Four new benzodipyran racemates, namely (±)-aspergiletals A–D (3–6), representing a rare pyrano[4,3-h]chromene scaffold were isolated together with eurotiumide G (1) and eurotiumide F (2) from the soft-coral-derived fungus Aspergillus sp. EGF 15-0-3. All the corresponding optically pure enantiomers were successfully separated by a chiral HPLC column. The structures and configurations of all the compounds were elucidated based on the combination of NMR and HRESIMS data, chiral separation, single-crystal X-ray diffraction, quantum chemical 13C NMR, and electronic circular dichroism calculations. Meanwhile, the structure of eurotiumide G was also revised. The TDP1 inhibitor activities and photophysical properties of the obtained compounds were evaluated. In the TDP1 inhibition assay, as a result of synergy between (+)-6 and (−)-6, (±)-6 displayed strong inhibitory activity to TDP1 with IC50 values of 6.50 ± 0.73 μM. All compounds had a large Stokes shift and could be utilized for elucidating the mode of bioactivities by fluorescence imaging.

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Herein, a series of 11‐ or 12‐substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl‐DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme‐based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC50 values ranging from 10 to 18 μM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT‐116 cells (0.25 μM). The most potent TDP1 inhibitor 43 (10 μM) could induce cellular TDP1cc formation and enhance topotecan‐induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF‐7 and MCF‐7/TDP1 cells.

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