Methotrexate structure

Figure 3 (a) Structure of methotrexate and the structures of three model compounds that could... 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

The antimetabolites interfere with various metabolic functions of cells, thereby disrupting normal cell functions. They inactivate enzymes or alter the structure of DNA, changing the DNA s ability to replicate These drag are most effective in the treatment of rapidly dividing neoplastic cells. Examples of the antimetabolites include methotrexate and fluorouracil (Adrucil). 

Matthews DA, Alden RA, Bolin JT, Filman DJ, Freer ST, Hamlin R, Hoi WG, Kisliuk RL, Pastore EJ, Plante FT, Xuong N, Kraut J. Dihydrofolate reductase from Lactobacillus casei. X-ray structure of the enzyme methotrexate-NADPH complex. J Biol Chem 1978 253 6946-54. 

Chemical structure of monomers and intermediates was confirmed by FT-IR and FT-NMR. Molecular weight distribution of polymers was assessed by GPC and intrinsic viscosity. The thermal property was examined by differential scanning calorimetry. The hydrolytic stability of the polymers was studied under in vitro conditions. With controlled drug delivery as one of the biomedical applications in mind, release studies of 5-fluorouracil and methotrexate from two of these polymers were also conducted. 

Figure 1.4 Left panel Space filing model of the structure of bacterial dihydrofolate reductase with methotrexate bound to the active site. Right panel Close-up view of the active site, illustrating the structural complementarity between the ligand (methotrexate) and the binding pocket. See color insert. Source Courtesy of Nesya Nevins.

Poe, K. Williams, and K. Hoogsteen, Dihydrofolate reductase X-ray structure of the binary complex with methotrexate, Science 197 452 (1977). 

Exposure to the fetus in the first 2 weeks after conception may have an all or nothing effect (i.e., could destroy the embryo or have no ill effect). Exposure during the period of organogenesis (18 to 60 days postconception) may result in structural anomalies (e.g., methotrexate, cyclophosphamide, diethylstilbestrol, lithium, retinoids, thalidomide, certain antiepileptic drugs, and coumarin derivative). 

Pignatello R, Toth I, Puglisi G (2001) Structural effects of lipophilic methotrexate conjugates on model phospholipid biomembranes. Thermochim. Acta 380 255-264. 

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

Rheumatoid arthritis (RA moderate to severe) In combination with methotrexate for reducing the signs and symptoms and inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active RA who have had an inadequate response to methotrexate. 

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