Comparative biological evaluation and G-quadruplex interaction studies of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands
Comparative biological evaluation and G-quadruplex interaction studies 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 (NHC) complexes of general formula [Au(N1-TBM)
2]BF
4 (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-4λ
4,5λ
4-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-quadruplex (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)
2]BF
4 family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)
2]
+ (AuTMX
2). 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
Meier-Menches, Samuel M.
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Aikman, Brech
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Döllerer, Daniel
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Klooster, Wim
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Coles, Simon J.
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Santi, Nicolò
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Luk, Louis
49434855-041a-4eaf-a094-cb91374fc2de
Casini, Angela
27012a50-6e79-4b89-b843-c813b358f332
Bonsignore, Riccardo
bfce63f3-2ab6-4a51-bc21-1ce8202386e1
January 2020
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 and G-quadruplex interaction studies 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).
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 (NHC) complexes of general formula [Au(N1-TBM)
2]BF
4 (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-4λ
4,5λ
4-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-quadruplex (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)
2]BF
4 family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)
2]
+ (AuTMX
2). 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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Accepted/In Press date: 8 September 2019
e-pub ahead of print date: 11 September 2019
Published date: January 2020
Additional Information:
Funding Information:
Cardiff University is acknowledged for funding. The authors are grateful to the Life Science Research Network Wales for providing a post-doctoral fellowship to S.M.M.. R.B. acknowledges funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement n° 663830 . Appendix A
Publisher Copyright:
© 2019 Elsevier Inc.
Keywords:
gold(I) organometallics, N-heterocyclic carbenes, Alkynyl ligands, G-quadruplexes, Cancer
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Local EPrints ID: 434618
URI: http://eprints.soton.ac.uk/id/eprint/434618
ISSN: 0162-0134
PURE UUID: 322b3efd-c5d3-4229-b84c-df3c3ef9ce29
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Date deposited: 03 Oct 2019 16:30
Last modified: 17 Mar 2024 02:48
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Contributors
Author:
Samuel M. Meier-Menches
Author:
Brech Aikman
Author:
Daniel Döllerer
Author:
Wim Klooster
Author:
Nicolò Santi
Author:
Louis Luk
Author:
Angela Casini
Author:
Riccardo Bonsignore
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