Miyasaka K, Kobayashi M: Characterization of the interaction of TZT-1027, a potent antitumor agent, with tubulin. Jpn J Cancer Res. 2000 Jul;91(7):737-47. [PubMed:10920282]
  4. Yoshida M, Matsui Y, Ikarashi Y, Usui T, Osada H, Wakasugi H: Antiproliferating activity of the mitotic inhibitor pironetin against vindesine- and paclitaxel-resistant human small cell lung cancer H69 cells. Anticancer Res. 2007 Mar-Apr;27(2):729-36. [PubMed:17465195]
  5. Fiebig HH, Schuler J, Bausch N, Hofmann M, Metz T, Korrat A: Gene signatures developed from patient tumor explants grown in nude mice to predict tumor response to 11 cytotoxic drugs. Cancer Genomics Proteomics. 2007 May-Jun;4(3):197-209. [PubMed:17878523]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. [PubMed:10490933]

Drug created on June 13, 2005 07:24 / Updated on November 05, 2018 17:48