2-CHLORO-2'-DEOXYADENOSINE (CLADRIBINE) AND ITS ANALOGS ARE GOOD SUBSTRATES AND POTENT SELECTIVE INHIBITORS OF ESCHERICHIA-COLI PURINE-NUCLEOSIDE PHOSPHORYLASE

2-Chloro-2'-deoxyadenosine (CldAdo), a nucleoside that has proven usef ul 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 K-i values of 4.5 mu M and 6.3 mu M, respectively. The examinat ion of a series of base-modified analogues of CldAdo has shown that se veral other compounds have similar inhibitor properties, and has indic ated that y-2-chloro-9-(2'-deoxy-beta-D-ribofuranosyl)purine is the mo st potent inhibitor with a K-i value of 0.5 mu M, competitive with res pect 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 degrade d with substrate efficiency, i.e. V-max/K-m similar to that observed f or Ino (130%), although the individual kinetic constants, K-m and V-ma x, are both approximately an order of magnitude lower than for Ino. Al l compounds tested are totally inactive as substrates and inhibitors f or mammalian (calf spleen) PNP and therefore constitute a new class of potent selective, although cleavable, inhibitors of bacterial phospho rylases. 8-Bromo-2-chloro-2'-deoxyadenosine and 8-thio-2-chloro-2'-deo xyadenosine are the only base-modified CldAdo derivatives showing inhi bitory activity against MOLT-3 (acute T-cell leukemia) and U-937 (hist iocytic lymphoma) cells and, as shown in this study, are resistant to degradation by E. coli PNP. The above-mentioned results suggest that b oth analogues could be effective as oral cytotoxic agents that are non cleavable by enteric bacteria.