Conversion of 5-iodo-2-pyrimidinone-2'-deoxyribose to 5-iodo-deoxyuridine by aldehyde oxidase. Implication in hepatotropic drug design.
5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) can be converted into 5-iodo-deoxyuridine (IUdR), a clinical radiosensitizer, by aldehyde oxidase in the liver. This conversion does not require exogenous cofactors and cannot be catalyzed by mixed-function oxidases, xanthine oxidase or many other oxido-reductases. This "IPdR oxidase" activity is enriched in the liver; thus, extensive conversion of IPdR to IUdR could be anticipated in the liver and the therapeutic index of IPdR could be better than that of IUdR as a radiosensitizer for primary liver cancers or tumors metastasized to the liver. Based on structure and activity relationship studies, nucleoside analogues which could be activated by this enzyme to compounds capable of inhibiting DNA synthesis could be designed and should be explored as agents against cancer, viruses or parasites in the liver.
Chang
C N
CN
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
Doong
S L
SL
Cheng
Y C
YC
D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism*; D000818:Animals; D015195:Drug Design; D006801:Humans; D007065:Idoxuridine / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D011741:Pyrimidine Nucleosides / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D051381:Rats; D013154:Spleen / Q000201:enzymology; D013379:Substrate Specificity; D014020:Tissue Extracts / Q000378:metabolism
D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; D014020:Tissue Extracts; C045889:ropidoxuridine; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D007065:Idoxuridine