New Discorhabdin Alkaloids from the Antarctic Deep-Sea Sponge .

The sponge genus is a prolific source of discorhabdin type pyrroloiminoquinone alkaloids. In the continuation of our research interest into this genus, we studied the Antarctic deep-sea sponge that showed potent in vitro anticancer activity. A targeted isolation process guided by bioactivity and molecular networking-based metabolomics yielded three known discorhabdins, (-)-discorhabdin L (), (+)-discorhabdin A (), (+)-discorhabdin Q (), and three new discorhabdin analogs (-)-2-bromo-discorhabdin D (), (-)-1-acetyl-discorhabdin L (), and (+)-1-octacosatrienoyl-discorhabdin L () from the MeOH-soluble portion of the organic extract. The chemical structures of - were elucidated by extensive NMR, HR-ESIMS, FT-IR, [α], and ECD (Electronic Circular Dichroism) spectroscopy analyses. Compounds , and showed promising anticancer activity with IC values of 0.94, 2.71, and 34.0 µM, respectively. Compounds - and the enantiomer of ((+)-discorhabdin L, ) were docked to the active sites of two anticancer targets, topoisomerase I-II and indoleamine 2,3-dioxygenase (IDO1), to reveal, for the first time, the binding potential of discorhabdins to these proteins. Compounds and are the first discorhabdin analogs with an ester function at C-1 and is the first discorhabdin bearing a long-chain fatty acid at this position. This study confirms sponges to be excellent sources of chemically diverse discorhabdin alkaloids.