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5-Substituted 2'-deoxyuridines: correlation between inhibition of tumor cell growth and inhibition of thymidine kinase and thymidylate synthetase.

Abstract：

:A large variety of 5-substituted 2'deoxyuridines (dUrds) and 2'-deoxyuridylates (dUMPs) have been evaluated for their inhibitory effects on the thymidine (dThd) kinase or thymidylate (dTMP) synthetase isolated from mouse leukemia L1210 cells. The most potent inhibitors of dThd kinase were 5-chloro-, 5-bromo- and 5-iodo-dUrd. Their Ki/Km values ranged from 0.57 to 0.82. All dUrd analogs tested showed competitive kinetics with respect to dThd. However, there was little, if any, correlation between the inhibitory effects of the compounds on L1210 cell growth and their inhibitory activities against dThd kinase (r = 0.16). The most potent inhibitors of dTMP synthetase were (in order of decreasing activity): 5-nitro-dUMP greater than 5-formyl-dUMP greater than 5-fluoro-dUMP greater than 5-oxime of 5-formyl-dUMP greater than 5-azidomethyl-dUMP greater than (E)-5-(2-bromovinyl)-dUMP. The ki/Km values for these compounds ranged from 0.001 to 0.665. All dUMP analogs tested showed competitive kinetics with respect to dUMP (if not preincubated with the enzyme at 37 degrees). There was a strong correlation (r = 0.833) between the inhibitory effects of these compounds on L1210 cell growth and their inhibitory activities against dTMP synthetase. Thus, the suppressive action of 5-substituted dUrd derivatives on tumor cell growth would involve prior conversion of the nucleoside analogs to the corresponding 5'-monophosphates followed by an inhibition of dTMP synthetase.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Balzarini J,De Clercq E,Mertes MP,Shugar D,Torrence PF

doi

10.1016/0006-2952(82)90594-9

subject

Has Abstract

pub_date

1982-11-15 00:00:00

pages

3673-82

issue

22

eissn

0006-2952

issn

1873-2968

pii

0006-2952(82)90594-9

journal_volume

31

pub_type

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