Aminopterin (T3D4741)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (2)XML
Targets (2)
Record Information
Version2.0
Creation Date2014-09-11 05:14:16 UTC
Update Date2014-12-24 20:26:56 UTC
Accession NumberT3D4741
Identification
Common NameAminopterin
ClassSmall Molecule
DescriptionAminopterin Syndrome Sine Aminopterin (ASSA, OMIM 600325) is an embryopathy caused by maternal treatment with the olic acid antagonist aminopterin has been recognized since 1952 when aminopterin was used as an abortifacient. The characteristic phenotype of the children who survived infancy after having been exposed to aminopterin or its methyl derivative, methotrexate, in early pregnancy included a very unusual facies, skull anomalies, and skeletal defects.(OMIM). Aminopterin is an antimetabolite drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. - Wikipedia. The effects of the drug on intracellular metabolic processes, due to the inhibitory action on the enzyme dihydrofolate reductase, show that the result of this inhibition is more complex and is not limited to blockade of the reduction of folic acid alone. Although rescue methods are important in prevention of lethal effects of methotrexate, some metabolic pathways are insufficiently rescued, resulting in toxic reactions following methotrexate administration. (1)
Compound Type
  • Amide
  • Amine
  • Drug
  • Ester
  • Folic Acid Antagonist
  • Food Toxin
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
4'-Amino-folsaeure
4-Amino-4-deoxypteroylglutamate
4-Amino-PGA
4-Aminofolate
4-Aminofolic acid
4-Aminopteroylglutamate
4-Aminopteroylglutamic acid
A-ninopterin
Aminopteridine
Aminopterine
APGA
L-N-[p-[[(2,4-Diamino-6-pteridinyl)methyl]amino]benzoyl]-Glutamic acid
Minopterin
N-(4-{[(2,4-Diamino-6-pteridinyl)methyl]amino}benzoyl)glutamic acid
Pteramina
Chemical FormulaC19H20N8O5
Average Molecular Mass440.413 g/mol
Monoisotopic Mass440.156 g/mol
CAS Registry Number54-62-6
IUPAC Name2-[(4-{[(2,4-diaminopteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
Traditional Nameaminopterin
SMILESNC1=C2N=C(CNC3=CC=C(C=C3)C(=O)NC(CCC(O)=O)C(O)=O)C=NC2=NC(=N)N1
InChI IdentifierInChI=1/C19H20N8O5/c20-15-14-16(27-19(21)26-15)23-8-11(24-14)7-22-10-3-1-9(2-4-10)17(30)25-12(18(31)32)5-6-13(28)29/h1-4,8,12,22H,5-7H2,(H,25,30)(H,28,29)(H,31,32)(H4,20,21,23,26,27)
InChI KeyInChIKey=TVZGACDUOSZQKY-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as folic acids. These are heterocyclic compounds based on the 4-[(pteridin-6-ylmethyl)amino]benzoic acid skeleton conjugated with one or more L-glutamate units.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPteridines and derivatives
Sub ClassPterins and derivatives
Direct ParentFolic acids
Alternative Parents
Substituents
  • Folic acid
  • Glutamic acid or derivatives
  • Hippuric acid or derivatives
  • Hippuric acid
  • N-acyl-alpha-amino acid
  • N-acyl-alpha amino acid or derivatives
  • Alpha-amino acid or derivatives
  • Aminobenzamide
  • Aminobenzoic acid or derivatives
  • Benzamide
  • Benzoic acid or derivatives
  • Benzoyl
  • Phenylalkylamine
  • Aniline or substituted anilines
  • Aminopyrimidine
  • Aralkylamine
  • Secondary aliphatic/aromatic amine
  • Pyrimidine
  • Pyrazine
  • Monocyclic benzene moiety
  • Benzenoid
  • Imidolactam
  • Dicarboxylic acid or derivatives
  • Heteroaromatic compound
  • Secondary carboxylic acid amide
  • Amino acid or derivatives
  • Amino acid
  • Carboxamide group
  • Secondary amine
  • Azacycle
  • Carboxylic acid derivative
  • Carboxylic acid
  • Hydrocarbon derivative
  • Amine
  • Organonitrogen compound
  • Organic oxide
  • Organic nitrogen compound
  • Organopnictogen compound
  • Carbonyl group
  • Primary amine
  • Organooxygen compound
  • Organic oxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Adipose Tissue
  • Spleen
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility3.0X103 mg/L
LogP-1.8
Predicted Properties
PropertyValueSource
Water Solubility0.11 g/LALOGPS
logP-0.25ALOGPS
logP-0.95ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)3.38ChemAxon
pKa (Strongest Basic)2.25ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count6ChemAxon
Polar Surface Area219.33 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity114.98 m³·mol⁻¹ChemAxon
Polarizability44.13 ųChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0005-2149100000-61d406d05355a4fc3d262017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-014i-3060950000-0b4e0db1ce895d3cb34e2017-10-06View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0006-0030900000-3c3d8f183a438cffe34c2012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-006x-0970000000-ddbb8b8c2d06b8da5f922012-07-24View Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-00fr-0900000000-dd78e5bb1683a2c0e5312012-07-24View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00fu-0322900000-764b96892d5bbce421b12017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004i-0953200000-ea1dce8ceb8c57ed00912017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-004i-1930000000-5593e0d8e055aa5cdebc2017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000i-0003900000-8e0519246e877792792b2017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00r2-0349500000-5275f7af7a7d4fc7d5422017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-8971000000-0fe59aca81e98939920d2017-09-01View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00bi-0018900000-a0606201fd010f93c94b2021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004j-2529300000-3b9e64ec8c7a3bf2727c2021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0udl-3921000000-34b66517bd8029a4d6222021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-0280900000-6e94abf6f12994dffe6f2021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0006-1594000000-111d532a6321012d45542021-09-22View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-004i-0930000000-b75a7510d239fbddc9832021-09-22View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, H2O, experimental)Not Available2012-12-04View Spectrum
1D NMR1H NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 100 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 1000 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 200 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 300 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 400 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 500 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 600 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 700 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 800 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR1H NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
1D NMR13C NMR Spectrum (1D, 900 MHz, D2O, predicted)Not Available2021-09-29View Spectrum
2D NMR[1H, 13C]-HSQC NMR Spectrum (2D, 600 MHz, 100%_DMSO, experimental)Not Available2012-12-05View Spectrum
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityAminopterin is an amino derivative of folic acid which binds competitively to the dihydrofolate reductase enzyme to block tetrahydrofolate synthesis. Tetrahydrofolate is essential in the production of purines and pyrimadines, thus it's deficiency results in a reduction of DNA, RNA and protein synthesis.
