Despite the success of genomics in identifying new essential oncogenic signaling pathways, there have been a limited number of sustainable leads in anticancer drug discovery to address increasing chemoresistance. To improve progress in this area, our lab synthesized several novel benzisoxazoloazinium tetrafluoroborates (1-3) with structural characteristics similar to clinically effective DNA binding drugs. From a series of eight tricyclic pyridinium compounds with various substituents, Compound 1a effectively inhibits proliferation in colon cancer cell lines (IC50 = 2.95 µM) and shows significant in silico and in vitro DNA binding affinity. Incorporation of a fourth ring generated quinolinium derivatives (2) that recapitulate DNA binding activity of ellipticine. Preliminary IC50 values range from 52 µM for 2b to 202 µM for 2a. To evaluate the impact of second nitrogen, we synthesized and evaluated a quinoxalinium analog (3); results for this compound (IC50 of 18 µM) show increased cytotoxicity compared to 2b. All compounds induce cell death via non-apoptotic pathways. Future work will involve the synthesis and evaluation of other quinoxalinium analogs, as well as evaluation of their activity against PC3 human prostate cancer cells.
Tryptanthrin (TRYP) is an indole quinazoline alkaloid with a range of pharmaceutical activities, but the specific mechanism of TRYP against colorectal cancer (CRC) remains obscure. The purpose of this study was to evaluate the antitumor effects of TRYP on CRC models both in vitro and in vivo and further analyze its concrete mechanisms. The results of the in vitro experiment show that TRYP effectively inhibited the proliferation and migration of SW620 cells, arrested the cell cycle at the S phase, and induced cell apoptosis. Deeply, TRYP dramatically increased the expression of Bax and cleaved caspase 3 while decreasing the expression of Bcl-2. The results of transcriptome sequencing implied that the inhibitory effects of TRYP were closely related to the mitogen-activated protein kinase (MAPK) signaling pathway, and the results of western blotting verified that TRYP could decrease the expression of p-Erk and increase the expression of p-p38 and p-Jnk. Besides, our results identified that topoisomerase I (Topo I) and indole amine 2,3-dioxygenase 1 (IDO1) were the targets of TRYP. In vivo, the results showed that different TRYP doses significantly inhibited tumor growth in mice, induced different degrees of necrosis in tumor tissues, decreased the expression level of Ki67 protein, and increased the apoptotic signal in tumor tissues. The findings demonstrated the inhibitory effects of TRYP on CRC, and the mechanisms were tightly connected to inhibiting the activity of Topo I and IDO1 and regulating the expression of the MAPK signaling pathway. Especially, it was first identified that TRYP could directly inhibit Topo I to arrest SW620 at the S phase. Therefore, this work established a scientific basis for the development of TRYP.
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