79640-75-8

Upstream product

• 67022-39-3 γ-methyl N'-<4--N-methylamino>benzoyl>-L-glutamate 
• 79640-69-0 tert-butyl N'-<4--N-methylamino>benzoyl>-L-glutamic acid γ-hydrazide 
• 1499-55-4 L-glutamic acid 5-methyl ester 
• 59-05-2 N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid 
• 79648-88-7 α-tert-butyl γ-methyl N'-<4--N-methylamino>benzoyl>-L-glutamate 
• 10541-83-0 N-methyl-p-aminobenzoic acid 

Downstream Products

• 121788-84-9 (S)-2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-4-[2,2,2-trifluoro-eth-(E)-ylidene-hydrazinocarbonyl]-butyric acid 
• 121788-83-8 (S)-4-Azidocarbonyl-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyric acid 

Relevant academic research and scientific papers

Synthesis of methotrexate-antibody conjugates by regiospecific coupling and assessment of drug and antitumor activities

In order to increase the retention of drug activity, regiospecific coupling has been used to synthesize conjugates of methotrexate (MTX, 1) with normal rabbit IgG (NRG) and a mouse anti-human renal cancer monoclonal IgG (Dal K-20). MTX γ-methyl ester (4) was produced either by selective esterification of MTX or by coupling of 4-amino-4-deoxy-N10-methylpteroic acid (2) with suitable glutamic acid derivatives. The MTX γ-methyl ester (4) was then converted to the corresponding hydrazide 6. An amide-linked conjugate was formed when the MTX γ-hydrazide (6) was converted to reactive acylating species 7 by using tert-butyl nitrite or trifluoroacetaldehyde, which were reacted with nucleophilic centers, presumably ε-amino groups, in native IgG. A hydrazone-linked conjugate was formed when MTX γ-hydrazide (6) was reacted directly with IgG that had first been oxidized with periodate to form polyaldehyde IgG. The regiospecifically synthesized conjugates were somewhat more effective inhibitors in vitro of dihydrofolate reductase and of colony formation by human renal cancer (Caki-1) cells than were control nonregiospecific conjugates.

Methotrexate Analogues. 14. Synthesis of New γ-Substituted Derivatives as Dihydrofolate Reductase Inhibitors and Potential Anticancer Agents

The γ-tert-butyl ester (1), γ-hydrazide (2), γ-n-butylamide (3), and γ-benzylamide (4) derivatives of methotrexate (MTX) were synthesized from 4-amino-4-deoxy-N10-methylpteroic acid (APA) and the appropriate blocked L-glutamic acid precursors with the aid of the peptide bond forming reagent diethyl phosphorocyanidate.The affinity of these side chain modified products for dihydrofolate reductase (DHFR) from Lactobacillus casei and L1210 mouse leukemic cells was determined spectrophotometrically or by competitive radioligand binding assay, and their cytotoxicity was evaluated against L1210 leukemic cells in culture.The results provide continuing support for the view that the "γ-terminal region" of the MTX side chain is an attractive site for molecular modification of this anticancer agent.