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Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS‐STING Pathway
Author(s) -
Liu Han,
Ottosen Rasmus N.,
Jennet Kira M.,
Svenningsen Esben B.,
Kristensen Tobias F.,
Biltoft Mette,
Jakobsen Martin R.,
Poulsen Thomas B.
Publication year - 2021
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.202105793
Subject(s) - innate immune system , natural product , sting , chemistry , cytotoxicity , computational biology , biology , biochemistry , in vitro , receptor , engineering , aerospace engineering
The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (−)‐vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity. The synthesis allows for a high degree of flexibility in modifying the macrocyclic framework, including the formation of all possible stereoisomers. In total, 18 analogues were prepared. Two analogues with minor structural modifications showed clearly enhanced cancer cell line selectivity and reduced toxicity. Moreover, these compounds possessed broad inhibitory activity against innate immunological pathways in human PBMCs, including the DNA‐sensing cGAS‐STING pathway. Initial mechanistic characterization suggests a surprising impairment of the STING‐TBK1 interaction.