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This article discusses the creation and evaluation of Furoxan-Piplartine hybrids as potential anti-cancer compounds. These hybrids were found to be more cytotoxic and selective in cancer cells compared to their precursors. Specifically, PC3 cells were most sensitive to certain hybrids, with NO generation and ROS induction observed. The compounds were shown to induce apoptosis in these cancer cells through the release of NO and increase in ROS production. This research sheds light on potential new compounds for cancer treatment.
Conjugation of the naturally occurring product piplartine (PPT, 1), which is a potent cytotoxic compound and ROS inducer, with a diphenyl sulfonyl-substituted furoxan moiety (namely, 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide), an important class of NO donor, via an ether linker of different chain lengths is described, characterized and screened for their anticancer potential. The cytotoxicity of these hybrids was evaluated on a panel of human cancer cell lines (MCF-7, PC3 and OVCAR-3) and two non-cancer human cells (MCF10A and PNT2). In general, the synthesized hybrids were more cytotoxic and selective compared to their furoxan precursors 4-6 and PPT in the above cancer cells. Particularly, PC3 cells are the most sensitive to hybrids 7 and 9 (IC50 values of 240 nM and 50 nM, respectively), while lower potency was found for the prostate normal cells (IC50 = 17.8 μM and 14.1 μM, respectively), corresponding to selectivity indices of ca. 75 and 280, respectively. NO generation by the PPT-furoxan compounds in PC3 cells was confirmed using the Griess reaction. Furthermore, the cell growth inhibitory effect of 9 was significantly attenuated by the NO scavenger carboxy-PTIO. The intracellular ROS generation by 7 and 9 was also verified, and different assays showed that co-treatment with the antioxidant N-acetyl-L-cysteine (NAC) protected against PPT-induced ROS generation. Further mechanistic studies revealed that 7 and 9 had strong cytotoxicity to induce apoptosis in PC3 cells, being mediated, at least in part, by the NO-releasing and increase in ROS production. Notably, the ability of 9 to induce apoptosis was stronger than that