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesAminopterin Syndrome Sine Aminopterin (ASSA, OMIM 600325) is an embryopathy caused by maternal treatment with the olic acid antagonist aminopterin has been recognized since 1952 when aminopterin was used as an abortifacient. Aminopterin is an antimetabolite drug used in treatment of cancer and autoimmune diseases.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB08878
HMDB IDHMDB01833
PubChem Compound ID2154
ChEMBL IDNot Available
ChemSpider ID2069
KEGG IDD02527
UniProt IDNot Available
OMIM ID
ChEBI ID376180
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkAminopterin
References
Synthesis Reference

http://www.sigmaaldrich.com/catalog/papers/16078850

MSDSLink
General References
  1. Lippens RJ: Methotrexate. I. Pharmacology and pharmacokinetics. Am J Pediatr Hematol Oncol. 1984 Winter;6(4):379-95. [6398629 ]
  2. Aftimos S: Fetal methotrexate/aminopterin syndrome in an adult: a likely case with ectodermal abnormalities. Clin Dysmorphol. 2009 Jan;18(1):53-5. doi: 10.1097/MCD.0b013e32831552c4. [19011571 ]
  3. Wheeler M, O'Meara P, Stanford M: Fetal methotrexate and misoprostol exposure: the past revisited. Teratology. 2002 Aug;66(2):73-6. [12210010 ]
  4. NICHOL CA, WELCH AD: On the mechanism of action of aminopterin. Proc Soc Exp Biol Med. 1950 Jun;74(2):403-11. [15440837 ]
  5. Menter A, Thrash B, Cherian C, Matherly LH, Wang L, Gangjee A, Morgan JR, Maeda DY, Schuler AD, Kahn SJ, Zebala JA: Intestinal transport of aminopterin enantiomers in dogs and humans with psoriasis is stereoselective: evidence for a mechanism involving the proton-coupled folate transporter. J Pharmacol Exp Ther. 2012 Sep;342(3):696-708. doi: 10.1124/jpet.112.195479. Epub 2012 May 31. [22653877 ]
  6. Cole PD, Drachtman RA, Smith AK, Cate S, Larson RA, Hawkins DS, Holcenberg J, Kelly K, Kamen BA: Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res. 2005 Nov 15;11(22):8089-96. [16299240 ]
  7. Le Blanc PE, Roncari DA, Hoar DI, Adachi AM: Exaggerated triglyceride accretion in human preadipocyte-murine renal line hybrids composed of cells from massively obese subjects. J Clin Invest. 1988 May;81(5):1639-45. [3366910 ]
  8. Malone MA, Costa Garcia A, Tunon Blanco P, Smyth MR: Phase-selective AC adsorptive stripping voltammetric assay for aminopterin and 10-Edam in human serum. J Pharm Biomed Anal. 1993 Oct;11(10):939-46. [8305599 ]
  9. Raache R, Rapaille A, Sondag-Thull D, Abbadi MC: [Production of monoclonal antibodies specific for the ABO blood group and rhesus D antigens]. Arch Inst Pasteur Alger. 1998;62:118-37. [11256302 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Mu-type opioid receptor
General Function:
Voltage-gated calcium channel activity
Specific Function:
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling whereas morphine induces only low desensitization and endocytosis. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 12 couples to GNAS and is proposed to be involved in excitatory effects. Isoform 16 and isoform 17 do not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity.
Gene Name:
OPRM1
Uniprot ID:
P35372
Molecular Weight:
44778.855 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC505.33 uMNVS_GPCR_hOpiate_muNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
Target Details
2. 5-hydroxytryptamine receptor 5A
General Function:
Serotonin receptor activity
Specific Function:
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins.
Gene Name:
HTR5A
Uniprot ID:
P47898
Molecular Weight:
40254.69 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC506.99 uMNVS_GPCR_h5HT5ANovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]