Crystal and Electronic Structures of Magnesium(II), Copper(II), and Mixed Magnesium(II)−Copper(II) Complexes of the Quinoline Half of Styrylquinoline-Type HIV-1 Integrase Inhibitors

• Published in: The journal of physical chemistry. B 2007-05, Vol.111 (21), p.6042-6050
• Main Authors: Courcot, B, Firley, D, Fraisse, B, Becker, P, Gillet, J.-M, Pattison, P, Chernyshov, D, Sghaier, M, Zouhiri, F, Desmaële, D, d'Angelo, J, Bonhomme, F, Geiger, S, Ghermani, N. E
• Format: Article
• Language: English
• Subjects: Chemical Physics; Chemical Sciences; Computer Simulation; Copper - chemistry; Crystallization; Crystallography, X-Ray; Electrons; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; Hydrogen Bonding; Magnesium - chemistry; Material chemistry; Models, Chemical; Models, Molecular; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Physics; Quantum Theory; Quinolines - chemistry; Static Electricity
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp0687551

A new target in AIDS therapy development is HIV-1 integrase (IN). It was proven that HIV-1 IN required divalent metal cations to achieve phosphodiester bond cleavage of DNA. Accordingly, all newly investigated potent IN inhibitors contain chemical fragments possessing a high ability to chelate metal cations. One of the promising leads in the polyhydroxylated styrylquinolines (SQLs) series is (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinoline carboxylic acid (1). The present study focuses on the quinoline-based progenitor (2), which is actually the most probable chelating part of SQLs. Conventional and synchrotron low-temperature X-ray crystallographic studies were used to investigate the chelating power of progenitor 2. Mg2+ and Cu2+ cations were selected for this purpose, and three types of metal complexes of 2 were obtained:  Mg(II) complex (4), Cu(II) complex (5) and mixed Mg(II)−Cu(II) complexes (6 and 7). The analysis of the crystal structure of complex 4 indicates that two tridentate ligands coordinate two Mg2+ cations, both in octahedral geometry. The Mg−Mg distance was found equal to 3.221(1) Å, in agreement with the metal−metal distance of 3.9 Å encountered in the crystal structure of Escherichia coli DNA polymerase I. In 5, the complex is formed by two bidentate ligands coordinating one copper ion in tetrahedral geometry. Both mixed Mg(II)−Cu(II) complexes, 6 and 7 exhibit an original arrangement of four ligands linked to a central heterometallic cluster consisting of three octahedrally coordinated magnesium ions and one tetrahedrally coordinated copper ion. Quantum mechanics calculations were also carried out in order to display the electrostatic potential generated by the dianionic ligand 2 and complex 4 and to quantify the binding energy (BE) during the formation of the magnesium complex of progenitor 2. A comparison of the binding energies of two hypothetical monometallic Mg(II) complexes with that found in the bimetallic magnesium complex 4 was made.