Folic acid and analogues

The biologically active relatives of folic acid and biopterin are the tetrahydro compounds with a reduced pyrazine ring. Reduction to this level occurs rapidly in vivo. The corresponding electrochemical process is well illustrated by reduction of the N-methylated analogue 28 [95], Reduction to the 5,8-dihydro stage is a reversible two-electron and two-proton process. The product rapidly tautomerises to the... 

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

Triamterene is the primary compound selected from a host. (synthetic pteridine analogues.Although it bears a slruc-aral resemblance to folic acid and certain dihydrofolate re-Juclase inhibitors, it has little, if any. of their activities. ... 

Quaglia, M. Chenon, K Hall, A. J. De Lorenzi, E. Sellergren, B., Target analogue imprinted polymers with affinity for folic acid and related compounds, J. Am. Chem. Soc. 2001, 123, 2146-2154... 

An unexpected feature of the chemistry of the above ureido ester analogues was the apparent ease with which they underwent at least partial racemization at the a-carbon during alkaline hydrolysis to ureido acids. Support for the conclusion that racemization was taking place came from a combination of direct polarometric measurements on the ureido diacids (low rotation in comparison with MTX and folic acid) and indirect evidence that hydrolysis was proceeding via a hydantoin intermediate. Thus, when the ester (VI.9) was heated in MeOH or CHCI3 in the presence of the strong organic base l,5-diazabicyclo[3.4.0]non-5-ene, a product formed in 61% yield which was tentatively identified as (VI.15). Alkaline hydrolysis of (VI.15) yielded (VI.8). 

The folic acid analogues, methotrexate (amethopterin) and aminop-terin, prevent the utilization of folic acid and of one-carbon units, and produce in animals symptoms of deficiency of this vitamin. 

The formation of thymidylate is specifically blocked by certain analogues of folic acid and by derivatives of 5-fluorouracil these agents have an important use in the treatment of cancer in humans. 

The first deuterated folate to be used as internal standard was [ H4]-folic acid labelled in the 4-aminobenzoate moiety the latter was the base for the first folate analogues for naturally occurring folates (Freisleben et al. 2002). The latter were the first to be used as internal standards for folates in foods not fortified with folic acid (Freisleben et al. 2003b). Further folate isotopologues were synthesized thereafter, and an extensive synthetic study was presented by Maunder et al. (1999) with routes to pH4]-folic acid and [ Csl-folic acid labelled in the glutamate moiety and the benzene moiety, respectively. 

The principle of selection is to place these cells into a selective medium in which the de novo pathway of nucleotide synthesis is inhibited. The key to this is the compound, aminopterin which is an analogue of folic acid and a specific inhibitor of dihydrofolate reductase, an essential enzyme for the formation of tetrahydrofolate (FH4) required as a coenzyme of the de novo purine nucleotide synthesis pathway. Tetrahydrofolate is also required for the formation of thymidine. However, if hypoxanthine and thymidine are provided in the culture media of HGPRT+ cells they will be able to grow normally. On the other hand HGPRT" cells would have no means of synthesizing purine nucleotides and consequently would be unable to grow. 

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