Thymectacin

Identification

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Name
Thymectacin
Accession Number
DB05116
Type
Small Molecule
Groups
Investigational
Description

Thymectacin, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel small molecule anticancer agent. Thymectacin is selectively active against tumor cells expressing high levels of thymidylate synthase (TS), a critical enzyme in DNA biosynthesis. Thymectacin was as efficacious as irinotecan, a drug recently approved for the treatment of 5-fluorouracil-resistant colon cancer.

Structure
Thumb
Synonyms
Not Available
External IDs
NB-1011 / NB1011
International/Other Brands
Thymectacin
Categories
UNII
2ZRZ4TSW3F
CAS number
232925-18-7
Weight
Average: 574.321
Monoisotopic: 573.051179
Chemical Formula
C21H25BrN3O9P
InChI Key
CFBLUORPOFELCE-BACVZHSASA-N
InChI
InChI=1S/C21H25BrN3O9P/c1-13(20(28)31-2)24-35(30,34-15-6-4-3-5-7-15)32-12-17-16(26)10-18(33-17)25-11-14(8-9-22)19(27)23-21(25)29/h3-9,11,13,16-18,26H,10,12H2,1-2H3,(H,24,30)(H,23,27,29)/b9-8+/t13-,16-,17+,18+,35?/m0/s1
IUPAC Name
methyl (2S)-2-[({[(2R,3S,5R)-5-{5-[(E)-2-bromoethenyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}-3-hydroxyoxolan-2-yl]methoxy}(phenoxy)phosphoryl)amino]propanoate
SMILES
COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@H](C[C@@H]1O)N1C=C(\C=C\Br)C(=O)NC1=O)OC1=CC=CC=C1

Pharmacology

Indication

Investigated for use/treatment in colorectal cancer.

Pharmacodynamics
Not Available
Mechanism of action

NB1011 targets thymidylate synthase (TS), which catalyzes the transformation of E-5-(2-bromovinyl)-2'-deoxyuridine-5'-monophosphate (BVdUMP) into cytotoxic reaction products. Due to the elevated levels of TS expression in tumor cells compared to normal cells, these cytotoxic products are preferentially generated inside tumor cells, and, as expected, NB1011 is more toxic to cells with higher levels of TS expression. Therefore, NB1011 therapy should kill tumor cells without severely damaging normal cells.

TargetActionsOrganism
UThymidylate synthaseNot AvailableHumans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Congiatu C, McGuigan C, Jiang WG, Davies G, Mason MD: Naphthyl phosphoramidate derivatives of BVdU as potential anticancer agents: design, synthesis and biological evaluation. Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):485-9. [PubMed:16247976]
  2. Sergeeva OA, Khambatta HG, Cathers BE, Sergeeva MV: Kinetic properties of human thymidylate synthase, an anticancer drug target. Biochem Biophys Res Commun. 2003 Jul 25;307(2):297-300. [PubMed:12859954]
  3. Dellinger RW, Karjian PL, Neuteboom ST: NB1011 induces Ser15 phosphorylation of p53 and activates the G2/M checkpoint. Anticancer Drugs. 2003 Jul;14(6):449-55. [PubMed:12853888]
  4. Neuteboom ST, Karjian PL, Boyer CR, Beryt M, Pegram M, Wahl GM, Shepard HM: Inhibition of cell growth by NB1011 requires high thymidylate synthase levels and correlates with p53, p21, bax, and GADD45 induction. Mol Cancer Ther. 2002 Apr;1(6):377-84. [PubMed:12477050]
  5. Boyer CR, Karjian PL, Wahl GM, Pegram M, Neuteboom ST: Nucleoside transport inhibitors, dipyridamole and p-nitrobenzylthioinosine, selectively potentiate the antitumor activity of NB1011. Anticancer Drugs. 2002 Jan;13(1):29-36. [PubMed:11914638]
  6. Li Q, Boyer C, Lee JY, Shepard HM: A novel approach to thymidylate synthase as a target for cancer chemotherapy. Mol Pharmacol. 2001 Mar;59(3):446-52. [PubMed:11179438]
  7. Sergeeva MV, Cathers BE: Cellular transformation of the investigational new anticancer drug NB1011, a phosphoramidate of 5-(2-bromovinyl)-2'-deoxyuridine, results in modification of cellular proteins not DNA. Biochem Pharmacol. 2003 Mar 1;65(5):823-31. [PubMed:12628478]
External Links
PubChem Compound
6440764
PubChem Substance
347827711
ChemSpider
4945015
Wikipedia
Thymectacin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentTumors1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0809 mg/mLALOGPS
logP1.33ALOGPS
logP1.26ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)9.62ChemAxon
pKa (Strongest Basic)-3.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area152.73 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity124.59 m3·mol-1ChemAxon
Polarizability50.22 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

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

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrimidine 2'-deoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Pyrimidine 2'-deoxyribonucleosides
Direct Parent
Pyrimidine 2'-deoxyribonucleosides
Alternative Parents
Alpha amino acid esters / Alanine and derivatives / Phenoxy compounds / Phosphoric diester monoamides / Pyrimidones / Hydropyrimidines / Organic phosphoramides / Oxolanes / Heteroaromatic compounds / Vinylogous amides
show 14 more
Substituents
Pyrimidine 2'-deoxyribonucleoside / Alpha-amino acid ester / Alanine or derivatives / Alpha-amino acid or derivatives / Phenoxy compound / Phosphoric diester monoamide / Pyrimidone / Monocyclic benzene moiety / Pyrimidine / Hydropyrimidine
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Thymidylate synthase activity
Specific Function
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name
TYMS
Uniprot ID
P04818
Uniprot Name
Thymidylate synthase
Molecular Weight
35715.65 Da

Drug created on October 21, 2007 16:23 / Updated on June 04, 2019 06:14