Total synthesis of a depsidomycin analogue by convergent solid-phase peptide synthesis and macrolactonization strategy for antitubercular activity

• Published in: Journal of peptide science 2011-10, Vol.17 (10), p.683-689
• Main Authors: Narayanaswamy, Venugopala K., Albericio, Fernando, Coovadia, Yacoob Mohamed, Kruger, Hendrik G., Maguire, Glenn E. M., Pillay, Melendhran, Govender, Thavendran
• Format: Article
• Language: English
• Subjects: Amino acids; Antimicrobial agents; antitubercular activity; Antitubercular Agents - chemical synthesis; Carboxylic Acids - chemistry; Clinical trials; cyclic depsipeptides; Head; HRMS characterization; Immunosuppressive agents; Immunosuppressive Agents - chemical synthesis; Lactones; linear peptides; macrolactonization reaction; Microbial Sensitivity Tests; Minimum inhibitory concentration; Oligopeptides - chemical synthesis; Peptide synthesis; Proline; solid-phase peptide synthesis; Solid-Phase Synthesis Techniques; Streptomyces; Structure-Activity Relationship
• ISSN: 1075-2617; 1099-1387; 1099-1387
• DOI: 10.1002/psc.1389

Depsidomycin is a cyclic heptadepsi‐peptide isolated from the cultured broth of Streptomyces lavendofoliae MI951‐62F2. It exhibits significant antimicrobial and immunosuppressive activity. The total synthesis of a depsidomycin analogue in which 1,2‐piperazine‐3‐carboxylic acid was substituted with proline is described. After several trials using different strategies, the desired depsidomycin analogue was obtained via stepwise synthesis starting by the amino acid ‘head’ and macrolactonization under Yamaguchi conditions. The cyclic depsipeptide was evaluated to have an minimum inhibitory concentration (MIC) of 4 µg/ml against H37RV and 16 µg/ml against MDR clinical strains of MTB (MDR‐MTB), while the linear precursor 8 also had MICs of 4 and 16 µg/ml for the susceptible and resistant strains, respectively. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. Total synthesis of depsidomycin analogue 2 by CSPPS and macrolactonization under Yamaguchi conditions are reported at 42 and 81%, yield respectively. The title compound exhibited antitubercular activity at 4 and 16 µg/ml against H37RV and MDR strains, respectively.