期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 1, 页码 294-312出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01399
关键词
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资金
- National Health and Medical Research Council (NHMRC) Australia [1021607, 1048972]
- NHMRC Senior Principal Research Fellowship [1062607]
- NHMRC RD Wright Fellowship [1083057]
- Cancer Institute NSW [10/CDF/2-15, 12ECF2-17]
- Sydney Medical School
- NHMRC [1037323]
- Sydney Medical School Foundation
- AMP Tomorrow Fund
- University of Sydney
- Australian Research Council [DP150104672]
- National Health and Medical Research Council of Australia [1083057] Funding Source: NHMRC
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.
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