106400-81-1

Basic information

• Product Name: Lometrexol
• Synonyms: Lometrexol;(6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid;N-[4-[2-[[(6R)-2-Amino-3,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin]-6-yl]ethyl]benzoyl]-L-glutamic acid;N-[4-[2-[[(R)-2-Amino-4-oxo-1,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin]-6-yl]ethyl]benzoyl]-L-glutamic acid;L-Glutamic acid, N-(4-(2-((6R)-2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido(2,3-D)pyrimidin-6-yl)ethyl)benzoyl)-;L-Glutamic acid, N-(4-(2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido(2,3-D)pyrimidin-6-yl)ethyl)benzoyl)-, (R)-;Lometrexolum;Lometrexolum [inn-latin]
• CAS NO: 106400-81-1
• Molecular Formula: C₂₁H₂₅N₅O₆
• Molecular Weight: 443.4531
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 106400-81-1.mol
• Article Data: 5

Chemical Properties

• Boiling Point: °Cat760mmHg
• Flash Point: °C
• Appearance: white to light yellow/
• Density: 1.56g/cm³
• Refractive Index: 1.709
• Storage Temp.: 2-8°C
• Solubility: DMSO: ≥5mg/mL
• PKA: 3.60±0.10(Predicted)
• CAS DataBase Reference: Lometrexol(CAS DataBase Reference)
• NIST Chemistry Reference: Lometrexol(106400-81-1)
• EPA Substance Registry System: Lometrexol(106400-81-1)

Safety Data

• Hazard Codes: T
• Statements: 25
• Safety Statements: 45
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 106400-81-1(Hazardous Substances Data)

Usage

Description

Glycinamide ribonucleotide formyltransferase (GART) is a folate-dependent enzyme required for de novo purine synthesis. Lometrexol is a folate analog antimetabolite with antineoplastic activity. At nanomolar conentrations, it inhibits GART preventing de novo purine synthesis, inhibiting DNA synthesis, arresting cells in the S phase of the cell cycle, and inhibiting tumor cell proliferation.

Uses

Different sources of media describe the Uses of 106400-81-1 differently. You can refer to the following data:
1. Lometrexol hydrate was used to compare the biological activity of potent inhibitor of human GARFTase.
2. It is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis.

Biochem/physiol Actions

Glycinamide Ribonucleotide Formyltransferase (GARFTase) is a folate-dependent enzyme required for de novo purine synthesis. Lometrexate is a potent inhibitor of GARFTase, but does not interfere with enzymes involved in the synthesis of folate. Lometrexerol has been tested clinically for the treatment of various cancers as an anti-folate like agent, similar to methotrexate. Treatment with lometrexol rapidly decreases ATP and GTP levels, cell cycle arrest and induces apoptosis. Although depletion of nucleotide pools induces p53 expression, lometrexol is cytotoxic in both wild-type and mutant p53 expressing tumor cells. Lometrexol is cytotoxic in CCRF-CEm leukemia cells with an IC50 of 2.9 nM.

InChI:InChI=1/C21H25N5O6/c22-21-25-17-14(19(30)26-21)9-12(10-23-17)2-1-11-3-5-13(6-4-11)18(29)24-15(20(31)32)7-8-16(27)28/h3-6,12,15H,1-2,7-10H2,(H,24,29)(H,27,28)(H,31,32)(H4,22,23,25,26,30)/t12-,15+/m1/s1

