Design of new tripodal ligands to advance the biomimetic Zinc chemistry

The goal of this work was the synthesis of a ligand system which coordinates zinc with the same features as those showed by the enzymes. This ligand was to be water soluble, was to form a hydrophobic cavity around zinc and was to provide additional functional groups with hydrogen bonding properties. Several zinc complexes of three new tripodal ligands that deal with these aspects have been synthesised. First, a water soluble tripodal ligand, (2-pyridylmethylamino)-3-(3,5-dimethylpyrazol-1-yl)-propionic acid (L1H) was synthesised. With this amino acid ligand seven zinc complexes were isolated and characterised. Two new water soluble zinc aqua complexes provided structural models for several hydrolytic zinc enzymes. The hydrolytic cleavage of tris(p-nitrophenylphosphate) promoted by the hydroxide complex L1Zn-OH appeared to be accelerated by increasing the water content of the reaction solution. Thus, the rate constant k2 in a 50% water/DMSO solution is 0.912 s-1M-1, while in a 75% water/DMSO solution it is 4.02 s-1M-1. Second, the ligand system N,N,N-Tris{2-[((4-nitrophenyl)methyl)amino]ethyl}amine (L2) with a big hydrophobic cavity was synthesised. With this TREN based ligand seven zinc complexes were isolated and characterised. Two new zinc aqua complexes provided structural models for the resting state of the enzyme carbonic anhydrase. These complexes could be deprotonated and the resulting hydroxide species reacted with CO2 producing two new carbonate complexes. The ability of the thiocyanate anion to inhibit this process was demonstrated by the isolation of the thiocyanate complex. Third, the new ligand system potassium hydrotris(3-(2'-furyl)-5-methylpyrazol-1-yl)borate (KL3) has been synthesised. With this ligand twenty-eight new zinc complexes were isolated and characterized. The reactions of the hydroxide complex L3Zn-OH in methanolic solutions have demonstrated that the L3Zn-methanolate complex present in the equilibrium mixture is the reactive species. The ability of L3Zn-OH to cleave phosphoester bonds has been demonstrated by its reaction with tris(p-nitrophenyl)phosphate. L3Zn-OH did not promote the hydrolytic cleavage of amide bonds. The structure determination of a TpZn-acetamide complex has demonstrated the ability of the L3 ligand to stabilize substrates in zinc complexes through hydrogen bonds. The acid-base properties of L3Zn-OH also enabled the deprotonation of 2-substituted pyridines and some amino acid derivatives. Reactions of L3Zn-OH with acetohydroxamic acid, benzoylacetone, ß-mercaptoethanol, salicylic aldehyde, 3-methylsalicylic acid and thiosalicylic acid led to six new complexes able to model the enzyme inhibitor complexes in matrix metalloproteinases. <br>This work has demonstrated that a better modelling of the secondary interactions of hydrophobic and hydrophilic nature in zinc model complexes provides new insights into the chemical functions and structural roles of biological zinc.

Author dc:creator

• Maldonado Calvo, José Antonio

Contributors dc:contributor

• Vahrenkamp, Heinrich

• Biomimetische Chemie
• Zink Komplexe
• Ligandentwicklung
• Modellkomplexe
• Zinkenzymen
• Biomimetic chemistry
• Zinc complexes
• ligand design
• model complexes
• Zinc enzymes

Repository record source_url

https://freidok.uni-freiburg.de/data/1767

OAI identifier oai:identifier

oai:freidok.uni-freiburg.de:1767