TY - BOOK

T1 - Synthesis of an oligopeptide library

AU - Seedorf, Tim

PY - 2023

Y1 - 2023

N2 - The oligopeptides cystobactamid and Myxovalargin A are natural products produced by myxobacteria. Both secondary metabolites exhibit high antibacterial activity and are currently in different stages of preclinical antibiotic development. In the present work syntheses of these natural products and their analogs were performed to establish their total synthesis and to optimize their antibacterial profile, respectively. Cystobactamids represent a new class of antibiotics. Since their discovery structure-activity-relationships (SAR) were stated through natural product isolation and totalsynthesis. In this work the SAR studies were extended by synthesis of an agent library und the antibacterial profile was optimized against representatives of all ESKAPE pathogens utilizing structural simplification, bioisosterism and novel structural motifs. Myxovalargin A exhibits biological activity against tuberculosis. Insufficient access through fermentation prevented the elucidation of the absolute stereoconfiguration for a long time. Therefore, synthetic studies towards the total synthesis of Myxovalargin A were performed in this work with the long term aim to pave the way for a medicinal chemistry program. A combination solid and liquid phase synthesis enabled the provision of advanced fragments of the natural product.

AB - The oligopeptides cystobactamid and Myxovalargin A are natural products produced by myxobacteria. Both secondary metabolites exhibit high antibacterial activity and are currently in different stages of preclinical antibiotic development. In the present work syntheses of these natural products and their analogs were performed to establish their total synthesis and to optimize their antibacterial profile, respectively. Cystobactamids represent a new class of antibiotics. Since their discovery structure-activity-relationships (SAR) were stated through natural product isolation and totalsynthesis. In this work the SAR studies were extended by synthesis of an agent library und the antibacterial profile was optimized against representatives of all ESKAPE pathogens utilizing structural simplification, bioisosterism and novel structural motifs. Myxovalargin A exhibits biological activity against tuberculosis. Insufficient access through fermentation prevented the elucidation of the absolute stereoconfiguration for a long time. Therefore, synthetic studies towards the total synthesis of Myxovalargin A were performed in this work with the long term aim to pave the way for a medicinal chemistry program. A combination solid and liquid phase synthesis enabled the provision of advanced fragments of the natural product.

U2 - 10.15488/14437

DO - 10.15488/14437

M3 - Doctoral thesis

CY - Hannover

ER -