ABSTRACT
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered DNA repair enzyme that can repair topoisomerase 2-mediated DNA damage, resulting in cancer cell resistance. In this study, two compounds, robustadial A and B, were isolated from a fraction of the ethyl acetate extract of Eucalyptus globulus Labill. fruits based on TDP2 inhibition screening. The biological experiments indicated that robustadial A and B have TDP2 inhibitory activity with EC50 values of 17 and 42 µM, respectively, but no tyrosyl-DNA phosphodiesterase 1 inhibition at 100 µM. Robustadial A showed significant synergistic effects with the anticancer drug etoposide in four human cancer cell lines, non-small cell lung cancer cell line (A549), prostate cancer cell line (DU145), breast cancer cell line (MCF-7), colorectal adenocarcinoma cell line (HCT-116), and chicken lymphoma cell line (DT40), and chicken lymphoma cell line complementation with human TDP2 (DT40 hTDP2) with combination index values ranging from 0.21 to 0.74. This work will facilitate future efforts for the development of robustadial A-based TDP2 selective inhibitors.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Eucalyptus , Neoplasms , Phosphodiesterase Inhibitors , Animals , Cell Line, Tumor , Chickens , DNA-Binding Proteins , Eucalyptus/chemistry , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester HydrolasesABSTRACT
Eleven new acylphloroglucinols, including six new formylated phloroglucinol-monoterpene meroterpenoids, eucalyprobusals A-F (1-6), one monomeric acylphloroglucinol, eucalyprobusone B (7), and four dimeric acylphloroglucinols, eucalyprobusones C-F (8-11) were purified from the fruits of Eucalyptus robusta. The establishment of the structures of 1-11 was achieved by a combination of NMR and HRESIMS data analyses, electron circular dichroism (ECD), and single-crystal X-ray diffraction. Compounds 6, 8, and an inseparable mixture of 10 and 11 were found to be potent AChE inhibitors with IC50 values of 3.22 ± 0.36, 3.82 ± 0.22, and 2.55 ± 0.28 µΜ, respectively. Possible interaction sites of 6, 8, 10, and 11 with AChE were investigated by means of molecular docking studies, and the results revealed that AChE residues Asn87, Ser125, Thr83, Tyr133, Tyr124, Tyr337, and Tyr341 played crucial roles in the observed activity of the aforementioned compounds.