2-Chloro-2'-deoxyadenosine (cladribine) and its analogues are good substrates and potent selective inhibitors of Escherichia coli purine-nucleoside phosphorylase.
2-Chloro-2'-deoxyadenosine (CldAdo), a nucleoside that has proven useful in the treatment of several chronic lymphoid malignancies, and its analogue, 2-bromo-2'-deoxyadenosine, are both effective inhibitors of the bacterial (Escherichia coli) purine-nucleoside phosphorylase (PNP), with Ki values of 4.5 microM and 6.3 microM, respectively. The examination of a series of base-modified analogues of CldAdo has shown that several other compounds have similar inhibitor properties, and has indicated that 6-benzyloxy-2-chloro-9-(2'-deoxy-beta-D-ribofuranosyl)purine is the most potent inhibitor with a Ki value of 0.5 microM, competitive with respect to inosine (Ino). CldAdo itself and its base-modified analogues, discounting those substituted at C(8), are also substrates for the E. coli PNP and undergo rapid glycosidic bond cleavage. CldAdo is degraded with substrate efficiency, i.e. Vmax/Km similar to that observed for Ino (130%), although the individual kinetic constants, Km and Vmax, are both approximately an order of magnitude lower than for Ino. All compounds tested are totally inactive as substrates and inhibitors for mammalian (calf spleen) PNP and therefore constitute a new class of potent selective, although cleavable, inhibitors of bacterial phosphorylases. 8-Bromo-2-chloro-2'-deoxyadenosine and 8-thio-2-chloro-2'-deoxyadenosine are the only base-modified CldAdo derivatives showing inhibitory activity against MOLT-3 (acute T-cell leukemia) and U-937 (histiocytic lymphoma) cells and, as shown in this study, are resistant to degradation by E. coli PNP. The above-mentioned results suggest that both analogues could be effective as oral cytotoxic agents that are noncleavable by enteric bacteria.
Department of Biophysics, University of Warsaw, Poland.
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Bzowska
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Kazimierczuk
D017338:Cladribine / Q000031:analogs & derivatives / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism*; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D017338:Cladribine; D011683:Purine-Nucleoside Phosphorylase