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2-Chloro-2′-deoxyadenosine (cladribine) and chlorambucil are two drugs used in the treatment of lymphoid malignancies. We have synthesized 5′-O-esters of cladribine and its parental nucleoside 2′-deoxyadenosine with chlorambucil (2-chloro-2′-deoxyadenosine–chlorambucil and 2′-deoxyadenosine–chlorambucil, respectively) and compared some properties of the esters with regard to their potential use as antileukemic prodrugs. The 5′-O-ester bond showed no spontaneous hydrolysis at pH 7.4, but was susceptible to hydrolysis by porcine liver esterase and enzymes present in human lymphocyte lysate and blood plasma. Both 2-chloro-2′-deoxyadenosine–chlorambucil and 2′-deoxyadenosine–chlorambucil were taken up more avidly than their parental nucleosides by normal and malignant human lymphoid cells. 2-Chloro-2′-deoxyadenosine–chlorambucil was by an order of magnitude more toxic than 2′-deoxyadenosine–chlorambucil to human leukemic MOLT4 cells in culture. On the other hand, 2-chloro-2′-deoxyadenosine–chlorambucil cytotoxicity did not exceed that of its parental 2-chloro-2′-deoxyadenosine in MOLT4 cells, whereas 2′-deoxyadenosine–chlorambucil was considerably more cytotoxic than free chlorambucil in a variety of myeloid and lymphoid human malignant cell lines. Moreover, acute toxicity of 2′-deoxyadenosine–chlorambucil was lower than that of chlorambucil in mice. In summary, 2′-deoxyadenosine–chlorambucil, but not 2-chloro-2′-deoxyadenosine–chlorambucil, shows promise for clinical utility as a chlorambucil prodrug and thus warrants a more detailed study in vivo.