Compounds > gamma-tert-butyl methotrexate
Page last updated: 2024-12-07

gamma-tert-butyl methotrexate

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Description

Gamma-tert-butyl methotrexate (GTBM) is a synthetic derivative of methotrexate, a potent antifolate drug, which has been investigated for its potential anti-cancer activity. GTBM was synthesized by attaching a tert-butyl group to the gamma-carbon of the glutamic acid moiety in methotrexate. This modification is designed to increase the compound's lipophilicity, potentially allowing it to penetrate cell membranes more easily and reach its target in the cell, dihydrofolate reductase (DHFR). The primary mechanism of action of GTBM, like methotrexate, is the inhibition of DHFR, an enzyme crucial for folate metabolism and DNA synthesis. By inhibiting DHFR, GTBM disrupts the synthesis of DNA, RNA, and other essential cellular components, ultimately leading to cell death. Studies have explored GTBM's anti-cancer effects in various cancer models, including leukemia, lymphoma, and solid tumors. However, research on GTBM has been limited, and its clinical efficacy and safety remain to be fully established. The potential advantages of GTBM over methotrexate include its increased lipophilicity, which may improve its delivery to the tumor, and its potential to overcome methotrexate resistance mechanisms. Despite the promising preclinical findings, further research is required to evaluate GTBM's potential as a therapeutic agent in cancer treatment. The investigation of GTBM is driven by the search for novel and effective anti-cancer drugs with improved pharmacokinetic properties and potential to overcome resistance to existing therapies.'
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gamma-tert-butyl methotrexate: structure given in first source [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

Cross-References

ID SourceID
PubMed CID100824
CHEMBL ID422225
MeSH IDM0131573

Synonyms (12)

Synonym
nsc378900
l-glutamic acid,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-, 5-(1,1-dimethylethyl) ester
79640-76-9
l-glutamic acid,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-, 1,1-dimethylethyl ester
nsc-378900
CHEMBL422225
gamma-tert-butyl methotrexate
2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid
gamma-tbmtx
l-glutamic acid, n-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-, 5-(1,1-dimethylethyl) ester
nsc 378900
(2s)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Protein Targets (2)

Other Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Dihydrofolate reductaseMus musculus (house mouse)ID500.00290.00200.01640.0500AID57317
Dihydrofolate reductaseLacticaseibacillus caseiID500.01850.00620.01620.0270AID57769; AID57770
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Ceullar Components (1)

Processvia Protein(s)Taxonomy
cytosolDihydrofolate reductaseMus musculus (house mouse)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (42)

