Abstract:
:The carbocyclic analogue of 5-nitro-2'-deoxyuridine (NO2dUrd), in which the sugar moiety is replaced by a cyclopentane ring and which was designated C-NO2dUrd, has been evaluated for its cytostatic, antimetabolic, and antitumor properties. The following findings are noted. C-NO2dUrd is about 500- to 2000-fold less inhibitory to tumor cell proliferation in vitro than NO2dUrd. Phosphorolysis of C-NO2dUrd by rabbit liver extracts was not observed under conditions where NO2dUrd was readily converted to 5-nitrouracil (NO2Ura). Also, C-NO2dUrd is converted to its 5'-monophosphate (C-NO2dUMP) by dThd kinase nearly as efficiently as the true nucleoside NO2dUrd. This metabolic conversion is necessary for the inhibitory effect of C-NO2dUrd on tumor cell proliferation in cell culture. The principal target enzyme for the cytostatic action of C-NO2dUrd is 2'-deoxythymidylate (dTMP) synthetase. C-NO2dUMP, the active metabolite of C-NO2dUrd, has a much lower affinity for dTMP synthetase than does NO2dUMP. This is the first demonstration of the interaction of a carbocyclic pyrimidine nucleotide analogue with dTMP synthetase. Neither NO2dUrd nor C-NO2dUrd exerts any significant antitumor activity in mice bearing L1210 or P388 leukemia; for NO2dUrd, this failure may be related to a rapid degradation to its inactive metabolite, NO2Ura; for C-NO2dUrd, it is most likely due to a decreased affinity of C-NO2dUMP for its target enzyme, dTMP synthetase.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Balzarini J,De Clercq E,Herdewijn P,Robins MJsubject
Has Abstractpub_date
1985-05-01 00:00:00pages
578-83issue
5eissn
0026-895Xissn
1521-0111journal_volume
27pub_type
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