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

The fungal secondary metabolite aspergillomarasmineA (AMA) has recently been identified as an inhibitor of metallo- beta -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...

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Bibliographic Details
Published in:Angewandte Chemie 2016-10, Vol.128 (42), p.13453-13456
Main Authors: Albu, Silvia A, Koteva, Kalinka, King, Andrew M, Al-Karmi, Salma, Wright, Gerard D, Capretta, Alfredo
Format: Article
Language:eng ; ger
Subjects:
Biological activity
Chemistry
Derivatives
Enzymatic activity
Enzyme activity
Exploration
Fungi
Inhibitors
Isomers
Metabolites
Metallography
Stereochemistry
Structure-activity relationships
Synthesis
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Summary:The fungal secondary metabolite aspergillomarasmineA (AMA) has recently been identified as an inhibitor of metallo- beta -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 invitro and in cells, the structure is highly tolerant of the changes in the stereochemistry at positions 3, 6, and 9.Original Abstract: AspergillomarasminA und verwandte Naturstoffe wurden ueber eine Sulfamidat-Route synthetisiert und anschliesend Struktur-Aktivitaets-Studien unterzogen. Waehrend das natuerliche LLL-Isomer von AMA die Aktivitaet des Enzyms NDM-1 invitro und in Zellen auch weiterhin am effektivsten hemmt, erwies sich die Struktur als hoch tolerant gegenueber stereochemischer Modifizierung in 3-, 6- und 9-Stellung. Cbz=Benzyloxycarbonyl.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201606657