The biochemical pharmacology of (2'-R)-chloropentostatin, a novel inhibitor of adenosine deaminase.
2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. The complex between adenosine deaminase and 2'-chloropentostatin dissociated with a half-life of approximately 3 hr, compared with 68 hr for the complex between adenosine deaminase and pentostatin. 2'-Chloropentostatin, at concentrations up to 10 micromolar, did not cause significant inhibition of growth of WI-L2 human B-cell lymphoblasts, or of CCRF-CEM human T-cell lymphoblasts in culture. However, it greatly potentiated the inhibitory potency of adenosine, 2'-deoxyadenosine, or arabinosyladenine towards these cell lines. This potentiating effect was equipotent for 2'-chloropentostatin and pentostatin. T-cells (CCRF-CEM) were much more sensitive to the inhibitory effect of combinations of adenosine or 2'-deoxyadenosine with 2'-chloropentostatin or pentostatin than were B-cells (WI-L2). Pentostatin and 2'-chloropentostatin had no significant antitumor activity against mouse leukemia L1210 in vivo. However, these adenosine deaminase inhibitors, at nontoxic doses, greatly potentiated the antitumor activity of ara-A 5'-phosphate. 2'-Chloropentostatin was somewhat more active in this regard than was pentostatin.
D000227:Adenine Nucleotides / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D009705:Nucleosides / Q000494:pharmacology*; D015649:Pentostatin / Q000031:analogs & derivatives; D051381:Rats; D011912:Rats, Inbred ACI; D001084:Vidarabine Phosphate / Q000494:pharmacology
D000227:Adenine Nucleotides; D058892:Adenosine Deaminase Inhibitors; D009705:Nucleosides; D001084:Vidarabine Phosphate; D003070:Coformycin; D015649:Pentostatin; C046686:adechlorin; D009700:Nucleoside Deaminases