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Design and synthesis of planar telomestatin analogs


Seyfried, M S. Design and synthesis of planar telomestatin analogs. 2011, University of Zurich, Faculty of Science.

Abstract

Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4. It is one of the most potent telomerase inhibitors reported to date, and it exhibits a broad range of biological activities.

The proposed mode of action of telomestatin involves selective binding of G-quadruplex structures present in the 3' telomeric overhang of human chromosomes. The high affinity and specificity of telomestatin for G-quadruplex DNA is rationalized by its size and shape complementarity with the G-tetrads of G-qadruplex DNA. In reality, the shape of telomestatin is not perfect for G-tetrad stacking due to the presence of a single thiazoline unit. This makes telomestatin a non-planar molecule. Due to high macrocyclic ring-strain, all attempts to synthesise a macrocycle containing eight azole-units have thus far proven fruitless. Ring-stain is reduced by replacing four oxazole units with thiazole in the macrocyclic system. We therefore pursued the synthesis of three new, fully planar telomestatin analogs, each containing four thiazoles and the remaining units comprising oxazoles, imidazoles or thiazoles. The following work presents the design and the synthetic efforts towards these target molecules starting with three different amino acids: serine, asparagine and cysteine.

Our synthetic strategy involves the coupling of amino acids followed by cyclodehydration reactions. The resulting azole-containing amino acids are tetramerized and macrolactamized using standard peptide chemistry. The remaining amino acid side chains are then used for four cyclodehydration reactions in a single step. In 18 synthetic steps total, the C4-symmetric 4TOP could be synthesised. This is the first macrocyclic compound containing eight azole units ever reported. Along the way towards this challenging goal, new synthetic methodologies were developed including the use of silyl-protected alcohols for cyclodehydration reactions, as well as a highly efficient and mild method for 18O labelling of protected amino acids.

Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4. It is one of the most potent telomerase inhibitors reported to date, and it exhibits a broad range of biological activities.

The proposed mode of action of telomestatin involves selective binding of G-quadruplex structures present in the 3' telomeric overhang of human chromosomes. The high affinity and specificity of telomestatin for G-quadruplex DNA is rationalized by its size and shape complementarity with the G-tetrads of G-qadruplex DNA. In reality, the shape of telomestatin is not perfect for G-tetrad stacking due to the presence of a single thiazoline unit. This makes telomestatin a non-planar molecule. Due to high macrocyclic ring-strain, all attempts to synthesise a macrocycle containing eight azole-units have thus far proven fruitless. Ring-stain is reduced by replacing four oxazole units with thiazole in the macrocyclic system. We therefore pursued the synthesis of three new, fully planar telomestatin analogs, each containing four thiazoles and the remaining units comprising oxazoles, imidazoles or thiazoles. The following work presents the design and the synthetic efforts towards these target molecules starting with three different amino acids: serine, asparagine and cysteine.

Our synthetic strategy involves the coupling of amino acids followed by cyclodehydration reactions. The resulting azole-containing amino acids are tetramerized and macrolactamized using standard peptide chemistry. The remaining amino acid side chains are then used for four cyclodehydration reactions in a single step. In 18 synthetic steps total, the C4-symmetric 4TOP could be synthesised. This is the first macrocyclic compound containing eight azole units ever reported. Along the way towards this challenging goal, new synthetic methodologies were developed including the use of silyl-protected alcohols for cyclodehydration reactions, as well as a highly efficient and mild method for 18O labelling of protected amino acids.

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Additional indexing

Item Type:Dissertation
Referees:Luedtke N W, Robinson J A, Bienz S
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:12 December 2011
Deposited On:05 Mar 2012 09:42
Last Modified:05 Apr 2016 15:33
Permanent URL: https://doi.org/10.5167/uzh-58123

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