As a part of our ongoing effort to develop isoquinoline antitumor agents, we recently synthesized a new group of compounds starting from (L)-tartaric acid applying our own methodology. The evaluations of their bioactivity disclosed, that these compounds inhibit topoisomerase type I and II. We synthesized derivatives in both optical forms bearing a variety of substituents as presented on structure A. The impact of substitution pattern and absolute configuration on bioactivity was analyzed to contribute to the rational design of more selective drugs to target topoisomerase proteins. New isoquinoline derivatives were tested for their anticancer potential in vitro against three different human cell lines, including MCF-7 and MDA-MB-231 breast cells, and AGS-CRL-1739 gastric cells. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. Confocal microscopy bioimaging was used to demonstrate the expression of pivotal proteins engaged in apoptosis (caspase-8, caspase-3, p53) and cell signaling (AKT, ERK1/2). The cytotoxic and antiproliferative effects of the novel compounds were associated with the induction of apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. The novel isoquinoline derivatives decreased the expression of AKT and ERK1/2. Their mechanism was associated with p53-mediated apoptosis, accumulation of cells in the G2/M phase of cell cycle and inhibition of topoisomerase type I and II.

Synthesis, cytotoxicity, and apoptosis induction study of new tetrahydroisoquinoline derivatives

2019 Fall National Meeting

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