Trimetrexate (T3D3000)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (2)XML
Targets (2)
Record Information
Version2.0
Creation Date2009-07-21 20:28:29 UTC
Update Date2014-12-24 20:25:55 UTC
Accession NumberT3D3000
Identification
Common NameTrimetrexate
ClassSmall Molecule
DescriptionA nonclassical folic acid inhibitor through its inhibition of the enzyme dihydrofolate reductase. It is being tested for efficacy as an antineoplastic agent and as an antiparasitic agent against pneumocystis pneumonia in AIDS patients. Myelosuppression is its dose-limiting toxic effect. [PubChem]
Compound Type
  • Amine
  • Antibiotic
  • Antifungal Agent
  • Antimetabolite, Antineoplastic
  • Antiprotozoal Agent
  • Drug
  • Ether
  • Folic Acid Antagonist
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
CI-898
Neutrexin
TMQ
TMX
Trimetrexato
Trimetrexatum
Trimetrexic acid
Chemical FormulaC19H23N5O3
Average Molecular Mass369.418 g/mol
Monoisotopic Mass369.180 g/mol
CAS Registry Number52128-35-5
IUPAC Name5-methyl-6-{[(3,4,5-trimethoxyphenyl)amino]methyl}quinazoline-2,4-diamine
Traditional Nametrimetrexate
SMILESCOC1=CC(NCC2=C(C)C3=C(NC(=N)NC3=N)C=C2)=CC(OC)=C1OC
InChI IdentifierInChI=1S/C19H23N5O3/c1-10-11(5-6-13-16(10)18(20)24-19(21)23-13)9-22-12-7-14(25-2)17(27-4)15(8-12)26-3/h5-8,22H,9H2,1-4H3,(H4,20,21,23,24)
InChI KeyInChIKey=NOYPYLRCIDNJJB-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazanaphthalenes
Sub ClassBenzodiazines
Direct ParentQuinazolinamines
Alternative Parents
Substituents
  • Quinazolinamine
  • Methoxyaniline
  • Aminophenyl ether
  • Aniline or substituted anilines
  • Phenylalkylamine
  • Phenoxy compound
  • Methoxybenzene
  • Phenol ether
  • Anisole
  • Secondary aliphatic/aromatic amine
  • Alkyl aryl ether
  • Aralkylamine
  • Aminopyrimidine
  • Pyrimidine
  • Benzenoid
  • Imidolactam
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Ether
  • Azacycle
  • Secondary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Amine
  • Primary amine
  • Organic oxygen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point215-217°C
Boiling PointNot Available
Solubility31.4 mg/L
LogP2.55
Predicted Properties
PropertyValueSource
Water Solubility0.031 g/LALOGPS
logP2.36ALOGPS
logP2.28ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)17.04ChemAxon
pKa (Strongest Basic)7.54ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area117.54 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity107.7 m³·mol⁻¹ChemAxon
Polarizability40.24 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
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, Positivesplash10-0ugj-0409000000-97a2080cda5a334649532017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00dr-0409000000-a9fcda741827d39a85bc2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-0903000000-d3e9f90709b809eb4f3d2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-2911000000-97342eb0d2ab1fad8f132016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-0209000000-e610f7928dd8d57d924c2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-0209000000-c28a10a57fcb7298832a2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00kf-9431000000-249d2de16520a29665852016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0109000000-a0632a23538eb5952dd12021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-0309000000-95e446c0693d174b1b3e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-0930000000-a03a19d017251496a0fb2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-0009000000-f667390d4352ff65f24d2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0gbi-0129000000-24c353e7a0c027954a2a2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00vj-2493000000-41a8bf8d77660b776bda2021-10-11View Spectrum
Toxicity Profile
Route of ExposureIntravenous injection
Mechanism of ToxicityIn vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.
MetabolismHepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate. Route of Elimination: Ten to 30% of the administered dose is excreted unchanged in the urine. Half Life: 11 to 20 hours
Toxicity ValuesLD50: 62 mg/kg (Intravenous, Mouse) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use, with concurrent leucovorin administration (leucovorin protection), as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Also used to treat several types of cancer including colon cancer.
Minimum Risk LevelNot Available
Health EffectsAntibiotic resistance
SymptomsThe most common side effects from antibiotics are diarrhea, nausea, vomiting. Fungal infections of the mouth, digestive tract and vagina can also occur with antibiotics
TreatmentIn the event of overdose, Trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. (3)
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01157
HMDB IDHMDB15288
PubChem Compound ID5583
ChEMBL IDCHEMBL119
ChemSpider ID5381
KEGG IDC11154
UniProt IDNot Available
OMIM ID
ChEBI ID119101
BioCyc IDNot Available
CTD IDNot Available
Stitch IDTrimetrexate
PDB IDTMQ
ACToR IDNot Available
Wikipedia LinkTrimetrexate
References
Synthesis Reference

Martin Stogniew, Javad M. Zadei, “Compositions comprising trimetrexate and methods of their synthesis and use.” U.S. Patent US6258821, issued January, 1974.

