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Inhibition of DNA Synthesis by Hydroxyurea: Structure-Activity Relationships¹

Divisions of Clinical Chemotherapy and Biological Chemistry, Sloan-Kettering Institute for Cancer Research, New York, New York 10021

The following compounds inhibited incorporation of thymidine-³H into the DNA of HeLa cells without significantly impairing cellular incorporation of uridine-³H into RNA or leucine-³H into protein; they are listed in order of potency. Dihydroxyurea > N-methylhydroxyurea > N-acetylhydroxyurea = hydroxyurea = N-hydroxyguanidine = N-hydroxyurethane = N-ethylhydroxyurea > 3-phenyl-1-hydroxyurea = formamidoxime > N-methylacetohydroxamic acid = N-methylhydroxylamine > acetohydroxamic acid. Hydroxylamine, N-hydroxyglycine amide and 3-phenyl-1-hydroxy-2-thiourea inhibited incorporation of all three labeled precursors. Methoxyamine, methoxyurea, and N-methylmethoxyurea had no effect upon thymidine uptake. Addition of three deoxyribonucleosides, deoxyadenosine (0.1 mM), deoxyguanosine (0.1 mM), and deoxycytidine (1.0 µM), to the culture medium provided partial protection against the inhibitory effects of hydroxyurea, hydroxyurethane, acetohydroxamic acid, hydroxyguanidine, formamidoxime, and N-methylhydroxylamine. The data suggest that all of these agents inhibit a reaction in the biosynthesis of deoxyribonucleotides from ribonucleotides. The relationship between chemical structure and inhibitory activity is discussed and some possible inhibitory mechanisms examined.

¹ This work was supported in part by NCI Grants CA-07860 and CA-08748.

Received 8/17/66. Accepted 11/ 1/66.

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