Abstract
Based on the structure of sanguinarine, fourteen phenanthridine derivatives were designed and synthesized in the current study. The cytotoxic activities of synthesized compounds were evaluated against five human cancer cell lines (MCF-7, PC3, Hela, A549, and HepG2 cell lines) via MTT assay. Among all the compounds tested, molecule 8a exhibited significant cytotoxic activity against MCF-7 cells with a IC50 value of 0.28 μM. A following up enzymatic assay indicated that compound 8a could inhibit the activity of DNA topoisomerase I/II. Further mechanistic studies performed in the MCF-7 cell line revealed that compound 8a could arrest cell cycle in S phase and induce cell apoptosis via downregulation of Bcl-2 and upregulation of Bax. Collectively, a potent DNA topoisomerase inhibitor (8a) was discovered, which exhibited potential as a candidate chemotherapeutic agent for the management of tumors in the present study.
Highlights
Sanguinarine (SA) belongs to the chrysene-skeleton-based heterocyclic benzo [c] phenanthridine alkaloids family (Figure 1), which are widely distributed in plants, such as Sanguinaria canadensis and Papaveraceae [1,2,3]
While reduced cells at the G2/M phase was detected from 23.46 to 10.45% (0.15 μM), 8.69% (0.3 μM), and 5.62% (0.6 μM) following treatment with compound 8a dose-dependently. These results suggest that compound 8a exhibited a significant antitumor effect and led to MCF-7 cell cycle arrest at the S phase in a dose-dependent manner
8a exhibited a broad spectrum of anti-proliferative activities against all the tested cancer cell lines
Summary
Sanguinarine (SA) belongs to the chrysene-skeleton-based heterocyclic benzo [c] phenanthridine alkaloids family (Figure 1), which are widely distributed in plants, such as Sanguinaria canadensis and Papaveraceae [1,2,3]. While reduced cells at the G2/M phase was detected from 23.46 to 10.45% (0.15 μM), 8.69% (0.3 μM), and 5.62% (0.6 μM) following treatment with compound 8a dose-dependently These results suggest that compound 8a exhibited a significant antitumor effect and led to MCF-7 cell cycle arrest at the S phase in a dose-dependent manner. To further investigate the role of apoptosis in the antitumor effect of compound 8a, Hoechst 33258 staining was performed to investigate the nuclear morphological changes following molecule 8a treatment on MCF-7 cells. The results indicated that compound 8a could significantly downregulate Bcl-2 levels and upregulate Bax levels in MCF7 cells, increasing the ratio of Bax/Bcl-2 in a dose-dependent manner (Figure 5) These results suggest that compound 8a induced apoptosis by regulating the expression of apoptosis-related proteins
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