Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure-Activity Relationships

Angew Chem Int Ed Engl. 2016 Oct 10;55(42):13259-13262. doi: 10.1002/anie.201606657.

Abstract

The fungal secondary metabolite aspergillomarasmine A (AMA) has recently been identified as an inhibitor of metallo-β-lactamases NDM-1 and VIM-2. Described herein is an efficient and practical route to AMA and its related compounds by a sulfamidate approach. In addition, a series of derivatives has been prepared and tested for biological activity in an effort to explore preliminary structure activity relationships. While it was determined that natural LLL isomer of AMA remains the most effective inactivator of NDM-1 enzyme activity both in vitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.

Keywords: antibiotics; enzymes; inhibitors; lactams; total synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter / drug effects
  • Acinetobacter / enzymology
  • Amides / chemistry
  • Amides / pharmacology*
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemical synthesis
  • Aspartic Acid / chemistry
  • Aspartic Acid / pharmacology
  • Dose-Response Relationship, Drug
  • Enterobacteriaceae / drug effects
  • Enterobacteriaceae / enzymology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Pseudomonas / drug effects
  • Pseudomonas / enzymology
  • Structure-Activity Relationship
  • beta-Lactamases / metabolism*

Substances

  • Amides
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Aspartic Acid
  • aspergillomarasmine A
  • beta-Lactamases
  • beta-lactamase NDM-1

Grants and funding