MSDSNot Available
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Drugs.com [Link]
  3. RxList: The Internet Drug Index (2009). [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Dihydrofolate reductase
General Function:
Nadph binding
Specific Function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0014 uMNot AvailableBindingDB 18268
Inhibitory0.013 uMNot AvailableBindingDB 18268
Inhibitory0.083 uMNot AvailableBindingDB 18268
IC500.0014 uMNot AvailableBindingDB 18268
IC500.0015 uMNot AvailableBindingDB 18268
IC500.0026 uMNot AvailableBindingDB 18268
IC500.01 uMNot AvailableBindingDB 18268
IC500.012 uMNot AvailableBindingDB 18268
IC500.016 uMNot AvailableBindingDB 18268
IC500.018 uMNot AvailableBindingDB 18268
IC500.027 uMNot AvailableBindingDB 18268
IC500.042 uMNot AvailableBindingDB 18268
IC500.047 uMNot AvailableBindingDB 18268
IC500.0809 uMNot AvailableBindingDB 18268
IC500.09 uMNot AvailableBindingDB 18268
IC500.26 uMNot AvailableBindingDB 18268
IC50340 uMNot AvailableBindingDB 18268
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Bertino JR, Zhao SC, Mineishi S, Ercikan-Abali EA, Banerjee D: Use of variants of dihydrofolate reductase in gene transfer to produce resistance to methotrexate and trimetrexate. Prog Exp Tumor Res. 1999;36:82-94. [10386066 ]
  3. Graffner-Nordberg M, Kolmodin K, Aqvist J, Queener SF, Hallberg A: Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii. J Med Chem. 2001 Jul 19;44(15):2391-402. [11448221 ]
  4. Warlick CA, Diers MD, Wagner JE, McIvor RS: In vivo selection of antifolate-resistant transgenic hematopoietic stem cells in a murine bone marrow transplant model. J Pharmacol Exp Ther. 2002 Jan;300(1):50-6. [11752096 ]
  5. Zhu WY, Bunni M, Priest DG, DiCapua JL, Dressler JM, Chen Z, Melera PW: Severe folate restriction results in depletion of and alteration in the composition of the intracellular folate pool, moderate sensitization to methotrexate and trimetrexate, upregulation of endogenous DHFR activity, and overexpression of metallothionein II and folate receptor alpha that, upon folate repletion, confer drug resistance to CHL cells. J Exp Ther Oncol. 2002 Sep-Oct;2(5):264-77. [12416030 ]
  6. Sweeney CL, Frandsen JL, Verfaillie CM, McIvor RS: Trimetrexate inhibits progression of the murine 32Dp210 model of chronic myeloid leukemia in animals expressing drug-resistant dihydrofolate reductase. Cancer Res. 2003 Mar 15;63(6):1304-10. [12649191 ]
  7. Rosowsky A, Mota CE, Wright JE, Freisheim JH, Heusner JJ, McCormack JJ, Queener SF: 2,4-Diaminothieno[2,3-d]pyrimidine analogues of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J Med Chem. 1993 Oct 15;36(21):3103-12. [8230096 ]
  8. Forsch RA, Queener SF, Rosowsky A: Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium. Bioorg Med Chem Lett. 2004 Apr 5;14(7):1811-5. [15026078 ]
  9. Rosowsky A, Fu H, Chan DC, Queener SF: Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridine s as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. J Med Chem. 2004 May 6;47(10):2475-85. [15115391 ]
  10. Gangjee A, Lin X, Queener SF: Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. J Med Chem. 2004 Jul 1;47(14):3689-92. [15214795 ]
  11. Gangjee A, Namjoshi OA, Raghavan S, Queener SF, Kisliuk RL, Cody V: Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles. J Med Chem. 2013 Jun 13;56(11):4422-41. doi: 10.1021/jm400086g. Epub 2013 May 21. [23627352 ]
  12. Rosowsky A, Forsch RA, Queener SF: 2,4-Diaminopyrido[3,2-d]pyrimidine inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii. J Med Chem. 1995 Jul 7;38(14):2615-20. [7629801 ]
  13. Gangjee A, Vasudevan A, Queener SF, Kisliuk RL: 6-substituted 2,4-diamino-5-methylpyrido[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents. J Med Chem. 1995 May 12;38(10):1778-85. [7752201 ]
  14. Piper JR, Johnson CA, Krauth CA, Carter RL, Hosmer CA, Queener SF, Borotz SE, Pfefferkorn ER: Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations. J Med Chem. 1996 Mar 15;39(6):1271-80. [8632434 ]
