Sulfonyl-Bridged Biscarbazoles and C−N-Linked Heterodimers from Mangrove-Derived Streptomyces sp. OUCMDZ-5511: Structural Identification, Biosynthetic Logic, and Cytotoxic Evaluation

Abstract

Chemical investigation of the mangrove-derived Streptomyces sp. OUCMDZ-5511, cultured on NaBr-supplemented solid media, led to the isolation of ten carbazole derivatives (1−10), including eight previously undescribed analogues (1−8). Their structures including absolute configurations were rigorously elucidated through a combination of 1D/2D NMR, HRESIMS, single-crystal X-ray diffraction, and ECD (Electronic Circular Dichroism) calculations. Compounds 3−5 feature a rare carbazole−pyrido[1,2-a]indole heterodimers and were resolved as three pairs of enantiomerically pure atropisomers via chiral HPLC. Compounds 6−8 possess an unprecedented sulfonyl-bridged unsymmetrical biscarbazole framework. Biological evaluation revealed that compound 8 was broadly cytotoxic to six cancer cell lines (IC50 2.47−7.12 μM) but showed limited selectivity over normal L-02 cells, whereas 6 showed selective activity against A549, 786-O, and 5637 cells (IC50 3.98−7.45 μM). Furthermore, genome-mining-based analysis suggested plausible biosynthetic pathways for 1−10, involving potential metabolic crosstalk model and radical-mediated mechanisms for the assembly of the unique heterodimers 3−8, although these proposals await experimental validation.