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Comparative biological evaluation of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands

Comparative biological evaluation of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands
Comparative biological evaluation of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands
Experimental organometallic gold(I) compounds hold promise for anticancer therapy. This study reports the synthesis of two novel families of gold(I) complexes, including N1-substituted bis-N-heterocyclic carbene (NHCs) complexes of general formula [Au(N1-TBM)2]BF4 (N1-TBM = N1-substituted 9-methyltheobromin-8-ylidene) and mixed gold(I) NHC-alkynyl complexes, [Au(N1-TBM)alkynyl]. The compounds were fully characterised for their structure and stability in aqueous environment and in the presence of N-acetyl cysteine by nuclear magnetic resonance (NMR) spectroscopy. The structures of bis(1-ethyl-3,7,9-trimethylxanthin-8-ylidene)gold(I), (4-ethynylpyridine)(1,9-dimethyltheobromine-8-ylidene)gold(I) and of (2,8-Diethyl-10-(4-ethynylphenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ4,5λ4-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinine)(1,3,7,9-tetramethylxanthin-8-ylidene)gold(I) were also confirmed by X-ray diffraction analysis. The compounds were studied for their properties as DNA G-quadruplexes (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)2]BF4 family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)2]+ (AuTMX2). However, the compounds also showed marked selectivity for binding to G4 structures with respect to duplex DNA in competition experiments. For selected complexes, the interactions with G4 s were also confirmed by circular dichroism (CD) studies. Furthermore, the gold(I) complexes were assessed for their antiproliferative effects in human cancer cells in vitro, displaying moderate activity. Of note, among the mixed gold(I) NHC-alkynyl compounds, one features a fluorescent boron-dipyrromethene (BODIPY) moiety which allowed determining its uptake into the cytoplasm of cancer cells by fluorescence microscopy.
gold(I) organometallics, N-heterocyclic carbenes, Alkynyl ligands, G-quadruplexes, Cancer
0162-0134
Meier-Menches, Samuel M.
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Aikman, Brech
e117e4cb-1bde-4c8c-bcf7-c975e8972cc6
Döllerer, Daniel
ac64442d-3b9b-4dbd-a384-e9a2627aa8ac
Klooster, Wim
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Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Santi, Nicolò
38e351f5-10eb-4d58-91e1-7a84864454df
Luk, Louis
49434855-041a-4eaf-a094-cb91374fc2de
Casini, Angela
27012a50-6e79-4b89-b843-c813b358f332
Bonsignore, Riccardo
bfce63f3-2ab6-4a51-bc21-1ce8202386e1
Meier-Menches, Samuel M.
a489f78b-568b-43b7-b843-2e9a591f23a0
Aikman, Brech
e117e4cb-1bde-4c8c-bcf7-c975e8972cc6
Döllerer, Daniel
ac64442d-3b9b-4dbd-a384-e9a2627aa8ac
Klooster, Wim
64dc0111-f415-4226-9189-45764c0933d9
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Santi, Nicolò
38e351f5-10eb-4d58-91e1-7a84864454df
Luk, Louis
49434855-041a-4eaf-a094-cb91374fc2de
Casini, Angela
27012a50-6e79-4b89-b843-c813b358f332
Bonsignore, Riccardo
bfce63f3-2ab6-4a51-bc21-1ce8202386e1

Meier-Menches, Samuel M., Aikman, Brech, Döllerer, Daniel, Klooster, Wim, Coles, Simon J., Santi, Nicolò, Luk, Louis, Casini, Angela and Bonsignore, Riccardo (2020) Comparative biological evaluation of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands. Journal of Inorganic Biochemistry, 202, [110844]. (doi:10.1016/j.jinorgbio.2019.110844).

Record type: Article

Abstract

Experimental organometallic gold(I) compounds hold promise for anticancer therapy. This study reports the synthesis of two novel families of gold(I) complexes, including N1-substituted bis-N-heterocyclic carbene (NHCs) complexes of general formula [Au(N1-TBM)2]BF4 (N1-TBM = N1-substituted 9-methyltheobromin-8-ylidene) and mixed gold(I) NHC-alkynyl complexes, [Au(N1-TBM)alkynyl]. The compounds were fully characterised for their structure and stability in aqueous environment and in the presence of N-acetyl cysteine by nuclear magnetic resonance (NMR) spectroscopy. The structures of bis(1-ethyl-3,7,9-trimethylxanthin-8-ylidene)gold(I), (4-ethynylpyridine)(1,9-dimethyltheobromine-8-ylidene)gold(I) and of (2,8-Diethyl-10-(4-ethynylphenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ4,5λ4-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinine)(1,3,7,9-tetramethylxanthin-8-ylidene)gold(I) were also confirmed by X-ray diffraction analysis. The compounds were studied for their properties as DNA G-quadruplexes (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)2]BF4 family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)2]+ (AuTMX2). However, the compounds also showed marked selectivity for binding to G4 structures with respect to duplex DNA in competition experiments. For selected complexes, the interactions with G4 s were also confirmed by circular dichroism (CD) studies. Furthermore, the gold(I) complexes were assessed for their antiproliferative effects in human cancer cells in vitro, displaying moderate activity. Of note, among the mixed gold(I) NHC-alkynyl compounds, one features a fluorescent boron-dipyrromethene (BODIPY) moiety which allowed determining its uptake into the cytoplasm of cancer cells by fluorescence microscopy.

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Restricted to Repository staff only until 11 September 2020.
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Accepted/In Press date: 8 September 2019
e-pub ahead of print date: 11 September 2019
Published date: January 2020
Keywords: gold(I) organometallics, N-heterocyclic carbenes, Alkynyl ligands, G-quadruplexes, Cancer

Identifiers

Local EPrints ID: 434618
URI: http://eprints.soton.ac.uk/id/eprint/434618
ISSN: 0162-0134
PURE UUID: 322b3efd-c5d3-4229-b84c-df3c3ef9ce29
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272

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Date deposited: 03 Oct 2019 16:30
Last modified: 30 Jan 2020 01:29

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