Assay IDTitleYearJournalArticle
AID200597Cell-growth inhibition against SCC25 cell line1988Journal of medicinal chemistry, Jul, Volume: 31, Issue:7
Methotrexate analogues. 33. N delta-acyl-N alpha-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: synthesis and in vitro antitumor activity.
AID200602Cell growth inhibition against human squamous cell carcinoma (SCC68) line1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID57317Compound was tested for inhibition of L1210 dihydrofolate reductase by competitive [3H]MTX binding assay in L1210 mouse leukemia cell lines1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
AID99183Cell growth inhibition against mouse leukemia L1210/R81 cells1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120932Antitumor activity against L1210 leukemia in mice by range survival days at 20 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID115361antitumor activity against L1210 leukemia in mice by % increase in life span at 80 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID46809Cell growth inhibition against CEM/MTX cell from human leukemic lymphoblasts1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120936Antitumor activity against L1210 leukemia in mice by range survival days at 60 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120923Antitumor activity against L1210 leukemia in mice by mean survival days at 20 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID110608Antitumor activity against L1210 leukemia in mice by % weight change in 7 days at 40 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID112747Antitumor activity against L1210 leukemia in mice by % increase in life span at 40 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120925Antitumor activity against L1210 leukemia in mice by mean survival days at 40 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID200604Cell growth inhibition against human squamous cell carcinoma (SCC68/R1) line1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID99174Cell growth inhibition against mouse leukemia L1210/R71 cells1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID200608Cell growth inhibition against human squamous cell carcinoma (SCC78/R1) line1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID45829Cell growth inhibition against CEM cell from human leukemic lymphoblasts1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID57922Ratio of compound ID50 relative to methotrexate, against Lactobacillus casei dihydrofolate reductase by competitive [3H]-MTX binding assay1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
AID120937Antitumor activity against L1210 leukemia in mice by range survival days at 80 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID200590Cell-growth inhibition against SCC15/R1 cell line1988Journal of medicinal chemistry, Jul, Volume: 31, Issue:7
Methotrexate analogues. 33. N delta-acyl-N alpha-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: synthesis and in vitro antitumor activity.
AID120930Antitumor activity against L1210 leukemia in mice by range survival days at 10 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID57923Ratio of compound ID50 relative to methotrexate, against Lactobacillus casei dihydrofolate reductase using spectrophotometric assay at 340 nm1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
AID98127Cell growth inhibition against mouse leukemia L1210 cells1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120934Antitumor activity against L1210 leukemia in mice by range survival days at 40 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID112745Antitumor activity against L1210 leukemia in mice by % increase in life span at 20 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120928Antitumor activity against L1210 leukemia in mice by mean survival days at 80 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID110604Antitumor activity against L1210 leukemia in mice by % weight change in 7 days at 10 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120927Antitumor activity against L1210 leukemia in mice by mean survival days at 60 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID200600Cell growth inhibition against human squamous cell carcinoma (SCC25/R1) line1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID57769Compound was tested for inhibition of Lactobacillus casei dihydrofolate reductase using competitive [3H]MTX binding assay1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
AID112743Antitumor activity against L1210 leukemia in mice by % increase in life span at 10 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID200606Cell growth inhibition against human squamous cell carcinoma (SCC78) line1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID112749Antitumor activity against L1210 leukemia in mice by % increase in life span at 60 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID96664Growth inhibitory activity against L1210 mouse leukemia cell line1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
AID200588Cell-growth inhibition against SCC15 cell line1988Journal of medicinal chemistry, Jul, Volume: 31, Issue:7
Methotrexate analogues. 33. N delta-acyl-N alpha-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: synthesis and in vitro antitumor activity.
AID110610Antitumor activity against L1210 leukemia in mice by % weight change in 7 days at 60 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID57921Ratio of compound ID50 relative to methotrexate against dihydrofolate reductase by competitive [3H]-MTX binding assay in mouse leukemia L1210 cell line1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
AID110606Antitumor activity against L1210 leukemia in mice by % weight change in 7 days at 20 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID110611Antitumor activity against L1210 leukemia in mice by % weight change in 7 days at 80 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID120786Antitumor activity against L1210 leukemia in mice by mean survival days at 10 mg/kg dose1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID200599Cell-growth inhibition against SCC25/R1 cell line1988Journal of medicinal chemistry, Jul, Volume: 31, Issue:7
Methotrexate analogues. 33. N delta-acyl-N alpha-(4-amino-4-deoxypteroyl)-L-ornithine derivatives: synthesis and in vitro antitumor activity.
AID200592Cell growth inhibition against human squamous cell carcinoma (SCC25) line1985Journal of medicinal chemistry, May, Volume: 28, Issue:5
Methotrexate analogues. 25. Chemical and biological studies on the gamma-tert-butyl esters of methotrexate and aminopterin.
AID57770Compound was tested for inhibition of Lactobacillus casei dihydrofolate reductase using spectrophotometric assay at 340 nm1981Journal of medicinal chemistry, Dec, Volume: 24, Issue:12
Methotrexate analogues. 14. Synthesis of new gamma-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agents.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (5)

TimeframeStudies, This Drug (%)All Drugs %
pre-19904 (80.00)18.7374
1990's1 (20.00)18.2507
2000's0 (0.00)29.6817
2010's0 (0.00)24.3611
2020's0 (0.00)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 12.51

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be weak demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index12.51 (24.57)
Research Supply Index1.79 (2.92)
Research Growth Index4.31 (4.65)
Search Engine Demand Index0.00 (26.88)
Search Engine Supply Index0.00 (0.95)

This Compound (12.51)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials0 (0.00%)5.53%
Reviews0 (0.00%)6.00%
Case Studies0 (0.00%)4.05%
Observational0 (0.00%)0.25%
Other5 (100.00%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]
SubstanceRelationship StrengthStudiesTrialsClassesRoles
trimetrexate
Trimetrexate: A 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.		1.9810
methotrexate
[no description available]		3.0650dicarboxylic acid;
monocarboxylic acid amide;
pteridines		abortifacient;
antimetabolite;
antineoplastic agent;
antirheumatic drug;
dermatologic drug;
DNA synthesis inhibitor;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor;
immunosuppressive agent
aminopterin
Aminopterin: A folic acid derivative used as a rodenticide that has been shown to be teratogenic.		2.3720dicarboxylic acidEC 1.5.1.3 (dihydrofolate reductase) inhibitor;
mutagen
ConditionIndicatedRelationship StrengthStudiesTrials
Leukemia L 1210
[description not available]		02.6530
Experimental Neoplasms
[description not available]		01.9710
Carcinoma, Epidermoid
[description not available]		01.9610
Leucocythaemia
[description not available]		01.9610
Carcinoma, Squamous Cell
A carcinoma derived from stratified SQUAMOUS EPITHELIAL CELLS. It may also occur in sites where glandular or columnar epithelium is normally present. (From Stedman, 25th ed)		01.9610
Leukemia
A progressive, malignant disease of the blood-forming organs, characterized by distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias were originally termed acute or chronic based on life expectancy but now are classified according to cellular maturity. Acute leukemias consist of predominately immature cells; chronic leukemias are composed of more mature cells. (From The Merck Manual, 2006)		01.9610
Leukemia, Lymphocytic
[description not available]		02.3820
Leukemia, Lymphoid
Leukemia associated with HYPERPLASIA of the lymphoid tissues and increased numbers of circulating malignant LYMPHOCYTES and lymphoblasts.		02.3820