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• W2022078345 abstract "The cytotoxicity showed by 1b, an interesting representant of the title compounds, for HT-29 human colon cancer cells (CI50 value of 1.95 × 10−7 M) has been related to the induced cell death at the G2 phase and not to DNA damage. This compound promotes the degradation of components of the G2/M checkpoint machinery, in particular cdc2, Cyclin B1 and Wee1, which represents a novel mechanism of cytotoxicity. Degradation of Wee1 seems to be mediated by proteasome activity but degradation of cdc2 has to occur through a different mechanism. The activity of 1b on G2 cell cycle components suggests that tumor cells that are arrested in G2/M by anticancer drugs like cisplatin could be targeted by compound 1b, increasing the apoptosis induction, and that their optimized analogs might be useful in the treatment of colon cancer through combination therapies with cisplatin or other anticancer drugs that affect the cytoskeleton integrity such as taxol and taxotere. SAR studies with compounds obtained by manipulation of the N(2) and C(4)-functional groups and the C(6)-chain of compound 1b have confirmed the importance of these structural features in the in vitro antitumor activity. Fused oxazolidine derivatives as compound 5 were inactive, and the lack of activity found in the replacement of the C(4)-lactam by a cyanoamine function, as in compounds 8–10, could be explained considering that their all-syn relative configuration makes them too stable to generate alkylating iminium species." @default.
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• W2022078345 date "2009-12-01" @default.
• W2022078345 modified "2023-10-01" @default.
• W2022078345 title "Cytotoxicity mechanisms of pyrazino[1,2-b]isoquinoline-4-ones and SAR studies" @default.
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• W2022078345 doi "https://doi.org/10.1016/j.bmc.2009.10.007" @default.
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