Methotrexate analogs

Rosowsky, A. Methotrexate analogs. 2. A facile method of preparation of lipophilic derivatives of methotrexate and 3 ,5 -dichloromethotrexate by direct esterification. J. Med. Chem. 16, 1190 (1973). 

Inhibitors of the enzyme dihydrofolate-reductase such as methotrexate (Figure 6.9) are used in the treatment of leukemia s. During the search for methotrexate analogs a... 

The methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (TMP), catalyzed by thymidylate synthase, is essential for the synthesis of DNA. The one-carbon fragment of methy-lene-tetrahydrofolate is reduced to a methyl group with release of dihydrofolate, which is then reduced back to tetrahydrofolate by dihydrofolate reductase. Thymidylate synthase and dihydrofolate reductase are especially active in tissues with a high rate of cell division. Methotrexate, an analog of 10-methyl-tetrahydrofolate, inhibits dihydrofolate reductase and has been exploited as an anticancer drug. The dihydrofolate reductases of some bacteria and parasites differ from the human enzyme inhibitors of these enzymes can be used as antibacterial drugs, eg, trimethoprim, and anti-malarial drugs, eg, pyrimethamine. 

Possible increased toxicity when given concurrently with alkylating agents, radiation, purine analogs, and methotrexate. 

Thioguanine is a purine analog that has been used as an alternative treatment for psoriasis when conventional therapies have failed. The typical dose is 80 mg twice weekly, increased by 20 mg every 2 to 4 weeks the maximum dose is 160 mg three times a week. Adverse effects include bone marrow suppression, GI complications (e.g., nausea, diarrhea), and elevation of liver fimction tests. 6-Thioguanine may be less hepatotoxic and therefore more useful than methotrexate in hepatically compromised patients with severe psoriasis. 

An electron impact mass spectrum of calcium leuco-vorin has not been obtained because the compound is not sufficiently volatile. It would be difficult to isolate the free acid without first dehydrating the compound. Due to its ionic nature, calcium leucovorin will not dissolve in common silylating reagents. Field desorption, another mass spectral technique, generally lends itself more to compounds like leucovorin. Indeed, this technique has been applied successfully to methotrexate and other folic acid analogs.1 ... 

Methotrexate Folic acid analog cancer chemotherapy, arthritis Inhibits proliferation T-cell suppression granulocytopenia lymphocytopenia... 

Szeto, D.W., Cheng, Y.C., Rosowsky, A., t al. (1979) Human thymidylate synthetase—III. Effects of methotrexate and folate analogs. Biochemical Pharmacology. 28, 2633-2637. 

Methotrexate is a folate analog that acts as a potent competitive inhibitor of dihydrofoiate reductase, causing a decreased supply of THF coenzymes needed by thymidylate synthetase. 

The answer is E. Methotrexate is an analog of folic acid that binds with very high affinity to the substrate-binding site of dihydrofolate reductase, the enzyme that catalyzes conversion of DHF to THE, which is used in various forms by enzymes of both the purine and pyrimidine de novo synthetic pathways. Thus, synthesis of dTMP from dUMP catalyzed by thymidylate synthetase and several steps in purine synthesis catalyzed by formyltransferase are indirectly blocked by the action of methotrexate because both those enzymes require THE coenzymes. 

Folic acid analogs methotrexate sodium raltitrexed disodium... 

Purine analogs and antimetabolites, eg, 6-mercaptopurine, methotrexate Mechanism uncertain may promote apoptosis of immune cells Generalized suppression of immune processes Moderately severe to severe Crohn s disease and ulcerative colitis GI upset, mucositis myelosuppression purine analogs may cause hepatotoxicity, but rare with methotrexate at the low doses used... 

Other useful targets for pharmaceutical agents are thymidylate synthase and dihydrofolate reductase, enzymes that provide the only cellular pathway for thymine synthesis (Fig. 22-49). One inhibitor that acts on thymidylate synthase, fluorouracil, is an important chemotherapeutic agent. Fluorouracil itself is not the enzyme inhibitor. In the cell, salvage pathways convert it to the deoxynucleoside monophosphate FdUMP, which binds to and inactivates the enzyme. Inhibition by FdUMP (Fig. 22-50) is a classic example of mechanism-based enzyme inactivation. Another prominent chemotherapeutic agent, methotrexate, is an inhibitor of dihydrofolate reductase. This folate analog acts as a competitive inhibitor the enzyme binds methotrexate with about 100 times higher affinity than dihydrofolate. Aminopterin is a related compound that acts similarly. 

Another dihydrofolate inhibitor trimethoprim is an important antibacterial drug, usually given together with a sulfonamide. Although it is not as close a structural analog of folic acid as is methotrexate, it is... 

Thymidylate synthase requires methylene tetrahydro-folate as a reductant and the reduction of dihydrofolate is also an important part of the process. In protozoa dihydrofolate reductase and thymidylate synthase occur as a singlechain bifunctional enzyme.f As has been pointed out in the main text, such folic acid analogs as methotrexate are among the most useful anticancer drugs. By inhibiting dihydrofolate reductase they deprive thymidylate synthase of an essential substrate. 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

The management of cancer includes treatment with alkylating agents (nitrogen mustards and alkyl sulfonates), antimetabolites (methotrexate and purine analogs), natural products (vinca alkaloids and antibiotics), miscellaneous compounds (hydroxyurea, procarbazine, and cis-platinum), hormones (estrogens and corticosteroids), and radioactive isotopes (see Chapter 62). 

The diazines (pyridazine, pyrimidine, and pyrazine) are six-membered aromatic heterocycles that have two nitrogens in the ring. Cytosine, thymine, and uracil are derivatives of pyrimidine that are important bases in nucleic acids (DNA and RNA). Heterocyclic analogs of the aromatic hydrocarbon naphthalene include pteridines, which have four nitrogens in the rings. Naturally occurring pteridine derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy. 

Some of the structural properties which have been ascribed to DA receptors appear to deserve attention for their heuristic value, but painfully few should engender much confidence in their reality. A sobering lesson is available from analysis of complexes of dihydrofolate reductase (], 8). Methotrexate is a very close analog of folic acid and is a potent inhibitor of the enzyme, but it is now almost certain that these ligands bind in the enzyme active site in aspects differing by a rota-... 

The alignment of the amino acid sequence of ADHFR with those of L. casei and E. coli shows a homology of 23 and 30%, respectively (see Fig. 2). Some amino acid residues are conserved in almost all known DHFRs (Beverley et al., 1986 Volz et al., 1982). Most of these residues are also conserved in ADHFR. The functions of some of the residues that are also conserved in ADHFR were inferred from the crystal structures. For instance, in E. coli DHFR, Ala-7, Ser-49, and Leu-54 are involved in binding of dihydrofolate and its analogous inhibitor methotrexate (Bolin et al., 1982). The bond between Gly-... 

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