Configurational vs. isotopic effect on gas phase reactivity of chiral tetra-amide macrocycle/nucleoside complexes

The enantioselective interactions between chiral tetra-amidic receptors and nucleosides have been investigated by the ESI-IT-MS and ESI-FT-ICR-MS methodologies. Configurational effects on the CID fragmentation of diastereomeric [MH2•H•A]+ aggregates (A=2'-deoxycytidine dC, citarabine (ara-C) were found to be mostly offset by isotope effect in [SX2•H•A]+ (X=H, D) differently from the results obtained on the analogues (A=cytidine C and gemcitabine G). This result points the involvement of two different nucleoside/tetraamide isoforms. The structural differences of the [MH2•H•A]+ (A=C and G) complexes vs. the [MH2•H•A]+ (dC and ara-C) onesis fully confirmed by the kinetics of their uptake of the 2-aminobutane enantiomers, measured byFT-ICR mass spectrometry. Indeed, uptake of the 2-aminobutane enantiomers by [MHn•H•A]+ (n=1,2; A=dC and ara-C) complexes is reversible, while that by [MHn•H•A]+(n=1,2; A=C and G) is not. The most encouraging result concerning the measured fragmentation and kinetic differences between C and ara-C, that are just epimers, indicates the possibility to subtly modulate the non-covalent drug/receptor interactions, through the electronic properties of the 2'-substituent on the nucleoside furanose ring, and furthermore on its three-dimensional position.