MTX Chemistry

MTX is a solid
odorless, yellow or orange-brown crystallite compound. Chemically MTX is
4-amino-4-deoxy-N-methyl- Pteroylglutamic acid. It shows the molecular structural difference from folic acid
only in that folic acid has a hydroxyl group (OH-) in place of the 4-amino group
on the pteridine ring and there is no methyl group at the N10 position (W. Bleyer, 1978). Methotrexate, (previously amethopterin), differs
from aminopterin in that the latter is also not methylated at the N10 position. Therefore the active
site of the molecule appears to involve the pteridine ring portion. MTX is a
weak organic acid in nature and lipid insoluble at physiological pH. Its
solubility in human urine is directly proportional to its increasing pH. It is
soluble in dilute solutions of alkali hydroxides and carbonates, slightly
soluble in dilute hydrochloric acid whereas practically insoluble in water and
alcohol (Lewis, R.J., Sr (Ed.). Hawley’s
Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons,
Inc. 1997., p. 722)

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Its molecular

structure differs from folic acid only in that folic

acid has a hydroxyl group in place of
the 4-

amino group on the pteridine ring
and there is

no methyl group at the N’Oposition. 
Methotrexate-

ate, also
known as amethopterin, differs from

aminopterin in that
the latter is also not methyl-

rated at the N’O  position.  Hence the active site of

the molecule
appears to involve the pteridine

ring portion.

Its molecular

structure differs from folic acid only in that folic

acid has a hydroxyl group in place of
the 4-

amino group on the pteridine ring
and there is

no methyl group at the position. 
Methotrexate-

ate, also
known as amethopterin, differs from

aminopterin in that
the latter is also not methyl-

rated at the N’O  position.  Hence the active site of

the molecule
appears to involve the pteridine

ring 
portion.

A)

 

 

Fig1.A) Pteridine, just to compare the common ring
all the structures mentioned. B) Methotrexate molecular structure, C) Folic
acid Molecular structure, D) Aminopterin Molecular structure E) Comparison
between B, C and D showing the structural difference in terms of functional
group. P.C: “All structural image
taken from Wikipedia the free encyclopedia”.

Wikipedia
the fee encyclopedia

D) Aminopterin

D)

E)

C) Folic Acid

B) Methotrexate

 

 

 

 

 

 

 

 

 

 

 

 

Molecular
weight is 454.44 g/mol and empirical formula is C20H22N8O5
with biological half-life 3-10 hours (lower doses, 30mg/m2). The bioavailability at
lower doses is approximately 60% and comparatively less at higher doses. (Trexall, Rheumatrex (methotrexate) dosing,
indications, interactions, adverse effects, and more”. Medscape Reference.
WebMD. Archived from the original on 8 February 2014. Retrieved 12 April 2014.)

 

 

 

 

Mechanism
of action

 

Methotrexate is
known to inhibit Dihydrofolate reductase (DHFR) competitively having 1000-fold
more affinity than folate. DHFR is a key enzyme functionally associated to
convert dihydrofolate to active tetrahydrofolate (reduced folate factors)  (Rajagopalan et al., 2002). Tetrahydrofolate (reduced folate factors) plays an
important role in transferring one carbon unit in biochemical reactions
specific for the synthesis of thymidylic acid and ionosinic acid. The former is an important component of DNA,
whereas latter is the precursor of purines involved in the synthesis of both
DNA and RNA (W. Bleyer, 1978). In humans,
MTX inhibits DNA synthesis to a greater degree as compared to RNA synthesis
signifying that thymidylate synthesis is a most
crucial mechanism for MTX cytotoxicity. This makes it cell cycle-dependent thereby acting primarily on DNA
synthesis (S-phase) (Hoffbrand and Tripp, 1972). Hence the cells undergoing rapid proliferation in the
cell cycle are more liable to the cytotoxic effect of MTX. Chemotherapy affects
in cell division by damaging DNA or RNA. If the cancer cells cannot divide, the
tumor will shrink. Chemotherapy drugs could be effective in dividing cells, (cell-cycle specific); or to
cells that are at rest, (cell-cycle non-specific) (“Methotrexate.” Scott
Hamilton CARES Initiative 21 Nov 2012.