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Synthesis and biological evaluation of novel anti-cancer agents
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Cancer is still one of the deadliest diseases worldwide despite the deep understanding of its etiology and efforts toward an early detection and the development of personalized therapeutic approaches. Thus, the development of novel molecules that maybe selectively inhibit the growth of cancer cells, avoid side effects and/or acquired resistance has long been the focus in chemotherapy. One such compounds, AM130 with the spiro[pyrrolidine-3, 3´-oxindole] moiety has shown antiproliferative and antimalarial activity. Here, we report the synthesis and the biological anitproliferative potential of this compound, as well as its mechanism of action in cancer cells.
Viability assays were performed in ovarian, colorectal and breast carcinoma cell lines and normal human fibroblasts, allowing the characterization of the antiproliferative potential of AM130. Results showed that AM130 has a higher cytotoxic effect as well as higher selectivity for the ovarian carcinoma cell line.
The observed antiproliferative activity was due to the induction of cell death by mitochondria-mediated apoptotic pathway and autophagy. DNA interaction studies demonstrated that AM130 interacts with DNA by groove-binding, however without causing genotoxicity or cell cycle arrest. In addition, AM130 showed a strong affinity to bovine serum albumin. Proteomics analysis revealed that the majority of the identified proteins are involved in apoptosis and stress response regulation, corroborating the previous results about ovarian carcinoma cells death.
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Carcinogenesis Chemotherapy Spirooxindole Drugs-DNA interaction Cytotoxicity