RESUMO
Two series of thymidine derivatives with additional nucleobases/aromatics attached to either the 5'(S)-C- or the 5-position were prepared by epoxide opening and/or "click chemistry" cycloaddition protocols and introduced into DNA duplexes. Interstrand base-base communication in the minor groove and intrastrand stacking interactions in the major groove were detected.
Assuntos
DNA/química , Timidina/análogos & derivados , Conformação de Ácido Nucleico , Desnaturação de Ácido Nucleico , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , Temperatura , Triazóis/químicaRESUMO
A synthetic strategy towards new aromatic nucleoside derivatives introducing additional aromatic functionality placed in the major groove of a modified DNA duplex is presented. The functionalities are introduced using Click Chemistry conditions and found to increase the overall duplex stability.
Assuntos
DNA/química , Nucleosídeos de Pirimidina/síntese química , Bioquímica/métodos , Modelos Moleculares , Conformação de Ácido Nucleico , Nucleosídeos de Pirimidina/químicaRESUMO
The preparation of various 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils with alkyl chain lengths C(1)-C(12) is described. The synthesis is based on the preparation of 5-[chloro-(4-nitro-phenyl)-methyl]-uracil and subsequent substitution of chlorine with appropriate alcohols. The resulting ethers were tested for their cytotoxic activity in vitro against five cancer cell lines. The compounds were less active in lung resistance protein expressing cell lines, suggesting the involvement of this multidrug resistant protein in control of the biological activity. Cytotoxic substances induced rapid inhibition of DNA and modulation of RNA synthesis followed by induction of apoptosis. The data indicate that the biological activity of 5-[alkoxy-(4-nitro-phenyl)-methyl]-uracils depends on the alkyl chain length.
