Methotrexate is theclassic antimetabolite of folic acid structurally derived by Nmethylationof the para-aminobenzoic acid residue (PABA)and replacement of a pteridine hydroxyl by the bioisostericamino group. The conversion of —MOH to —MNH2 increasesthe basicity of N-3 and yields greater enzyme affinity. Thisdrug competitively inhibits the binding of the substrate folicacid to the enzyme DHFR, resulting in reductions in the synthesisof nucleic acid bases, perhaps most importantly, theconversion of uridylate to thymidylate as catalyzed bythymidylate synthetase.In addition, purine synthesis is inhibitedbecause the N-10-formyl tetrahydrofolic acid is aformyl donor involved in purine synthesis.
Recall that in Scheme 10.16, THFs are cofactors in at leasttwo key steps in the normal biosynthesis of purines.Methotrexate is a broad-spectrum antineoplastic agentcommonly used in the treatment of acute lymphoblastic andmyeloblastic leukemia and other lymphomas and sarcomas.The major side effects seen are bone marrow suppression,pulmonary fibrosis, and GI ulceration. Leucovorin is oftengiven 6 to 24 hours after methotrexate to prevent the longtermeffects on normal cells by preventing the inhibition ofDNA synthesis. Related to this is Pemetrexed, but its scopeis greater in that it not only inhibits DHFR but also TS andglycinamide ribonucleotide formyltransferase (GARFT),which is involved in purine biosynthesis.The material is taken into tumor cells by the reduced folatecarriersystems and subsequently converted to the polyglutamate,which is retained in the cell.
