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Issue 7, 2019
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Design, synthesis, and biological evaluation of C7-functionalized DMXAA derivatives as potential human-STING agonists

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Abstract

STING, a central protein in the innate immune response to cytosolic DNA, has emerged as a hot target for the development of vaccine-adjuvants and anticancer drugs. The discovery of potent human-STING (hSTING) agonist is expected to revolutionize the current cancer immunotherapy. Inspired by the X-ray crystal structure of DMXAA (5,6-dimethylxanthenone-4-acetic acid) and hSTINGG230I complex, we designed various DMXAA derivatives that contain a hydrogen bonding donor/acceptor or a halide at the C7 position. While 7-bromo- and 7-hydroxyl-DMXAA showed notable binding to mouse-STING (mSTING), our newly synthesized C7-functionalized DMXAA derivatives did not bind to hSTING. Nevertheless, our newly developed synthetic protocol for the C7-functionalization of DMXAA would be applicable to access other C7-substituted DMXAA analogues as potential hSTING agonists.

Graphical abstract: Design, synthesis, and biological evaluation of C7-functionalized DMXAA derivatives as potential human-STING agonists

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Supplementary files

Article information


Submitted
26 Jul 2018
Accepted
10 Aug 2018
First published
13 Aug 2018

Org. Biomol. Chem., 2019,17, 1869-1874
Article type
Paper

Design, synthesis, and biological evaluation of C7-functionalized DMXAA derivatives as potential human-STING agonists

J. Hwang, T. Kang, J. Lee, B. Choi and S. Han, Org. Biomol. Chem., 2019, 17, 1869
DOI: 10.1039/C8OB01798K

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