Synthesis and antitumor evaluation of acyclic 1-[omega-(N'-2-chloroethyl-N'-nitrosoureido)alkyl]thymidine nucleoside analogues.
In the preparation of acyclic thymidine nucleoside analogues, K(2)CO(3) (or NaH) treated thymine in DMSO was alkylated with omega-chloroalkyl nitrite (Cl-(CH(2))(n)-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(omega-cyanoalkyl)thymine (2a-d) and 1,3-bis(omega-cyanoalkyl)thymine in approximately 5ratio1 ratios. Reduction of the cyano function2a-d with NaBH(4)/CoCl(2).6H(2)O gave the corresponding 1-(omega-aminoalkyl)thymine (3a-d). The newly formed primary amino function in3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[omega-(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 NaNO(2) powder in anhydrous CH(2)Cl(2) 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 5ratio1 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 IC(50) values. Compounds3d and4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.
Kim
J C
JC
Department of Chemistry, College of Natural Sciences, Pusan National University, 609-735, Pusan, Korea.
Kim
Y H
YH
Park
J I
JI
Kim
S H
SH
Choi
S K
SK