Synthesis of Myrtucommulone D: A Selective Inhibitor of Tyrosyl-DNA Phosphodiesterase 2 Promoting Drug Resistance Reversal in Lung Cancer Cells

Chemoresistance has emerged as a critical barrier in the treatment of lung cancer. The recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 2, can repair topoisomerase 2-mediated DNA damage, thereby contributing to cancer cell resistance. This study reported the identification of the natural product myrtucommulone D as a selective tyrosyl-DNA phosphodiesterase 2 inhibitor and presented its first enantioselective total synthesis. The enantiomeric excess (ee) of (+)- and (‒)-myrtucommulone D was determined to be 95.3 and 95.1%, respectively. Biological experiments indicated that (+)-myrtucommulone D inhibited tyrosyl-DNA phosphodiesterase 2 with an IC 50 value of 0.69 µM and exhibited significant synergistic effects with the anti-cancer drug etoposide in various human lung cancer cell lines, including non-small cell lung cancer cell line (A549), large cell lung cancer cell line (NCI-H460), small cell lung cancer cell line (NCI-H446), and etoposide resistant small cell lung cancer cell line (NCI-H446/VP). Further investigation revealed that the combination of (+) - myrtucommulone D and etoposide could induce drug-resistant cancer cell (NCI-H446/VP) apoptosis, inhibit colony formation, and potentially suppress cancer cell metastasis. The present study delineates the enantioselective total synthesis of myrtucommulone D and its role in combatting anti-tumor drug resistance as a tyrosyl-DNA phosphodiesterase 2 inhibitor. Graphical Abstract