Antimetabolites availability

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

Capecitabine is an antimetabolite neoplastic and cyclophosphamide is an alkylating neoplastic, both of which can be administered orally. Carboplatin is a platinum compound (antineoplastic). All currently available platinum compounds are administered parenterally via the intravenous route. 

Antimetabolites are structurally related to normal cellular components. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects S-phase (and therefore cell-cycle) specific. 

Insect chemosterilants may act in several ways. They may cause the insects to fail to produce ova or sperm antimetabolites, when they are also chemosterilants, act in this way. Compounds that cause the death of sperm and ova after they have been produced would also be considered chemosterilants, but I do not know of any compounds of this type which are being considered for use in insect control. A third type of action, and the one in which we are most interested at the present time, is that shown by the radiomimetic compounds. These compounds apparently injure the chromatin, or genetic material, in the sperm and ova so severely that, although they remain alive and the sperm retain full motility, the zygotes, if formed, do not complete development into mature progeny. This type of action is desired because the males sterilized in this manner compete readily with normal males for the available females and transfer motile sperm to the spermathecae of the females, with the result that the mating requirements of the females are satisfied to the same extent as in a mating with a normal male. 

However, this does not apply to the special situation when (1) the enzyme is a synthetase which catalyzes the formation of a covalent bond between the metabolite (or antimetabolite) and a second substrate, and (2) the second substrate is available only in a limited amount. In this case, the antimetabolite competes with the metabolite not only for the enzyme but also for the second substrate, with which it will combine covalently to form an inert product. Although this enzyme-mediated reaction of the antimetabolite is reversible by the corresponding metabolite in a competitive manner, due to its potentially crucial metabolic effect, (i.e., the elimination of another, limiting metabolite which is required for the same reaction step of the metabolic pathway), this reaction per se could be responsible for the over-all inhibitory effect of the antimetabolite. That is, in such particular cases, the metabolic target of the inhibitory action of the antimetabolite may be an enzymic reaction step in which it actually plays the role of a substrate. One might think that this type of situation is a rather special and unusual one, as it may be indeed however, it so happens that the first descovered and still important class of classical and semi-classical antimetabolites, the sulfonamides, appears to act in this manner, as indicated by the results of a recent study8 (see Section 3.2.). 

Many antineoplastic dru are available to treat malignancies. The antineoplastic dru covered in diis chapter include the alkylating dru, antibiotics, antimetabolites, hormones, mitotic inhibitors, and selected miscellaneous dru. Many antineoplastic dni not specifically discussed in diis chapter are listed in the Summary Drug Table Antineoplastic Dru. ... 

Currently, the compound 217 is the only available antimetabolite drug having antifungal activity. It inhibits fungal protein synthesis by replacing 187 with 177 in fungal RNA. 217 also inhibits thymidylate synthetase via 5-fluorodeoxyuridine monophosphate and thus interferes with fungal DNA synthesis. 

Metabolism For uptake and transport of G., see Lit. d-G. plays a central part in the carbohydrate metabolism. It is degraded to smaller molecules in complicated reaction sequences (glycolysis) with release of energy - one example is pyruvic acid, which can enter the citric acid cycle via acetyl-CoA - or (pentose phosphate pathway) can be converted to derivatives of other sugars for biosynthetic purposes under the concomitant availability of reduction equivalents. Alternatively d-G. can be stored in the liver and muscles as areserve substance glycogen (in plants starch). An antimetabolite of d-G. is 5-thio-D-glucose. For detection, see Lit.. ... 

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