Semisynthetic Approach toward Biologically Active Derivatives of Phenylspirodrimanes from S. chartarum

Abstract

The phenylspirodrimanes (PSDs) from Stachybotrys chartarum represent a structurally diverse group of meroterpenoids, which, on the one hand, exhibit a structural exclusivity since their occurrence is not known for any other species and, on the other hand, offer access to chemically and biologically active compounds. In this study, phenylspirodrimanes 1–3 were isolated from S. chartarum and their water-mediated Cannizzaro-type transformation was investigated using quantum chemical DFT calculations substantiated by LC-MS and NMR experiments. Considering the inhibitory activity of PSDs against proteolytic enzymes and their modulatory effect on plasminogen, PSDs 1–3 were used as a starting material for the synthesis of their corresponding biologically active lactams. To access the library of the PSD derivatives and screen them against physiologically relevant serine proteases, a microscale semisynthetic approach was developed. This allowed us to generate the library of 35 lactams, some of which showed the inhibitory activity against physiologically relevant serine proteases such as thrombin, FXIIa, FXa, and trypsin. Among them, the agmatine-derived lactam 16 showed the highest inhibitory activity against plasma coagulation factors and demonstrated the anticoagulant activity in two plasma coagulation tests. The semisynthetic lactams were significantly less toxic compared to their parental natural PSDs.

New Phenylspirodrimanes from the Sponge-Associated Fungus Stachybotrys chartarum MUT 3308

“…All this data allowed us to identify compound 1 as a PSD derivative never isolated before, named stachybotrin J ( 1 ). Although this compound was semi-synthesized by Steinert et al in 2022, the absolute configuration of the stereogenic center of the arginine residue was not determined [ 32 ].…”

“…In an identical way, amino acids, such as glycine, L -phenylalanine, and L -arginine, would react with stachybotrydial ( 16 ) to yield stachybotrin H ( 4 ), stachybotrin I ( 3 ), and stachybotrin J ( 1 ), respectively. Very recently, some PSD derivatives, such as stachybotrin J ( 1 ), have been obtained by semi-synthesis from stachybotrydial ( 16 ) and amino acids to support this hypothesis [ 32 ]. However, the absolute configurations of these compounds have not been reported.…”