Jorumycidine, a hexacyclic bis-tetrahydroisoquinoline alkaloid from marine symbiosis reveals new biosynthetic logic for anticancer design

Marine opisthobranch mollusks are a valuable source of structurally diverse bioactive metabolites arising from de novo biosynthesis or dietary origins. Jorumycidine (4) is a novel bis-tetrahydroisoquinoline (bis-THIQ) alkaloid with an unprecedented hexacyclic skeleton, isolated together with jorumycin (2), renieramycin E (3), and new 21-deoxy analogues (5, 6) from the nudibranch Jorunna funebris and its dietary sponge Haliclona sp. The structure of jorumycidine, featuring a unique oxazolidine ring, was elucidated by spectroscopic, spectrometric, and chiroptical analyses. LC-MS/MS diagnostic fragmentation filtering (DFF), combined with re-annotation of the ren biosynthetic gene cluster recently identified in a Haliclona endosymbiont, supported a hybrid NRPS-PKS origin and revealed enzymatic conversion of sponge-derived renieramycins into jorumycins by the nudibranch. Jorumycidine exhibited potent nanomolar cytotoxicity (IC₅₀ = 13.8 nM) against multiple myeloma cells, outperforming its congeners. These findings expand bis-THIQ chemical diversity and demonstrate how interspecies metabolic interplay can generate bioactive scaffolds with therapeutic potential.