当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization.

Novel Mechanism of Cytotoxicity for the Selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3-selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization.

Abstract：

:Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-L-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure-activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Al-Eisawi Z,Stefani C,Jansson PJ,Arvind A,Sharpe PC,Basha MT,Iskander GM,Kumar N,Kovacevic Z,Lane DJ,Sahni S,Bernhardt PV,Richardson DR,Kalinowski DS

doi

10.1021/acs.jmedchem.5b01399

subject

Has Abstract

pub_date

2016-01-14 00:00:00

pages

294-312

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

杂志文章

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