Synthesis and biological evaluation of xanthone derivatives as anti-cancer agents targeting topoisomerase II and DNA

Abstract

Topoisomerase is one of the most important targets of anticancer drugs. In order to develop effective and low-toxic topoisomerase inhibitors, a series of xanthone derivatives have been designed and synthesized using the principles of skeleton transition. In vitro growth inhibition experiments of human breast cancer(MCF-7), gastric cancer (MGC-803), and cervical cancer(Hela) cell lines were used to evaluate the compound's anti-tumor cell proliferation activity. Most of the compounds showed anti-tumor growth activity, and also showed low toxicity to human normal cells L929. In the enzyme activity inhibition experiment, compounds 7d and 8d showed the best inhibitory activity. The DNA binding studies disclosed that the most potent compounds 7d and 8d can intercalate into DNA, induce apoptosis in MGC-803 cells and arrested at G2/M phase. Molecular docking showed that compounds 7d and 8d could bind with topoisomerase II and DNA through hydrogen bonds and π-stacking interactions.

Phytochemical screening and potential antioxidant, antibacterial and anti-melanoma activities of <i>Rollinia dolabripetala</i> leaves

“…Cytotoxic phytocompounds present in different species of the genera Rollinia (Araujo et al, 2021;Cunha et al, 2009) and other annonaceous (George et al, 2021;Handayani & Yuzammi, 2021;Khan et al, 2020;Perrone et al, 2022;Rocha et al, 2021;Shehata et al, 2021) support the experimental results obtained here, with selective cytotoxic effect on normal cells (Ribeiro et al, 2018;Shehata et al, 2021). The antitumor action of xanthones and derivatives (Huang et al, 2021;Kurniawan et al, 2021;Nguyen et al, 2022;Pinto et al, 2021;Song et al, 2021Song et al, , 2022Zhao et al, 2022), and tannins (Musial et al, 2021;Shehata et al, 2021;Zeng et al, 2022;Zhang et al, 2021) also reinforces the data. Regarding the results exhibited by the phytochemical xanthone, new experimental tests need to be conducted to understand its cytotoxic action on cellular pathways as a function of the chemical groups (such as 1.7dihydroxy-xanthone) present in this polyphenol.…”

“…Xanthones polyphenols and their synthetic derivatives exhibit antitumor potential (Huang et al, 2021;Kurniawan et al, 2021;Pinto et al, 2021;Song et al, 2021Song et al, , 2022 and, interestingly, the treatment with RDLE that exhibits this phytochemical in its leaves, showed a very discrepant GI 50 . An investigation into a possible antagonistic effect among the extract's phytochemicals may clarify this result.…”

“…Xanthonic derivatives (such as α-mangostine, βmangostine, γ-mangostine, gartanine, 8-deoxygartanine, garcinone C, garcinone D, 9-hydroxycalabaxanthone, mangaxanthone B, and 3-isomangostine) present in Garcinia (Clusiaceae) show effects on the viability of different tumor cell lines (Nguyen et al, 2022;Song et al, 2022;Zhao et al, 2022). The strongest inhibitors were α-mangostine and γ-mangostine, indicating that the position of the main functional groups, including hydroxyl and isoprenyl groups, are important in promoting anti-proliferative effects against prostate and breast cancer cells by inducing apoptosis through human estrogen receptors and fatty acid synthase signaling pathways See et al (2022), or through the inhibition of cyclin-dependent kinases (CDK2/CyclinE1), central regulators in tumorigenesis Nauman et al (2021).…”

“…The strongest inhibitors were α-mangostine and γ-mangostine, indicating that the position of the main functional groups, including hydroxyl and isoprenyl groups, are important in promoting anti-proliferative effects against prostate and breast cancer cells by inducing apoptosis through human estrogen receptors and fatty acid synthase signaling pathways See et al (2022), or through the inhibition of cyclin-dependent kinases (CDK2/CyclinE1), central regulators in tumorigenesis Nauman et al (2021). Xanthonic phytocompounds also promote the interruption of the cell cycle at G2/M phase exhibiting strong antitumor cell proliferation and topoisomerase II inhibitory activity (Song et al, 2022) and between G0/G1 and S phases, strongly inducing apoptosis via caspases 3/7, 8 and 9 activation and disrupted the mitochondrial membrane potential in different cancer cells lines (Kuete et al, 2014). Temporally, cytotoxicity is more effective in treatments in relation to chemotherapeutic control, in which a larger population of melanoma tumor cells is eliminated when exposed to the most effective concentrations previously determined for phytocompounds and plant leaf extracts.…”

“…Detected in RDLE, tannins (G'massampou et al, 2021;Sieniawska & Baj, 2017;Smeriglio et al, 2017) and several xanthone derivatives (Huang et al, 2021;Pinto et al, 2021;Song et al, 2021;Yuanita et al, 2020) exhibit anti-Staphylococcal bioactivity. Leaf extracts of A. crassiflora that had these phytochemicals removed, and no inhibitory effects on bacterial growth were observed (Ribeiro et al, 2018).…”