CHEMISTRY AND BIOACTIVITIES OF MARINE NATURAL PRODUCTS FROM SPONGES ACANTHODENDRILLA SP. AND XESTOSPONGIA SP.

Abstract

Investigation of chemical constituents from the sponge Acanthodendrilla sp. led to the isolation of twenty-one bromotyrosine alkaloids, including two new natural products, 13-oxosubereamolline D and acanthodendrilline. The chemical structures of these alkaloids were determined by means of spectroscopic analysis, including UV, IR, mass, and NMR spectroscopy, as well as comparison of those with previously reported data. The absolute configuration of 13-oxosubereamolline D was determined by comparing the CD spectrum and specific optical rotation value with those of the related compounds. The absolute configuration of acanthodendrilline was determined as 11-S by comparing the specific optical rotation value with that of the synthetic enantiomers. These isolated alkaloids were evaluated for acetylcholinesterase inhibitory activity, and the most active compound was identified as homoaerothionin (IC50 4.5 µM), which acted as a competitive enzyme inhibitor. The bisspirocyclohexadienylisoxazoline moiety and the specific length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. Moreover, both synthetic enantiomers of acanthodendrilline were evaluated for cytotoxicity against H292 non-small cell lung cancer (NSCLC) cell line. Interestingly, (S)-acanthodendrilline exhibited approximately 3-fold more potent than (R)-acanthodendrilline, suggesting that the stereochemistry at C-11 is a key feature related to the cytotoxicity. Regarding the chemical and cytotoxicity studies of bistetrahydroisoquinolinequinone alkaloids from the blue sponge Xestospongia sp., eighteen 22-O-ester derivatives of jorunnamycin A (JA), having a benzoyl or trans-cinnamoyl moiety with electronegative and electron-withdrawing functional groups, together with nitrogen-heterocyclic rings, were prepared from JA. The starting material JA was prepared from renieramycin M (RM), which was isolated as a major component from the sponge. Their cytotoxicity was evaluated against H292 and H460 NSCLC cell lines. The finding suggested that the nitrogen-heterocyclic esters of the analogues elevated the cytotoxicity, and 22-O-(4-pyridinecarbonyl)jorunnamycin A was the most potent among all analogues, exhibiting 20-fold and 5-fold more cytotoxic than RM toward H292 and H460 cell lines, respectively. Further investigation revealed that RM at a subtoxic concentration was a potential anti-metastatic agent by sensitizing anoikis-resistant H460 cells to anoikis through the suppression of the levels of proteins p-ERK, p-AKT, BCL2 and MCL1. Moreover, RM at a subtoxic concentration also attenuates stem cell-like cancer cells in H460 cell line.