N4-Hydroxy-5-Halogeno-2′-Deoxycytidine S and Their 5′-Mono-Phosphates as Inhibitors of Thymidylate Synthase and in Vitro Antileukemic Agents

Krzysztof Felczak , Maria Bretner , Jolanta M. Dzik , B. Gołos , Z. Zieliński , W. Rode , Tadeusz Kulikowski


A rare example of dUMP analogue that is C(4)-substituted and, nevertheless, a strong inhibitor of thymidylate synthase, a target in chemotherapy, is N4-hydroxy-2′- deoxycytidine-5′-mono-phosphate (N4-OH-dCMP). It inactivates the enzyme via time- dependent formation of a ternary covalently bound complex with thymidylate synthase and N5,10-methylenetetrahydro-folate,1,2 with 5-fluoro substitution (in N4-OH-FdCMP) potentiating this process.3 In order to test antitumour activity of N4-hydroxy-FdCyd (N4- OH-dCyd), as well as its 5-chloro (N4-OH-CldCyd) and 5-bromo (N4-OH-BrdCyd) congeners, they were studied as murine leukemia L5178Y cell growth inhibitors. Inhibitory activities with purified L1210 cell thymidylate synthase of N4-hydroxy-5-chloro-dCMP (N4-OH-CldCyd) and N4-hydroxy-5-bromo-dCMP (N4-OH-BrdCMP) were also studied.
Author Krzysztof Felczak SWFS
Krzysztof Felczak,,
- The Phisical Education Centre
, Maria Bretner ZTiBSL
Maria Bretner,,
- Department Of Drug Technology And Biotechnology
, Jolanta M. Dzik
Jolanta M. Dzik,,
, B. Gołos
B. Gołos,,
, Z. Zieliński
Z. Zieliński,,
, W. Rode
W. Rode,,
, Tadeusz Kulikowski
Tadeusz Kulikowski,,
Book Griesmacher Andrea, Müller MathiasM., Chiba Peter (eds.): Purine and Pyrimidine Metabolism in Man IX, Advances in Experimental Medicine and Biology, vol. 431, 1998, Springer US, ISBN 978-1-4613-7456-5
URL http://dx.doi.org/10.1007/978-1-4615-5381-6_119
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