Pseudopeptide proteasome inhibitors
Provider: Grantová agentura ČR
Programme: Standardní projekty
Implementation period: 01.01.18 - 31.12.20
Workplace:
Fakulta chemicko-technologická - Ústav organické chemie a technologie
Investigator: Imramovský AlešTeam member: Pauk Karel
Description:
Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells and tumor growth even in the clinical settings. Some proteasome inhibitors have been validated as drugs for the treatment of of multiple myeloma and mantle cell lymphoma, but the side-effects in patients stimulate further development. Our preliminary experiments identified new proteasomal inhibitors in a library of 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, hereafter referred to as pseudopeptides. These compounds show partial structural similarity to the proteasome inhibitor and clinically used anticancer drug bortezomib. Our experiments have confirmed that some pseudopeptides display potent cytotoxic activity in several cancer cell lines and markedly induce apoptosis in a dose-dependent manner. We therefore plan to extend our findings by preparing a library of related compounds, study structure-activity relationships, design more potent derivatives and confirm mechanism of cytotoxic activity of the most potent candidates.
Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells and tumor growth even in the clinical settings. Some proteasome inhibitors have been validated as drugs for the treatment of of multiple myeloma and mantle cell lymphoma, but the side-effects in patients stimulate further development. Our preliminary experiments identified new proteasomal inhibitors in a library of 2-hydroxy-N-[1-(2-hydroxyphenylamino)-1-oxoalkan-2-yl]benzamides, hereafter referred to as pseudopeptides. These compounds show partial structural similarity to the proteasome inhibitor and clinically used anticancer drug bortezomib. Our experiments have confirmed that some pseudopeptides display potent cytotoxic activity in several cancer cell lines and markedly induce apoptosis in a dose-dependent manner. We therefore plan to extend our findings by preparing a library of related compounds, study structure-activity relationships, design more potent derivatives and confirm mechanism of cytotoxic activity of the most potent candidates.
