title: Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure-Activity Relationships.
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.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St W, Hamilton, ON, Canada.
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Albu
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, Canada.
authors.forename: Kalinka
authors.initials: K
authors.lastname: Koteva
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: King
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St W, Hamilton, ON, Canada.
authors.forename: Salma
authors.initials: S
authors.lastname: Al-Karmi
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, Canada. wrightge@mcmaster.ca.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St W, Hamilton, ON, Canada. capretta@mcmaster.ca.|Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, 1280 Main St W, Hamilton, ON, Canada. capretta@mcmaster.ca.
authors.forename: Alfredo
authors.identifier: 0000-0002-8832-0011
authors.initials: A
authors.lastname: Capretta
mesh_terms: D000150:Acinetobacter / Q000187:drug effects / Q000201:enzymology; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004755:Enterobacteriaceae / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011549:Pseudomonas / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D001224:Aspartic Acid; C069862:aspergillomarasmine A; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1
keywords: antibiotics; enzymes; inhibitors; lactams; total synthesis