Other Anti-metabolites

Over the years, hundreds of purines and pyrimidines have been prepared and tested for their anti-tumour activity (and more recently antiviral activity). Of 

While emphasis has been given to the use of anti-metabolites in the treatment of acute lymphoblastic leukaemia in children, they are also used with varying success with other types of cancer. For the other common forms of leukaemias - acute myeloid and monocytic leukaemias - which affect adults in the age range 55-75, a cocktail of drugs that includes cytarabine, 6-thioguanine (an analogue of 6-mercaptopurine) and daunorubicin (a structural relative of doxorubicin, discussed later) can induce remission in up to 80% of patients. Bone-marrow transplantation has also become a standard part of the treatment, once remission has been achieved, and the resultant rate of cure is usually around 50%, especially in patients under 65 years. 

In addition, 5-FU and methotrexate are used to treat certain forms of breast cancer, and methotrexate is the drug of choice for the treatment of choriocarcinoma in women. It is also effective in the treatment of psoriasis, a disease in which there is an over-proliferation of epidermal cells in the skin. Finally, it is worth recalling that azidothymidine (AZT) was first synthesised in 1964 as a potential anti-metabolite for cancer chemotherapy, but proved to be ineffective in this role. Its subsequent efficacy as an inhibitor of viral reverse transcriptase in the treatment of HIV infections has assured its place in the history of the 20th century. 

None of these drugs can claim to be a magic bullet since there are serious, dose-limiting adverse effects associated with their administration. However, like the alkylating drugs discussed in the previous section, there is often some selective toxicity towards cancer cells, and there are countless thousands of children (in particular) who owe their lives to these drugs. 

PERIWINKLES, MAYAPPLES AND YEW TREES ANTI-CANCER DRUGS FROM PLANTS 

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Other anti-metabolites of proven value in prophylaxis and therapy. 355... 

It is non-nucleotide reverse transcriptase inhibitor extensively metabolized by the CYP3A P450 isoform to hydroxylated metabolites and excreted in urine. It is indicated in combination with other anti-retroviral agents in a dose of 200 mg OD-BD for first 14 days. It is also been shown to be effective in the prevention of transmission of HIV from mother to new bom. 

Pharmacokinetic properties The compound is readily absorbed from the gastrointestinal tract, but rapidly and extensively metabolized in the liver (Karim et al.,1972), which strongly reduces systemic and CNS availability. The main metabolite is the free diphenoxylic acid, which still has anti-diarrheal properties. Other inactive metabolites and their glucuronides are excreted in faeces. 

High Pressure Liquid Chromatography. In plasma quinidine and other anti-arrhythmic agents, sensitivity 500 ng/ml, UV detection—R. R. Bridges and T. A. Jennison, J. analyt. Toxicol., 1983, 7, 65-68. In plasma quinidine, hydroquinidine, and 2 quinidine metabolites, sensitivity 50 ng/ml for quinidine, fluorescence detection—L. K. Pershing eta/., J. analyt. Toxicol., 1982, 6,153-156. In plasma or urine quinidine, hydroquinidine and quinidine metabolites, detection limit 10 ng/ml for quinidine, fluorescence and UV detection—T. W. Guentert et al., J. Chromat., 1980,183, Biomed. AppL, 9, 514-518. 

Table 3. The effect of different classes of anti-tumour agent on some transplanted tumours. The TLX5 (R) is a line with acquired resistance to a triazene and is cross resistant to BCNU. Triazenes and BCNU are active against tumours which do not respond to anti-metabolites and others that are insensitive to alkylating agents. The platinum complex was cis dichloro-bis(cyclopentylamine)platinum(II) and the triazene 5-(3,3-dimethyl-l-triazeno)-4-carbethoxy-2-me thy limidazole...

For other anti-inflammation drugs such as Naproxen59 and Fenoprofen,60 only the S-isomer is biologically active. Since tedious resolutions are necessary to prepare these compounds, it would be desirable to develop a general asymmetric synthesis of the S(+) arylpropionic acids by microbial oxidation of pro-chiral substrates. This concept has been successfully applied in the preparation of a chiral metabolite of 29. Oxidation of one of the enan-tiotopic methyl groups in 30 with sulfurescens furnished the chiral diol 31.61 A similar oxidation of isobutyric acid (32)62 to S-(+)-3-hydroxy-2-mdthylpropionic acid (33) has been recently employed in the synthesis of the a-tocopherol synthon (34).63... 

Anti-metabolites need not be analogues of metabolites. In fact substances which do not resemble metabolites in any way can be used to combine with or destroy an apoenzyme, a coenzyme, or a substrate (Fildes, 1940). All that is necessary is a high affinity, and the combination is often effected by covalent bonds. These antagonists are not displaceable by the substrate. An example of such an antagonist is the porphyrin, haemin, which splits thiamine into two substances, one containing the pyrimidine ring and the other the thiazole ring. This causes thiamine-deprivation symptoms in animals fed on raw fish, in which this substance is abundant (Woolley, 1952). 

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