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Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues

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Abstract

In the preparation of acyclic thymidine nucleoside analogues, K2CO3 (or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite (Cl-(CH2)n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5∶1 ratios. Reduction of the cyano function2a-d with NaBH4/CoCl2·6H2O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N′2-chloroethy-lureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N′-2-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry NaNO2 powder in anhydrous CH2Cl2 gave two types of regioisomeric nitrosoureas, 1-[5-(N′-2-chloroethyl-N′-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N′-2-chloroethyl-N-nitrosoureido)pentyl]thymine in approximately 5∶1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as IC50 values. Compounds3d and4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.

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Correspondence to Jack C. Kim.

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Kim, J.C., Kim, Y., Park, J.I. et al. Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues. Arch. Pharm. Res. 20, 259 (1997). https://doi.org/10.1007/BF02976154

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Key words

  • Acyclic thymidine nucleoside analogues
  • 1-[4-(N′-2-chloroethyl-N′-nitrosoureido) butyl]thymine
  • Regioisomeric nitrosoureas
  • In vitro cytotoxicity
  • Human chronic myelogenous leukemia cell
  • Mouse lymphoid neoplasma cell
  • Mouse mammary caruisoma cell
  • IC50