Six recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ERα positive MCF-7, triple negative MDA-MB-231, and Her2+ SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the γ-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 μM), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 μM, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic death in breast cancer cells, and both compounds showed no significant toxicity on healthy cells (e.g., MCF-10A) and red blood cells. An in-depth mechanistic study based on molecular biology, immunoblotting analysis and in silico docking calculations suggested that α,β-unsaturated γ-lactam derivatives could interfere with the functioning of PI3K and PDK-1, two key enzymes in the PI3K/AKT signaling pathway, whose overactivation is related to the regulation of cell growth and survival in several malignancies.

Anticancer potential of novel α,β-unsaturated γ-lactam derivatives targeting the PI3K/AKT signaling pathway

Brindisi M.;Frattaruolo L.;Mancuso R.;Ziccarelli I.;Gabriele B.;Cappello A. R.
2021-01-01

Abstract

Six recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ERα positive MCF-7, triple negative MDA-MB-231, and Her2+ SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the γ-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 μM), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 μM, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic death in breast cancer cells, and both compounds showed no significant toxicity on healthy cells (e.g., MCF-10A) and red blood cells. An in-depth mechanistic study based on molecular biology, immunoblotting analysis and in silico docking calculations suggested that α,β-unsaturated γ-lactam derivatives could interfere with the functioning of PI3K and PDK-1, two key enzymes in the PI3K/AKT signaling pathway, whose overactivation is related to the regulation of cell growth and survival in several malignancies.
2021
Apoptosis
Breast cancer
Cytotoxicity
PI3K/AKT signaling pathway
α,β-Unsaturated lactams
α-Methylene-γ-lactams
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/325496
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