Folate analogues

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

Sulphonamides are structural analogues of PABA. They competitively inhibit the incorporation of PABA into dihydropteroic acid and there is some evidence for their incorporation into false folate analogues which inhibit subsequent metabolism. The presence of excess PABA will reverse the inhibitory action of sulphonamides, as will thymine, adenine, guanine and methionine. However, these nutrients are not normally available at the site of infections for which the sulphonamides are used. 

Spark, M. J., D. A. Winkler, and P. R. Andrews. 1982. Conformational Analysis of Folates and Folate Analogues. Int. J. Quant. Chem., Quant. Biol. Symp. 9, 321. 

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

In stark contrast, the second historically significant anti-cancer drug, methotrexate, originated from nutritional research. The observation that the vitamin folic acid stimulated prohferation of acute lymphoblastic leukemia (ALL) cells in children prompted synthesis of folate analogues. In the late 1940s methotrexate became the first drug to induce remissions in children with ALL [11]. 

Folate analogues continue to have importance in chemotherapy, especially heterocyclic analogues other than pteridines which are covered in Chapters 10.15-10.17 and 10.19. 1,3-Dimethyllumazine analogues of folates for use as model compounds have been prepared by side-chain elaboration of 6-bromomethyl-l,3-dimethyllumazine (Scheme 34) <1996JHC341>. More notable in this work, however, was the synthesis of the bromomethyl precursor itself in addition to routine bromination of the 6-methyllumazine 175 prepared by condensation of dihydroxyacetone with 5,6-diamino-l,3-dimethyluracil, a cycloaddition reaction between trimethylsilyl enol ethers and the pyrimidyl bisimine 177, via cycloadducts such as 176, afforded substituted pteridines in moderate to good yields. 

Kaplan, H. G. 1980. Inhibition of buttermilk xanthine oxidase by folate analogues and derivatives. Biochem. Pharmacol. 29, 2135-2141. 

The first reported 10-deaza folate analogues were 10-deazaFA (471) and 10-deaza-9,10-dehydroFA (470) [179], Treatment of 2-acetylpterin-6-carbox-aldehyde [464) with ylide (465) furnished (466). Alkaline hydrolysis of (466) and reacetylation gave (468) which was converted to (470) under standard conditions. Catalytic hydrogenation of (466) with subsequent saponification and oxidation produced (467) which was converted analogously to (471) (,Scheme 3.93). 

Methanopterin (20) is a folate analogue that is isolated from an archae-bacteria, Methanosarcina thermophila, and the bacteria produces methane from CO2 under anaerobic conditions [18-24]. In the methane-producing metabolic process (Scheme 2), tetrahydromethanopterin (21) is known to work as a cofactor for the reduction of the Ci unit. Here, 21 accepts a formyl group that originates from CO2 and transforms it into the formyl... 

Routes to the pyrrolo[3,2-[Pg.260]

Deazaaminopterin derivatives (folate analogues) are potent antineoplastics <88USP4725687, 91USP5077404) particularly in treating tumors resistant to methotrexate or aminopterin <90MIP9000172>. Some derivatives are equipotent with methotrexate, both as inhibitors of bovine liver dihydrofolate reductase and of L1210 murine leukemia cells. 

Folate in the human organism is converted to tetrahydrofolate (THF or FH4) by a reductive process. The reduction reaction is a stepwise one folate to dihydrofolate, then to THF. A single enzyme, dihydrofolate reductase, catalyzes both steps. The reaction is inhibited by folate analogues and the antitumor agents methotrexate and aminopterin (Figure 6.3). Because THF is required for DNA biosynthesis (Chapter 10) and tumors have a very high level of DNA biosynthetic activity, even modest decreases in THF availability will inhibit tumor growth. 

Category Antimetabolite Antineoplastic Folate analogue Half-life Terminal up to 198 Hours Clinically important, potentially hazardous interactions with folic acid/folates, L-methylfolate... 

Inhibition of Dihydrofolate Reductase Folate-dependent reactions in the body are inhibited by folate analogues (or antagonists, e.g., methotrexate). Before it can function as a coenzyme in one-carbon transfer reactions, folate (F) must be reduced by dihydrofolate reductase to tetrahydrofolate (FH4). Dihydrofolate... 

Folate analogues, such as methotrexate (Figure 27-3), are folate antagonists. They block production of FH2 and FH4 by dihydrofolate reductase and lead to diminished purine biosynthesis (inhibition of reactions 3 and 9 in Figure 27-8). Methotrexate also affects metabolism of amino acids and pyrimidine (inhibition of thymidylate synthesis) and inhibits DNA, RNA, and protein synthesis. It is effective in the treatment of breast cancer, cancer of the head and neck, choriocarcinoma, osteogenic sarcoma, and acute forms of leukemia. High doses of methotrexate can be tolerated provided that the patient also receives folinic... 

W6. Williams, J. W., Duggleby, R. G., Cutler, R., and Morrison, J. F., Hie inhibition of dihydrofblate reductase by folate analogues Structural requirements for slow and tight-binding inhibition. Biochem. Pharmacol. 29, 589-595 (1980). 

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