  15. Gangjee A, Devraj R, Queener SF: Synthesis and dihydrofolate reductase inhibitory activities of 2,4-diamino-5-deaza and 2,4-diamino-5,10-dideaza lipophilic antifolates. J Med Chem. 1997 Feb 14;40(4):470-8. [9046337 ]
  16. Gangjee A, Shi J, Queener SF: Synthesis and biological activities of conformationally restricted, tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases. J Med Chem. 1997 Jun 6;40(12):1930-6. [9191971 ]
  17. Rosowsky A, Papoulis AT, Queener SF: 2,4-Diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine analogues of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J Med Chem. 1998 Mar 12;41(6):913-8. [9526565 ]
  18. Gangjee A, Guo X, Queener SF, Cody V, Galitsky N, Luft JR, Pangborn W: Selective Pneumocystis carinii dihydrofolate reductase inhibitors: design, synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines. J Med Chem. 1998 Apr 9;41(8):1263-71. [9548816 ]
  19. Gangjee A, Vidwans AP, Vasudevan A, Queener SF, Kisliuk RL, Cody V, Li R, Galitsky N, Luft JR, Pangborn W: Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents. J Med Chem. 1998 Aug 27;41(18):3426-34. [9719595 ]
  20. Gangjee A, Adair O, Queener SF: Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl] pyrido[2,3-d]pyrimidines. J Med Chem. 1999 Jul 1;42(13):2447-55. [10395486 ]
  21. Rosowsky A, Cody V, Galitsky N, Fu H, Papoulis AT, Queener SF: Structure-based design of selective inhibitors of dihydrofolate reductase: synthesis and antiparasitic activity of 2, 4-diaminopteridine analogues with a bridged diarylamine side chain. J Med Chem. 1999 Nov 18;42(23):4853-60. [10579848 ]
  22. Rosowsky A, Bader H, Wright JE, Keyomarsi K, Matherly LH: Synthesis and biological activity of N omega-hemiphthaloyl-alpha,omega- diaminoalkanoic acid analogues of aminopterin and 3',5-dichloroaminopterin. J Med Chem. 1994 Jul 8;37(14):2167-74. [8035423 ]
  23. Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL: Synthesis of classical and nonclassical, partially restricted, linear, tricyclic 5-deaza antifolates. J Med Chem. 2002 Nov 7;45(23):5173-81. [12408727 ]
  24. Stevens MF, Phillip KS, Rathbone DL, O'Shea DM, Queener SF, Schwalbe CH, Lambert PA: Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase. J Med Chem. 1997 Jun 6;40(12):1886-93. [9191966 ]
  25. Schormann N, Velu SE, Murugesan S, Senkovich O, Walker K, Chenna BC, Shinkre B, Desai A, Chattopadhyay D: Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg Med Chem. 2010 Jun 1;18(11):4056-66. doi: 10.1016/j.bmc.2010.04.020. Epub 2010 Apr 9. [20452776 ]
  26. Gangjee A, Vidwans A, Elzein E, McGuire JJ, Queener SF, Kisliuk RL: Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. J Med Chem. 2001 Jun 7;44(12):1993-2003. [11384244 ]
  27. Kuyper LF, Baccanari DP, Jones ML, Hunter RN, Tansik RL, Joyner SS, Boytos CM, Rudolph SK, Knick V, Wilson HR, Caddell JM, Friedman HS, Comley JC, Stables JN: High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size. J Med Chem. 1996 Feb 16;39(4):892-903. [8632413 ]
  28. Rosowsky A, Mota CE, Queener SF, Waltham M, Ercikan-Abali E, Bertino JR: 2,4-Diamino-5-substituted-quinazolines as inhibitors of a human dihydrofolate reductase with a site-directed mutation at position 22 and of the dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii. J Med Chem. 1995 Mar 3;38(5):745-52. [7877140 ]
Target Details
2. Dihydrofolate reductase
General Function:
Nadp binding
Specific Function:
Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Gene Name:
Not Available
Uniprot ID:
P16184
Molecular Weight:
23883.325 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.042 uMNot AvailableBindingDB 18268
References
  1. Chan DC, Laughton CA, Queener SF, Stevens MF: Structural studies on bioactive compounds. 34. Design, synthesis, and biological evaluation of triazenyl-substituted pyrimethamine inhibitors of Pneumocystis carinii dihydrofolate reductase. J Med Chem. 2001 Aug 2;44(16):2555-64. [11472209 ]