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(IT) complexes (ZnL) of macrocyclic tetramines, cyclens, bearing a lkyl chains of four different lengths (propyl, octyl, dodecyl, and hex adecyl) have been tested as new carriers for highly selective extracti on and transport of imide-containing nucleosides and nucleotides (L = cyclen = 1-alkyl-1,4,7,10-tetraazacyclododecane). The most lipophilic Zn2+-hexadecylcyclen was found to most effectively extract thymidine ( dT) from an aqueous solution into a CHCl3 layer, while it did not extr act 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 Zn2+-hexadecylcyclen. The H-1 NMR spectra of the CDCl3-extracted AZT by Zn2+-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). Whi le apparent 1:1 complexation constants, log K-app (K-app(S--ZnL) = [S- -ZnL]/[(HS + S-)(free)][ZnLfree] (M-1)), for Zn2+-octylcyclen with dT and AZT at pH 7.6 are the same value of 3.4 +/- 0.1 (determined by pot entiometric pH titration) in aqueous solution at 25 degrees C with I = 0.1 (NaNO3), the log K-app values for Zn2+-hexadecylcyclen with dT an d AZT in the presence of a neutral detergent Triton X-100 (10 mM) at p H 7.6 (50 mM HEPES with I = 0.1 (NaNO3)) and 25 OC are 3.3 +/- 0.1 and 4.4 +/- 0.1, respectively (determined by isothermal calorimetric titr ation). These results support the observation that the extraction of A ZT with Zn2+-hexadecylcyclen is more favorable than that of dT. The CH Cl3-extracted dT was more easily released into an acidic (pH 6.0) aque ous 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 DH 5.0 aqueous solution (Aq II) mediated by a Liquid CHCl3 membra ne containing 1 mM Zn2+-hexadecylcyclen was carried out.