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Aminopeptidase N Inhibitors as Pointers for Overcoming Antitumor Treatment Resistance

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FARSA Oldřich BALLAYOVÁ Veronika ŽÁČKOVÁ Radka KOLLÁR Peter KAUEROVÁ Tereza ZUBÁČ Peter

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj International Journal of Molecular Sciences
Fakulta / Pracoviště MU

Farmaceutická fakulta

Citace
www https://www.mdpi.com/1422-0067/23/17/9813/htm
Doi http://dx.doi.org/10.3390/ijms23179813
Klíčová slova aminopeptidase N; acetamidophenones; Schiff bases; semicarbazones; thiosemicarbazones; inhibition of proliferation
Popis Aminopeptidase N (APN), also known as CD13 antigen or membrane alanyl aminopeptidase, belongs to the M1 family of the MA clan of zinc metallopeptidases. In cancer cells, the inhibition of aminopeptidases including APN causes the phenomenon termed the amino acid deprivation response (AADR), a stress response characterized by the upregulation of amino acid transporters and synthetic enzymes and activation of stress-related pathways such as nuclear factor kB (NFkB) and other pro-apoptotic regulators, which leads to cancer cell death by apoptosis. Recently, APN inhibition has been shown to augment DR4-induced tumor cell death and thus overcome resistance to cancer treatment with DR4-ligand TRAIL, which is available as a recombinant soluble form dulanermin. This implies that APN inhibitors could serve as potential weapons for overcoming cancer treatment resistance. In this study, a series of basically substituted acetamidophenones and the semicarbazones and thiosemicarbazones derived from them were prepared, for which APN inhibitory activity was determined. In addition, a selective anti-proliferative activity against cancer cells expressing APN was demonstrated. Our semicarbazones and thiosemicarbazones are the first compounds of these structural types of Schiff bases that were reported to inhibit not only a zinc-dependent aminopeptidase of the M1 family but also a metalloenzyme.

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