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Article: An Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

TitleAn Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target
Authors
Keywordsantitumor agents
asparagine synthetase
N-heterocyclic carbenes
platinum complexes
thermal proteome profiling
Issue Date2019
PublisherWiley - VCH Verlag GmbH & Co. KGaA. The Journal's web site is located at http://www3.interscience.wiley.com/journal/26737/home
Citation
Angewandte Chemie (International Edition), 2019, v. 58 n. 32, p. 10914-10918 How to Cite?
AbstractNew anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor PtII complex targeting a tumor‐associated protein, rather than DNA, under cellular conditions. Complex [(bis‐NHC)Pt(bt)]PF6 (1 a; Hbt=1‐(3‐hydroxybenzo[b]thiophen‐2‐yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis‐NHC‐ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active‐site cysteine of ASNS.
Persistent Identifierhttp://hdl.handle.net/10722/274827
ISSN
2019 Impact Factor: 12.959
2015 SCImago Journal Rankings: 6.229

 

DC FieldValueLanguage
dc.contributor.authorHu, D-
dc.contributor.authorYang, C-
dc.contributor.authorLok, CN-
dc.contributor.authorXING, F-
dc.contributor.authorLee, PY-
dc.contributor.authorFung, YME-
dc.contributor.authorJiang, H-
dc.contributor.authorChe, CM-
dc.date.accessioned2019-09-10T02:29:38Z-
dc.date.available2019-09-10T02:29:38Z-
dc.date.issued2019-
dc.identifier.citationAngewandte Chemie (International Edition), 2019, v. 58 n. 32, p. 10914-10918-
dc.identifier.issn1433-7851-
dc.identifier.urihttp://hdl.handle.net/10722/274827-
dc.description.abstractNew anticancer platinum(II) compounds with distinctive modes of action are appealing alternatives to combat the drug resistance and improve the efficacy of clinically used platinum chemotherapy. Herein, we describe a rare example of an antitumor PtII complex targeting a tumor‐associated protein, rather than DNA, under cellular conditions. Complex [(bis‐NHC)Pt(bt)]PF6 (1 a; Hbt=1‐(3‐hydroxybenzo[b]thiophen‐2‐yl)ethanone) overcomes cisplatin resistance in cancer cells and displays significant tumor growth inhibition in mice with higher tolerable doses compared to cisplatin. The cellular Pt species shows little association with DNA, and localizes in the cytoplasm as revealed by nanoscale secondary ion mass spectrometry. An unbiased thermal proteome profiling experiment identified asparagine synthetase (ASNS) as a molecular target of 1 a. Accordingly, 1 a treatment reduced the cellular asparagine levels and inhibited cancer cell proliferation, which could be reversed by asparagine supplementation. A bis‐NHC‐ligated Pt species generated from the hydrolysis of 1 a forms adducts with thiols and appears to target an active‐site cysteine of ASNS.-
dc.languageeng-
dc.publisherWiley - VCH Verlag GmbH & Co. KGaA. The Journal's web site is located at http://www3.interscience.wiley.com/journal/26737/home-
dc.relation.ispartofAngewandte Chemie (International Edition)-
dc.rightsThis is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectantitumor agents-
dc.subjectasparagine synthetase-
dc.subjectN-heterocyclic carbenes-
dc.subjectplatinum complexes-
dc.subjectthermal proteome profiling-
dc.titleAn Antitumor Bis(N-Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target-
dc.typeArticle-
dc.identifier.emailHu, D: hudi@hku.hk-
dc.identifier.emailYang, C: yangchen@HKUCC-COM.hku.hk-
dc.identifier.emailLok, CN: cnlok@hkucc.hku.hk-
dc.identifier.emailLee, PY: puiyanle@HKUCC-COM.hku.hk-
dc.identifier.emailFung, YME: eva.fungym@hku.hk-
dc.identifier.emailChe, CM: chemhead@hku.hk-
dc.identifier.authorityLok, CN=rp00752-
dc.identifier.authorityFung, YME=rp01986-
dc.identifier.authorityChe, CM=rp00670-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/anie.201904131-
dc.identifier.pmid31165553-
dc.identifier.scopuseid_2-s2.0-85068329874-
dc.identifier.hkuros303754-
dc.identifier.volume58-
dc.identifier.issue32-
dc.identifier.spage10914-
dc.identifier.epage10918-
dc.publisher.placeGermany-

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