Two novel nucleoside ester derivatives of chlorambucil as potential antileukemic prodrugs: a preliminary study.
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.
Kryczka
Tomasz
T
Department of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center, Warsaw, Poland. tkryczka@cmdik.pan.pl
Kazimierczuk
Zygmunt
Z
Kozłowska
Mariola
M
Chrapusta
Stanisław J
SJ
Vilpo
Leena
L
Vilpo
Juhani
J
Stachnik
Krzysztof
K
Janisz
Monika
M
Grieb
Paweł
P
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D004952:Esters / Q000138:chemical synthesis / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes; D009705:Nucleosides / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*
D018906:Antineoplastic Agents, Alkylating; D004952:Esters; D007202:Indicators and Reagents; D009705:Nucleosides; D011355:Prodrugs; D002699:Chlorambucil