posted on 2019-04-09, 20:13authored byElisa G.-Doyagüez, Paula Carrero, Andrés Madrona, Patricia Rodriguez-Salamanca, Belén Martínez-Gualda, María José Camarasa, María
Luisa Jimeno, Philip R. Bennallack, Jordan G. Finnell, Tsz-Ming Tsang, Kenneth A. Christensen, Ana San-Félix, Michael S. Rogers
We previously showed that a small molecule of natural origin, 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG), binds
to capillary morphogenesis gene 2 (CMG2) with a submicromolar IC50 and also has antiangiogenic activity in vitro and in vivo.
In this work, we synthetized derivatives of PGG with different sugar
cores and phenolic substituents and tested these as angiogenesis inhibitors.
In a high-throughput Förster resonant energy transfer-based
binding assay, we found that one of our synthetic analogues (1,2,3,4,6-penta-O-galloyl-β-d-mannopyranose (PGM)), with
mannose as central core and galloyl substituents, exhibit higher (up
to 10×) affinity for CMG2 than the natural glucose prototype
PGG and proved to be a potent angiogenesis inhibitor. These findings
demonstrate that biochemical CMG2 binding in vitro predicts inhibition
of endothelial cell migration ex vivo and antiangiogenic activity
in vivo. The molecules herein described, and in particular PGM, might
be useful prototypes for the development of novel agents for angiogenesis-dependent
diseases, including blinding eye disease and cancer.