Total synthesis and a systematic structure-activity relationship study of WAP-8294A2

Delin Chen; Liwen Tian; Kathy Hiu Laam Po; Sheng Chen; Xuechen Li

doi:10.1016/j.bmc.2020.115677

Total synthesis and a systematic structure-activity relationship study of WAP-8294A2

Bioorg Med Chem. 2020 Sep 15;28(18):115677. doi: 10.1016/j.bmc.2020.115677. Epub 2020 Jul 30.

Authors

Delin Chen¹, Liwen Tian¹, Kathy Hiu Laam Po², Sheng Chen², Xuechen Li³

Affiliations

¹ Department of Chemistry, The University of Hong Kong, Hong Kong, China.
² Department of Infectious Diseases and Public Health, The City University of Hong Kong, PR China.
³ Department of Chemistry, The University of Hong Kong, Hong Kong, China. Electronic address: xuechenl@hku.hk.

PMID: 32828420
DOI: 10.1016/j.bmc.2020.115677

Abstract

WAP-8294A2 is a cyclic peptide antibiotic with novel structure and excellent activity against Gram-positive pathogens. Herein, we report the total synthesis of complex macrocyclic peptide WAP-8294A2 (W1), ent-analogue W2, deoxy analogue W3 and de-methyl analogue W4 using a solid-phase synthetic route followed by a final stage solution-phase cyclization reaction. Exploitation of this process allowed the synthesis of eleven alanine-scanning analogues and eight lysine-scanning analogues. The antimicrobial activity of these analogues was evaluated in vitro against Gram-positive bacteria. Based on the MIC results, a primary systematic structure-activity relationship has been established.

Keywords: Alanine scan; Lysine scan; Total synthesis; WAP-8294A2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / chemistry
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / chemistry*
Cyclization
Depsipeptides / chemical synthesis*
Depsipeptides / chemistry*
Gram-Positive Bacteria / drug effects
Microbial Sensitivity Tests
Structure-Activity Relationship

Substances

Amino Acids
Anti-Bacterial Agents
Depsipeptides
lotilibcin