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Total Synthesis of Aspergillomarasmine A and Related Compounds: A Sulfamidate Approach Enables Exploration of Structure–Activity Relationships
Author(s) -
Albu Silvia A.,
Koteva Kalinka,
King Andrew M.,
AlKarmi Salma,
Wright Gerard D.,
Capretta Alfredo
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201606657
Subject(s) - metabolite , stereochemistry , in vitro , chemistry , total synthesis , secondary metabolite , enzyme , structure–activity relationship , computational biology , biochemistry , biology , gene
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.