New guanidinium compounds for the molecular recognition of carboxylates and contributions to the synthesis of bivalent NPY Y1 receptor antagonists

Item type:	Thesis of the University of Regensburg (PhD)
Date:	5 March 2007
Referee:	Burkhard (Prof. Dr.) König
Date of exam:	24 March 2006
Institutions:	Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Burkhard König
Keywords:	Molekulare Erkennung , Neuropeptid Y , Carboxylate , Supramolekulare Chemie , Fluoreszenzspektroskopie , Guanidiniumverbindungen , Carbonylverbindungen , Ethoxygruppe , Chemische Synthese , Chemische Bindung , NMR-Spektroskopie , Titration , Fluorophore , , Molecular recognition , Guanidines , NPY Y1 antagonists , fluorescence titrations , synthesis of guanidines
Dewey Decimal Classification:	500 Science > 540 Chemistry & allied sciences
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	10492

Abstract (English)

The chemical properties of the guanidinium group as well as its ability to form H-bonds, charge pairing and cation-π interactions opens up a large number of possibilities in molecular recognition and pharmaceutical chemistry. In the first chapter, the synthesis of Artificial Ethoxycarbonyl Guanidinium Amino Acids is reported. Carboxy� and amino-groups can be selectively deprotected, but ...

Abstract (English)

The chemical properties of the guanidinium group as well as its ability to form H-bonds, charge pairing and cation-π interactions opens up a large number of possibilities in molecular recognition and pharmaceutical chemistry.

In the first chapter, the synthesis of Artificial Ethoxycarbonyl Guanidinium Amino Acids is reported. Carboxy� and amino-groups can be selectively deprotected, but peptide coupling reactions are limited to simple amines and acids. The Ethoxycarbonyl-group can be selectively cleaved by the pig liver esterase EC 3.1.1.1. The binding ability of the Ethoxycarbonyl-protected guanidine to carboxylates in DMSO was investigated by NMR-titrations. The value is comparable with the binding constant of thioureas in DMSO.

In further studies, luminescent Guanidinium Amino Acids (GuAA´s) as new synthetic receptor building blocks for molecular recognition of carboxylates were prepared. The binding constants were determined by fluorescence titrations in different solvents. The binding constants are in MeOH in the range of 5*105 M-1, in DMSO 2*104 M-1 and in H2O (pH = 7.0) in the range of 7*103 M-1. The stoichiometry of all binding processes is 1:1 and was determined by Job`s plot analysis. The synthesis of a tripeptide 33 containing two GuAA molecules gave the target compound in 17 % yield.

Guanidinium compounds play a major role in pharmaceutical chemistry. The Y1 receptor antagonist BIBP 3226 and NG-acylated BIBP 3226 derivatives are highly active compounds. We have reported the synthesis of bis-guanidines 24 and 28. The alcohol 10 could be obtained in good yields starting from commercially available Boc-D-Glu(OBn)-OH 15. The double Mitsunobu reaction of alcohol 10 with bis-guanidine 24 to form the bivalent ligand 30 failed. To investigate the reason for the failure of the Mitsunobu reaction, simple model reactions were carried out. As a result we found that the diphenyl-part in the primary alcohol 10 has an influence on the reaction mechanism of the Mitsunobu reaction. One explanation could be the steric shielding of the OH-function by the two phenyl rings. Furthermore the synthesis of alkylated BIBP 3226 derivatives could be achieved by simple Mitsunobu reaction of the alcohol 34 with 1,3-di-Cbz-2-methyl-isothiourea 38 to get the isothiourea 39. The compound is useful as a precursor for the synthesis of alkylated guanidines by treatment with different amines.

Translation of the abstract (German)

Im ersten Kapitel der Arbeit wird die Synthese von Ethoxycarbonyl Guanidinium Aminosäuren beschrieben. Carboxy- und Aminoende können durch geeignete Methoden weiter funktionalisiert werden. Die Ethoxycarbonylgruppe kann enzymatisch mittels einer Esterase (E.C. 3.1.1.1) abgespalten werden. Die Bindungseigenschaften gegenüber Carboxylaten wurden mittels NMR-Titrationen untersucht. In weiteren ...

Translation of the abstract (German)

Im ersten Kapitel der Arbeit wird die Synthese von Ethoxycarbonyl Guanidinium Aminosäuren beschrieben. Carboxy- und Aminoende können durch geeignete Methoden weiter funktionalisiert werden. Die Ethoxycarbonylgruppe kann enzymatisch mittels einer Esterase (E.C. 3.1.1.1) abgespalten werden. Die Bindungseigenschaften gegenüber Carboxylaten wurden mittels NMR-Titrationen untersucht.

In weiteren Studien wurden weitere Guanidinium Aminosäuren mit einem Fluorophor synthetisiert. Mittels Fluoreszenzspektroskopie wurden die Bindungseigenschaften gegenüber verschiedenen Carboxylaten in verschiedenen Lösungsmitteln (Wasser, Methanol und Dimethylsulfoxid) durchgeführt.
es konnte außerdem ein entsprechendes Dimer synthetisiert werden.

Guanidinium Verbindungen spielen darüberhinaus eine wichtige Rolle in der pharmazeutischen Forschung. Der NPY Y1 Antagonist BIBP 3226 war der erste selektive Y1 Antagonist. In diesem Projekt sollten sog. bivalente Y1 Antagonisten synthetisiert werden. Eine Synthese derartiger bivalenter Liganden konnte im Rahmen dieser Arbeit nicht durchgeführt werden. Dafür konnte ein effektiver Zugang zu alkylierten BIBP 3226 Derivaten gefunden werden.

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