Folic acid reactions

Benkovic, S. J., Barrows, T. H., Farina, P. R. (1973). Studies on models for tetrahydro-folic acid reactions of amines with formamidinium tetrahydroquinoxaline analogs,... 

The first L-folic acid synthesis was based on the concept of a thiee-component, one-pot reaction (7,22). Ttiainino-4(3JT)-pyrirnidinone [1004-45-7] (10) was reacted simultaneously with C -dibromo aldehyde [5221-17-0] (11) and j )-aminoben2oyl-L-glutamic acid [4271-30-1] (12) to yield fohc acid (1). 

Folic acid is synthesized both in microorganisms and in plants. Guanosine-5-ttiphosphate (GTP) (33), -aminobenzoic acid (PABA), and L-glutamic acid are the precursors. Reviews are available for details (63,64). The sequence of reactions responsible for the enzymatic conversion of GTP to 7,8-dihydrofohc acid (2) is shown. 

Catalytic reduction of folic acid to 5,6,7,8-tetrahydrofolic acid (225) proceeds fast in trifluoroacetic acid (66HCA875), but a modified method using chemical reductants leads with sodium dithionite to 7,8-dihydrofolic acid (224). Further treatment with sodium borohydride gives (225) which has been converted into 5-formyl-(6i ,S)-5,6,7,8-tetrahydro-L-folic acid (leucovorin) (226) by reaction with methyl formate (equation 70) (80HCA2554). 

Folic acid is detected by irradiating the chromatogram with broad-spectrum UV light for 30 min before reaction with Bratton-Marshall reagent (detection limit 200ng)[12]. 

FIGURE 18.35 Formation of THF from folic acid by the dihydrofolate reductase reaction. The R group on these folate molecules symbolizes the one to seven (or more) glutamate units that folates characteristically contain. All of these glutamates are bound in y-carboxyl amide linkages (as in the folic acid structure shown in the box A Deeper Look Folic Acid, Pterins, and Insect VFingis). The one-carbon units carried by THF are bound at N, or at or as a single carbon attached to both... 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

Vitamin B12. Figure 2 Selected reactions in which folic acid coenzymes are involved. 

Few adverse reactions are associated with the administration of folic acid and leucovorin. Rarely, parenteral administration may result in allergic hypersensitivity. 

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

Possibly the most significant discovery in the metabolism of aromatic azo compounds had implications that heralded the age of modem chemotherapy. It was shown that the bactericidal effect of the azo dye Prontosil in vivo was in fact due to the action of its transformation product, sulfanilamide, which is an antagonist of 4-aminobenzoate that is required for the synthesis of the vitamin folic acid. Indeed, this reduction is the typical reaction involved in the first stage of the biodegradation of aromatic azo compounds. 

Folic acid is also well tolerated. Some nonspecific adverse effects include allergic reactions, flushing, malaise, and rash. Folic acid has been reported to decrease phenytoin levels by inducing its metabolism. 

Folic acid bad taste and nausea, rash, and allergic reactions... 

Fig. 20 Reaction mechanism for surface modification of luminomagnets with folic acid. (Adapted from [76])...

One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine. Methylenetetra-hydrofolate reductase (Fig. 40-4 reaction 11) reduces... 

A relatively large number of agents have been utilized to treat this intractable disorder folinic acid (5-formyl-tetrahydrofolic acid), folic acid, methyltetrahydrofolic acid, betaine, methionine, pyridoxine, cobalamin and carnitine. Betaine, which provides methyl groups to the beta i ne ho mocystei ne methyltransferase reaction, is a safe treatment that lowers blood homocysteine and increases methionine. 

In living systems, folinic acid can be synthesized ultimately from folic acid by reduction to tetrahydrofolic acid followed by addition of a 1-carbon fragment to the molecule (N5.N1°-methylenetetrahydrofolate, V). After a 2-step oxidation, the formyl group resides either at the N5 or N10 position or as an equilibrium mixture. The essential reactions are summarized below 32... 

The nature of folic acid activity in serum is still obscure despite many clues. Perhaps the best lead has been furnished by the isolation of the previously mentioned N5-methyltetrahydrofolic acid. This is a newly isolated intermediate which is involved in the synthesis of methionine via the reaction in Scheme 1 (L2). This intermediate supports... 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

The chemical structure of folate (or folic acid) is shown in Figure 5.8. In humans, folate usually occurs as polyglutamate derivatives. The active form of folate is THF, sometimes shown as FH4) is derived from folate via two reductase reactions. THF functions as a carrier of one-carbon groups in varying oxidation states (Table 5.1). 

---