Analogues of folic acid

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

Synthesis of Analogues of Folic Acid, Aminopterin and Methotrexate as Antitumour Agents... 

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. 

Aminopterin and amethopterin (methotrexate) are 4-amino analogues of folic acid (Fig. 11.3) and interfere with the production of the active folate coenzyme by blocking the enzyme dihydrofolate reductase (reaction b in Fig. 13.1) (see also Fig. 11.6). 

Several dozen patents have been granted for work in the pyrimidopyrimidine series. Most of them have been reported in the review by Delia and Warner pyrimidine analogues of folic acid (111) have been prepared and screened for antitumor activity... 

Methotrexate, a common antimetabolite, was introduced several decades ago for the treatment of psoriasis and remains an effective therapeutic approach. It is a synthetic analogue of folic acid that acts as a competitive inhibitor of the enzyme dihydrofolate reductase, that is responsible for the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is an essential cofactor for the synthesis of thymidy-late and purine nucleotides required for DNA and RNA synthesis. Methotrexate inhibits replication and function of T and B cells and suppresses secretion of various cytokines such as IL-1, IFN-y,... 

Nonclassical 2,4-diaminoquinazoline analogues of folic acid have been of interest as potential chemotherapeutic agents since the early 1970s. Some possess interesting levels of antibacterial activity and remarkable antimalarial effects. The drug trimetrexate (693) displays potent anti-malarial, antibacterial, and antitumor activities, and has been through clinical trials as an anticancer... 

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 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. 

Progress has been made in the study of a number of analogues of folic acid in folic reductase systems, and has given some indication of the types of molecular alteration that might lead to antagonists. 

Another class of much used drugs, interfering with the synthesis of DNA, acts by inhibiting dihydrofolate hydrogenase. This is the enzyme that reduces dihydrofolic acid to 5,6,7,8-tetrahydrofolic acid, a substance only one step short of the coenzymes for synthesis of the purine bases and thymine. Analogues of folic acid, based on 2,6-diaminopteridine, such as methotrexate (4.6), are useful anticancer drugs (see Section 9.3c) but... 

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