Discovery of potent antiosteoporotic cyclic depsipeptides with an unusual nitrile hydroxy acid from Microascus croci

Two cyclic octadepsipeptides, microascusins A and B ( 1 and 2 ), were identified from the marine sponge-associated Microascus croci IMB19-064 co-cultivated with Escherichia coli . Their structures and conformations in solution were determined by comprehensive spectroscopic data analysis. The absolute configurations of amino and hydroxy acids were determined by the advanced Marfey’s and O -Marfey’s methods, respectively, as well as chiral-phase HPLC analysis. Microascusins A ( 1 ) and B ( 2 ) represent a new type of cyclic octadepsipeptides characterized by the presence of the unique hydroxy acid l -2-hydroxy-4-cyanobutyric acid. Compound 1 exhibited potent in vitro antiosteoporotic activity with dual regulation effects of promoting the osteoblast-mediated bone formation as well as inhibiting the RANKL-induced osteoclast differentiation at the concentration of 0.1–10 nM. Further in vivo study showed that compound 1 could improve bone mineralization after dexamethasone-induced bone damage in zebrafish through up-regulating the expression of the osteoblast-specific genes Bmp2 and Oc .