title: The chemical cell biology of zinc: structure and intracellular fluorescence of a zinc-quinolinesulfonamide complex.
abstract: Fluorescent cell-permeant compounds based on 6-methoxy-8-p-toluenesulfonamido-quinoline, TSQ, are potentially powerful probes of intracellular zinc chemistry; however, the structure, thermodynamics, and stoichiometry of the metal complexes, and the molecular basis of Zn(II) recognition, remain open issues. To address these, we report the first structural characterization of a Zn(II) complex of a TSQ derivative, namely 2-methyl-6-methoxy-8-p-toluenesulfonamido-quinoline (3) and describe its unusual coordination chemistry. The crystal structure of the fluorescent complex of 3 with zinc reveals a 2:1 stoichiometry wherein bidentate coordination of two nitrogens from each ligand gives rise to a highly distorted tetrahedral Zn(II) center. Both sulfonamido groups in the zinc complex are tilted away from zinc to make room for coordination of the amide nitrogens. Zn-O(2) and Zn-O(4) distances are essentially nonbonding (3.06 and 3.10 A, respectively). The bond angles [N(1)-Zn-N(2) 83.5 degrees and N(3)-Zn-N(4) 83.0 degrees] are quite small relative to the 109 degrees angle of an ideal tetrahedral center. This result provides an insight into the zinc-binding mode of the TSQ derivative zinquin, in which a methyl group replaces the hydrogen in the 2-position of the quinoline ring. The methyl group and sulfonamide oxygen atoms clearly hinder formation of both square planar and octahedral complexes. We also show here that the Zn(II) complex of 3 in DMSO-water (80/20 w/w) exhibits an overall binding stability (log beta 2 = 18.24 +/- 0.02) similar to zinquin. Fluorescence microscopy suggests that each of these members of this family demarks a similar set of Zn(II)-enriched compartments that are common to all eukaryotic cells examined to date, and further shows that the ester function is not required for observation of these ubiquitous Zn-loaded compartments. The combined structural, thermodynamic, and physiological results provide a basis for design of other Zn(II)-specific membrane permeant probes with a range of Zn(II) affinities and photophysical properties.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Nasir
authors.forename: C J
authors.initials: CJ
authors.lastname: Fahrni
authors.forename: D A
authors.initials: DA
authors.lastname: Suhy
authors.forename: K J
authors.initials: KJ
authors.lastname: Kolodsick
authors.forename: C P
authors.initials: CP
authors.lastname: Singer
authors.forename: T V
authors.initials: TV
authors.lastname: O'Halloran
mesh_terms: D016475:3T3 Cells; D000634:Aminoquinolines / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D005453:Fluorescence; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011199:Potentiometry; D014105:Tosyl Compounds / Q000737:chemistry* / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: C403534:2-methyl-6-methoxy-8-(4-toluenesulfonamido)quinoline; D000634:Aminoquinolines; D014105:Tosyl Compounds; D015032:Zinc