Alanine Scan of [l-Dap2]Ramoplanin A2 Aglycon:  Assessment of the Importance of Each Residue

• Published in: Journal of the American Chemical Society Vol. 129; no. 28; pp. 8747 - 8755
• Main Authors: Nam, Joonwoo, Shin, Dongwoo, Rew, Yosup, Boger, Dale L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 18.07.2007; Amer Chemical Soc
• Subjects: Alanine - genetics; Amino Acids; Anti-Bacterial Agents; Chemistry; Chemistry, Multidisciplinary; Depsipeptides - genetics; Glycoproteins - genetics; Mutagenesis, Site-Directed; Peptide Library; Physical Sciences; Science & Technology; PEPTIDOGLYCAN BIOSYNTHESIS; SUBSTRATE-BINDING; VANCOMYCIN; BETA-SHEET; SOLUTION CONFORMATION; ENDURACIDIN; RAMOPLANIN A-16686; CHLORINE SUBSTITUENTS; LIPOGLYCODEPSIPEPTIDE; STRUCTURE ELUCIDATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja068573k

In efforts that define the importance of each residue and that identify key regions of the molecule, an alanine scan of the ramoplanin A2 aglycon, a potent antibiotic that inhibits bacterial cell wall biosynthesis, is detailed. As a consequence of both its increased stability (lactam vs lactone) and its “relative” ease of synthesis, the alanine scan was conducted on [Dap2]ramoplanin A2 aglycon, which possesses antimicrobial activity equal to or slightly more potent than that of ramoplanin A2 or its aglycon. Thus, 14 key analogues of the ramoplanin A2 aglycon, representing a scan of residues 3−13, 15, and 17, were prepared enlisting a convergent solution-phase total synthesis that consolidated the effort to a manageable level. The antimicrobial activity of the resulting library of analogues provides insight into the importance and potential role of each residue of this complex glycopeptide antibiotic.