Purine Analogs inhibitors

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

The dialkoxyphosphinydifluoromethyllithium reagent has also been used in the preparation of bioactive compounds such as 2-amino-7,7-difluoro-7-phos-phonoheptanoic acid for evaluation in the -methyl-D-aspartic acid binding assay [265], 9-(5,5-difluoro-5-phosphonopentyl)quanine as a multisubstrate analog inhibitor of purine nucleoside phosphorylase [266], fluorinated phosphoserine analog [267, 268] (Scheme 91) and nucleoside 5 -deoxy-5 -di-fluoromethylphosphonates [267,269] (Scheme 92). 

Scheme 7 Structure of 2,6,9-trisubstituted purines analogs prepared by Raynaud and coworkers as CDK-2 inhibitors for PK profiling...

Category Purine analog Xanthine oxidase inhibitor Half-life 1-3 hours... 

An ADA-resistant purine analog, cladribine (2-chlorodeoxyadenosine 2-CdA) has demonstrated potent activity in hairy cell leukemia, CLL, and low-grade lymphomas. After intracellular phosphorylation by deoxycytidine kinase and conversion to cladribine triphosphate, it is incorporated into DNA. It produces DNA strand breaks and depletion of NAD and adenosine triphosphate (ATP), as well as apoptosis, and is a potent inhibitor of ribonucleotide reductase. The drug does not require cell division to be cytotoxic. Resistance is associated with loss of the activating enzyme, deoxycytidine kinase, or escape of ribonucleotide reductase from inhibition. 

Inhibitors of phosphodiesterase increase the intracellular level of cyclic AMP, which is associated with increased myocardial contractility. One of the first POE-inhibitors so studied is theophylline (21), an important drug in the treatment of asthma. Its actions have been extensively reviewed.81 Several recent studies have indicated that it might stimulate contractility also by adenosine receptor antagonism.82 In patients with chronic obstructive pulmonary disease, theophylline (14 mg/kg, p.o.) improved cardiac performance.83,94 severe adverse side effects were observed.85,96 Many derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than... 

The xanthine oxidase inhibitor is the substance that inhibits the activity of xanthine oxidase, involved in purine metabolism. There are two kinds of xanthine oxidase inhibitors purine analogs and non-purine-related compounds. The first category includes allopurinol (5), oxypurinol (6), and tisopurine (7). The second group... 

FIGURE 16.8 (a) Phosphoglycolohydroxamate is an analog of the enediolate transition state of the yeast aldolase reaction, (b) Purine riboside, a potent inhibitor of the calf intestinal adenosine deaminase reaction, binds to adenosine deaminase as the 1,6-hydrate. The hydrated form of purine riboside is an analog of the proposed transition state for the reaction. 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

Cyclin-dependent kinase Inhibitor analog Purine 22... 

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