The First Selective and Efficient Transport of Imide-Containing Nucleosides and Nucleotides by Lipophilic Cyclen−Zinc(II) Complexes (Cyclen = 1,4,7,10-Tetraazacyclododecane)

Zinc(II) complexes (ZnL) of macrocyclic tetramines, cyclens, bearing alkyl chains of four different lengths (propyl, octyl, dodecyl, and hexadecyl) have been tested as new carriers for highly selective extraction and transport of imide-containing nucleosides and nucleotides (L = cyclen = 1-alkyl-1,4,7,10-tetraazacyclododecane). The most lipophilic Zn 2+ −hexadecylcyclen was found to most effectively extract thymidine (dT) from an aqueous solution into a CHCl 3 layer, while it did not extract other nucleobase derivatives (C, A, and G) at all. More lipophilic thymidine derivatives (HS) such as 3‘-azido-3‘-deoxythymidine (AZT), 1-methylthymine (1-MeT), and ftorafur (Ff) were almost quantitatively extracted by an equivalent amount of Zn 2+ −hexadecylcyclen. The 1 H NMR spectra of the CDCl 3 -extracted AZT by Zn 2+ −hexadecylcyclen confirmed the formation of the 1:1 complex (S - −ZnL) bound through imide-N - anion and zinc(II) cation (S - denotes the deprotonated dT derivatives). While apparent 1:1 complexation constants, log K app ( K app (S - −ZnL) = [S - −ZnL]/[(HS + S - ) free ][ZnL free ] (M - 1 )), for Zn 2+ −octylcyclen with dT and AZT at pH 7.6 are the same value of 3.4 ± 0.1 (determined by potentiometric pH titration) in aqueous solution at 25 °C with I = 0.1 (NaNO 3 ), the log K app values for Zn 2+ −hexadecylcyclen with dT and AZT in the presence of a neutral detergent Triton X-100 (10 mM) at pH 7.6 (50 mM HEPES with I = 0.1 (NaNO 3 )) and 25 °C are 3.3 ± 0.1 and 4.4 ± 0.1, respectively (determined by isothermal calorimetric titration). These results support the observation that the extraction of AZT with Zn 2+ −hexadecylcyclen is more favorable than that of dT. The CHCl 3 -extracted dT was more easily released into an acidic (pH 6.0) aqueous solution than AZT. As a support of the extraction experiments, the transport of dT and AZT (1 mM) from a pH 9.0 aqueous solution (Aq I) to a pH 5.0 aqueous solution (Aq II) mediated by a liquid CHCl 3 membrane containing 1 mM Zn 2+ −hexadecylcyclen was carried out.