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Phosphatase Activity of Homo- and Heterodinuclear Transition Metal Complexes of Patellamide Derivatives

Mehrkens, Nina

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Abstract

Naturally occuring cyclic peptides exist in the ascidians Lissoclinum Patella of the Pacific and Indian Oceans. The biological role of these structural interesting marine secondary metabolites is still unclear. The patellamides are able to bind a variety of transition metal ions. Some of the copper(II) complexes of cyclic pseudo-peptides are known to form carbonato-bridged complexes when exposed to CO2. Thus, in previous studies a library of patellamide derivatives has been designed and prepared. The copper(II) coordination properties of these patellamide derivatives is widely understood. Interestingly, the corresponding dinuclear copper(II) complexes are able to efficiently, catalytically hydrolyze phosphoesters and hydrate CO2. The natural peptides are produced by the cyanobacteria prochloron didemnid, a photosynthetic symbiont of L.Patella. Since the patellamides are extracted from hydrophyllic cytoplasmic environment, together with notably high concentrations of some transition metal ions like copper(II) and zinc(II). It is likely that a natural function of probably existing transition metal complexes in this environment is hydrolase activity. The biologic background as well as the state of art regarding the copper(II) coordination chemistry is summarized in Chapter 1. The synthesis of the patellamide derivatives is shortly discussed. In Chapter 3, the electrochemistry of the copper(II) complexes is discussed. Cyclic voltammetry and square wave voltammetry were used to study the existence of a complexation equilibrium between various species in solution. From the obtained results, it is concluded that the copper(I/II) redox chemistry is propably not a biologic relevant biologic function at neutral pH. Under basic conditions, it is possible that stable copper(I) species exist. It can be proposed that these are carbonate or bicarbonate bridged. Moreover, under basic conditions an oxygenation test reaction was performed, and it was shown that a dinuclear copper(II) complex of an patellamide derivative is involved in an oxygenation reaction under these rather unphysiological conditions. A tentative mechanistic proposal is discussed, which is based on the observation of a radical coupling product and insights obtained from a low temperature NMR experiment. In addition the proposed copper(II) complexation equilibria of the ligand H4pat4 is discussed, and the respective EPR spectra with their simulations are in the focus of the last section of Chapter 3. Especially while regarding the formation of heterodinuclear copper(II)/ zinc(II) complexes with H4pat4 in Chapter 5this equilibrium is requested. Since biological relevant hydrolysis chemistry is often based on zinc(II) enzymes, zinc(II) complexes of the macrocyclic peptides were studied. Chapter 4 presents the formation of zinc(II) complexes, which are explored using isothermal calorimetric titrations in combination with NMR spectroscopy and mass spectrometry. After an overview of the biological relevance of zinc(II) based hydrolases, Chapter 4 presents a proposed zinc(II) complexation equilibrium. In Chapter 5, the formation of heterodinuclear copper(II)/ zinc(II) complexes is described based on spectroscopic results. EPR spectroscopy, paramagnetic NMR and UV/vis spectroscopy in combination with mass spectrometry are used to describe two different heterodinuclear complexes. Furthermore, Chapter 5 describes the formation of a copper(II)/ zinc(II) complex due to a distinct cooperative effect, with a ligand that does not form stable spectroscopically characterizable homodinuclear zinc(II) complex. Phosphoester hydrolysis reactions with a model substrate of all complexes, described in Chapters 3,4 and 5 have been investigated in a kinetic assay. The pH dependent results are discussed in Chapter 6. Furthermore the substrate dependency of the initial rate was tested. All complexes discussed exhibit catalytic activity in a pH range close to neutral. Comparison of all data obtained shows that the zinc(II) complexes are slightly more active than the corresponding homodinuclear copper(II) complexes.

Item Type: Dissertation
Supervisor: Comba, Prof. Dr. Peter
Place of Publication: Heidelberg
Date of thesis defense: 23 October 2015
Date Deposited: 08 Dec 2015 07:47
Date: 2015
Faculties / Institutes: Fakultät für Chemie und Geowissenschaften > Institute of Inorganic Chemistry
Subjects: 540 Chemistry and allied sciences
Controlled Keywords: patellamide, complex, phosphatase
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