Total synthesis and biological evaluation of Zelkovamycin release_lsjnie5uincwxas54y4rxo5jt4

Abstract

In this thesis, the first total synthesis, the synthesis of derivatives and the first focused biological evaluation of the natural product Zelkovamycin are described. To this end, this work has been divided into three main parts. In the first section, a conclusive structure assignment of the natural product Zelkovamycin was achieved. For this purpose, a fragmentation-based sequence analysis via mass spectrometry in combination with intense LC-MS- and NMR-analyses were carried out. In addition, a Marfey's analysis was performed to elucidate the complete stereochemical configuration of this natural product. Overall, these structural studies led to a structure revision of Zelkovamycin. The second part of the work describes the total synthesis of Zelkovamycin via a convergent synthesis route. The established synthesis strategy also enabled the generation of in total four Zelkovamycin analogues. In the third part, the first focused biological evaluation of Zelkovamycin was carried out. This evaluation included the investigation of the inhibitory effect of Zelkovamycin on the proteasome (in vitro) and the ubiquitin-proteasome system (in vivo). In addition, it was found that Zelkovamycin displays a so far unknown 'acidifying' effect, most probably caused by an impairment of mitochondrial function.
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