Upstream product

• 3140-73-6 2-chloro-4,6-dimethoxy-1 ,3,5-triazine 
• 1118-89-4 diethyl-L-glutamate hydrochloride 
• 1878-68-8 2-(4-bromophenyl)-acetic acid 
• 127633-57-2 (S)-<2-(Azidomethyl)-4-(4-bromophenyl)butyl>propanedioic acid diethyl ester 
• 127633-58-3 (R)-(-)-<2-(Azidomethyl)-4-(4-bromophenyl)butyl>propanedioic acid diethyl ester 
• 136210-13-4 (S)-4-<2-(2-Amino-1,4,5,6,7,8-hexahydro-4-oxopyrido<2,3-d>pyrimidin-6-yl)ethyl>benzonic acid 
• 127633-60-7 (R)-(-)-4-<2-(2-Amino-1,4,5,6,7,8-hexahydro-4-oxopyrido<2,3-d>pyrimidin-6-yl)ethyl>benzonitrile 
• 127633-59-4 (S)-4-<2-(2-Amino-1,4,5,6,7,8-hexahydro-4-oxopyrido<2,3-d>pyrimidin-6-yl)ethyl>benzonitrile 
• 127633-51-6 (R)-(-)-2-Amino-6-<2-(4-bromophenyl)ethyl>-5,6,7,8-tetrahydropyrido<2,3-d>pyrimidin-4(3H)-one 
• 127633-50-5 (S)-2-Amino-6-<2-(4-bromophenyl)ethyl>-5,6,7,8-tetrahydropyrido<2,3-d>pyrimidin-4(3H)-one 
• 246043-59-4 (3RS,5R)-5-<2-(4-Bromophenyl)ethyl>-2-oxo-3-piperidinecarboxylic acid ethyl ester 
• 127633-49-2 (3RS,5S)-5-<2-(4-Bromophenyl)ethyl>-2-oxo-3-piperidinecarboxylic acid ethyl ester 
• 127633-47-0 (R)-(+)-β-(Azidomethyl)-4-bromobenzenebutanol 
• 127633-48-1 (S)-(-)-β-(Azidomethyl)-4-bromobenzenebutanol 

Relevant articles and documents

Synthesis of (6R)- And (6S)-5,10-dideazatetrahydrofolate oligo-γ-glutamates: Kinetics of multiple glutamate ligations catalyzed by folylpoly-γ-glutamate synthetase

Folylpoly-γ-glutamate synthetase (FPGS, EC 6.3.2.17) catalyzes the ATP-dependent ligation of glutamic acid to reduced folates including (6S)-5,6,7,8-tetrahydrofolate (H4PteGlu), as well as to anticancer drugs such as 5,10-dideaza-5,6,7,8-tetrahydrofolate ((6R)-DDAH 4PteGlu1, (6R)-DDATHF, Lometrexol(tm)). Synthesis of unlabeled mono- and polyglutamates, DDAH4PteGlu n (6R, n = 1-6; 6S, n = 1-2), as well as (6R)-DDAH 4Pte[14C]Glu1, was effected from (6R)- or (6S)-5,10-dideazatetrahydropteroyl azide and glutamic acid, H-Glu-γ- Glun-y-Glu-OH (n = 0-4), or [14C]glutamic acid, respectively. These compounds were evaluated as FPGS substrates to determine steady-state kinetic constants. Michaelis-Menten kinetics were observed for (6-R)-DDAH4PteGlu1, the isomer corresponding to H 4PteGlu, whereas marked substrate inhibition was observed for (6S)-DDAH4PteGlun (n = 1-2) and (6R)-DDAH 4PteGlun (n = 2-5), but not (6.R)-DDAH 4PteGlu6. Multiple ligation of glutamate renders a quantitative analysis of these data difficult. However, approximate values of KM = 0.65-1.6 μM and K1, = 144-417 μM for DDAH 4PteGln were obtained using a simple kinetic model. The Royal Society of Chemistry 2005.

Enantioselective synthesis of antifolates

A process and intermediates for the enantioselective synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid are disclosed.

Synthesis and Antifolate Activity of 5-Methyl-5,10-dideaza Analogues of Aminopterin and Folic Acid and an Alternative Synthesis of 5,10-Dideazatetrahydrofolic Acid, a Potent Inhibitor of Glycinamide Ribonucleotide Formyltransferase

The title compounds were prepared in extensions of a general synthetic approach used earlier to prepare 5-alkyl-5-deaza analogues of classical antifolates.Wittig condensation of 2,4-diaminopyridopyrimidine-6-carboxaldehyde (2a) and its 5-methyl ana