Optical sensing of l-dihydroxy-phenylalanine in water by a high-affinity molecular receptor involving cooperative binding of a metal coordination bond and boronate–diol

Abstract

Selective recognition and sensing of catecholamine-based neurotransmitters by fluorescent synthetic receptors capable of operating in pure water is a central topic of modern supramolecular chemistry that impacts biological and analytical chemistry. Despite advances achieved in the recognition of some neurotransmitters such as dopamine, little effort has been invested in the optical recognition of other neurotransmitters of paramount importance in biochemistry and medicinal chemistry such as the drug L-dihydroxy-phenylalanine (levodopa). Herein, a cationic Cu(II)–terpyridine complex bearing an intramolecular fluorescent quinolinium ring covalently linked to phenylboronic acid (CuL¹) was synthesized, structurally described by single-crystal X-ray diffraction and studied in-depth as a fluorescent receptor for neurotransmitters in water. The complex CuL¹ was designed to act as a receptor for levodopa through two Lewis acids of different natures (Cu(II) and B atoms) as cooperative binding points. The receptor CuL¹ was found to have a strongly acidified –B(OH)₂ group (pK_a = 6.2) and exceptionally high affinity for levodopa (K = 4.8 × 10⁶ M⁻¹) with selectivity over other related neurotransmitters such as dopamine, epinephrine, norepinephrine and nucleosides in the micromolar concentration range at physiological pH. Such levodopa affinity/selectivity for a boronic acid-based receptor in water is still rare. On the basis of spectroscopic tools (¹¹B NMR, UV-vis, EPR, and fluorescence), high-resolution ESI-MS, crystal structure, and DFT calculations, the interaction mode of CuL¹ with levodopa is proposed in a 1 : 1 model using two-point recognition involving a boronate–catechol esterification and a coordination bond Cu(II)–carboxylate. Furthermore, a visual sensing ensemble was constructed using CuL¹ and the commercial fluorescent dye eosin Y. Levodopa is efficiently detected by the displacement of the eosin Y bound to the Cu(II)–receptor, monitoring its green emission. The use of Cu(II)–boronate complexes for fast and selective neurotransmitter sensing was unexplored until now.