A summary of the main targets for antifolate drugs and their relationships with nucleic acid biosynthesis is given in Fig. 2.34.

6.3. Inhibitors of phosphoribosylformylglycinamidine synthetase

This enzyme catalyzes the reaction of formylglycinamide ribonucleotide with ammonia to give formylglycinamidine ribonucleotide, with glutamine as a cofactor. The enzyme activates the amide group adjacent to the ribose ring to nucleophilic attack by its transformation into iminoether 2.28. In addition, another catalytic site of the enzyme hydrolyzes glutamine to glutamic acid and ammonia, which is then channeled to the first site and reacts with 2.28 by an addition-elimination mechanism, affording the amidine 2.29 (formylglycinamidine ribonucleotide) (Fig. 2.35).

Some analogs of glutamine bearing a diazomethyl moiety have antitumor activity because of their ability to inhibit several reactions in which glutamine is involved as a cofactor, specially the one catalyzed by formylglycinamidine ribonucleotide synthetase. Azaserine (O-diazoacetyl-l-serine) and 6-diazo-5-oxo-l-norleucine (DON) are two antitumor natural products, isolated from Streptomyces broths that act as covalent inhibitors of the enzyme. Reversible attachment using the binding points normally employed by the cofactor glutamine positions the diazomethyl group close to a cysteine sulfhydryl group in the active site. After protonation, this unit is transformed into a diazonium group, which covalently links to the cysteine thiol group (Fig. 2.36). Clinical trials have shown good

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