Synthesis and biological activity of new oxindol compounds with antitumor properties. Santos LMR1; Castro FV1;Vasconcellos B2;Ribeiro NM2;Pinto AC2; Panek AD1; Eleutherio ECA1; Pereira M.D1
1Laboratório de Investigação de Fatores de Estresse (LIFE), Departamento de Bioquímica, Instituto de Química, UFRJ, Rio de Janeiro, RJ, Brazil; 2Departamento de Química Orgânica, Instituto de Química, UFRJ, Rio de Janeiro, RJ, Brazil
Cancer is the cause death of 6.0 millions people in year, representing 12% of total mortality around the world. The development of resistance to drugs is a challenge in the treatment of cancer and microbial diseases. On the last few years, many compounds of oxindol class are on focus against some kinds of cancer due to its ability to inhibit the protein tyrosin kinase. This class of enzyme has been related with critical components of cell signaling that leads to cell proliferation and differentiation. Besides, compounds containing the ferrocen group have been shown to be effective to inhibit cell proliferation. In this study, the oxindol with the ferrocene, chloro or brome groups were chemically synthesized and their biological activities were tested. For this purpose, we used, as an eukaryotic model, cells of the yeast Saccharomyces cerevisiae harboring specific mutations in genes of the antioxidant defense system. First of all, we analyzed the conditions for the synthesis of oxindol from isatins, and then to condense the special groups (ferrocene, chloro and brome) within oxindol moiety. For testing the biological activity of these new compounds, yeast cells were plated on rich media supplied with different drug concentrations (25, 50, 75, 100, 300mg/mL). Cells were incubated at 28°C, during 24 and 48h, for analysis of cellular growth as well as colony morphology. All drugs, especially those containing the ferrocene group, showed capacity to inhibit cell proiferation. Interesting enough, the inhibitory effect on growth was higher in the S. cerevisiae cells defficient on Cu/Zn-superoxide dismutase, suggesting that these drugs could be involved in superoxide radical generation. Regarding colony morphology, cells growing on plates with oxindol moieties containing 1-chloro, as well as brome, showed a mucoid aspect suggesting that these drugs could interfere in the cell wall and membrane properties. Finally, this work demonstrates that new oxindol compounds with different groups could be synthesized with potential antitumor activities. Further studies will be needed to elaborate the precise mechanism of action involved in inhibitory cell proliferation, as well as the citotoxic effect of these compounds.
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