resumo
A new dichloroazacalix[2]arene[2]triazine receptor (1) with two chiral urea binding moieties is reported. The binding affinity of this macrocycle was evaluated by H-1 NMR titrations in CDCl3 for the dicarboxylate anions oxalate (ox(2-)), malonate (mal(2-)), succinate (suc(2-)), glutarate (glu(2-)), diglycolate (dg(2-)), fumarate (fum(2-)), maleate (male(2-)), and (R,R)- and (S,S)-tartarate (tart(2-)) enantiomers. Among the first five linear anions, the higher association constants were calculated for the larger anions glu(2-) and dg(2-) and for the smallest anion ox(2-), with K-ass values following the sequence dg(2-)> glu(2-)> ox(2-)> suc(2-)> mal(2-). Despite the high binding affinity of 1 for both tart(2-) enantiomers, no enantioselectivity was observed. By contrast, K-ass for fum(2-) is ca. 8.9 times greater than that for male(2-), showing the selectivity of 1 for the trans isomer. These binding preferences were further elucidated by theoretical methods. Molecular dynamics simulations showed that the linear anions are lodged between both pendant arms and that each anion can assume two distinct binding poses, with one or two carboxylate groups establishing intermittent hydrogen bonds with both urea binding units. On the other hand, the recognition of male(2-) ensues in an alternative scenario, characterised by the interaction between a carboxylate group and a single urea binding unit, mirroring the lower experimental binding affinity relatively to fum(2-). A linear increase of the receptor's N-urea center dot center dot center dot N-urea and the anions' -O2C center dot center dot center dot CO2- distances versus experimental K-ass was established for mal(2-), suc(2-), glu(2-) and dg(2-) associations, indicating that the match between these two distances determines the anion binding strength. The affinity for ox(2-) was associated with the most negative values of electrostatic potential positioned near carboxylate groups.
palavras-chave
MOLECULAR-DYNAMICS SIMULATIONS; SURFACE-ELECTROSTATIC POTENTIALS; RECEPTOR CHEMISTRY HIGHLIGHTS; PARTICLE MESH EWALD; CARBOXYLATE ANIONS; BINDING ABILITY; PI INTERACTIONS; KREBS CYCLE; CONSTANTS; AMBER
categoria
Chemistry
autores
Santos, MM; Marques, I; Carvalho, S; Moiteiro, C; Felix, V
nossos autores
Igor Oliveira Marques
Investigador Júnior
Sílvia Cristina Ferreira de Carvalho
Bolseiro de pós-Doutoramento
Vítor Félix
Professor Associado com Agregaçãoagradecimentos
The authors are grateful for funding from QREN-FEDER through the COMPETE programme and FCT under the project PTDC/QUI-QUI/101022/2008. FCT is acknowledged by M.S. and I.M. for the PhD scholarships SFRH/BD/48490/2008 and SFRH/BD/87520/2012, respectively, and by S.C. for the post-doctoral grant SFRH/BPD/42357/2007. We would also like to thank Dr M. J. V. Brito for assistance with the VT 1H NMR experiments and Dr Paula Branco from ASAE for the mass spectra.