Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes
The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom o...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/13/7146 |
| _version_ | 1797479753837445120 |
|---|---|
| author | Yann Le Gal Agathe Filatre-Furcate Dominique Lorcy Olivier Jeannin Thierry Roisnel Vincent Dorcet Diana Fontinha Denise Francisco Miguel Prudncio Marta Martins Catarina Soeiro Sílvia A. Sousa Jorge H. Leitão Tnia S. Morais Ins Bártolo Nuno Taveira Joana F. Guerreiro Fernanda Marques |
| author_facet | Yann Le Gal Agathe Filatre-Furcate Dominique Lorcy Olivier Jeannin Thierry Roisnel Vincent Dorcet Diana Fontinha Denise Francisco Miguel Prudncio Marta Martins Catarina Soeiro Sílvia A. Sousa Jorge H. Leitão Tnia S. Morais Ins Bártolo Nuno Taveira Joana F. Guerreiro Fernanda Marques |
| author_sort | Yann Le Gal |
| collection | DOAJ |
| description | The biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)<sub>2</sub>) and the counter-ion (Ph<sub>4</sub>P<sup>+</sup> or Et<sub>4</sub>N<sup>+</sup>). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC<sub>50</sub> values ranged from 0.1–8 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>M (A2780) and 0.8–29 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>M (OVCAR8). The complexes with the Ph<sub>4</sub>P<sup>+</sup> ([<span style="color: #ff1b00;"><b>P</b></span>]) counter-ion are in general more active than their Et<sub>4</sub>N<sup>+</sup> ([<span style="color: #2dc26b;"><b>N</b></span>]) analogues, presenting IC<sub>50</sub> values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [<span style="color: #ff1b00;"><b>P</b></span>] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)<sub>2</sub>) enhanced the compounds toxicity. Most complexes containing the [<span style="color: #ff1b00;"><b>P</b></span>] counter ion exhibited exceptional antiplasmodial activity against the <i>Plasmodium berghei</i> parasite liver stages, with submicromolar IC<sub>50</sub> values ranging from 400–700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [<span style="color: #2dc26b;"><b>N</b></span>] counter-ion. Auranofin and two selected complexes [<span style="color: #ff1b00;"><b>P</b></span>][AuSBu(=S)] and [<span style="color: #ff1b00;"><b>P</b></span>][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [<span style="color: #ff1b00;"><b>P</b></span>] [AuSBu(=S)], [<span style="color: #ff1b00;"><b>P</b></span>] [AuSEt(=S)], [<span style="color: #ff1b00;"><b>P</b></span>] [AuSEt(=Se)] and [<span style="color: #ff1b00;"><b>P</b></span>] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability. |
| first_indexed | 2024-03-09T21:50:20Z |
| format | Article |
| id | doaj.art-df73d4cf90744436b08b1fef8d4d3640 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:50:20Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-df73d4cf90744436b08b1fef8d4d36402023-11-23T20:08:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012313714610.3390/ijms23137146Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) ComplexesYann Le Gal0Agathe Filatre-Furcate1Dominique Lorcy2Olivier Jeannin3Thierry Roisnel4Vincent Dorcet5Diana Fontinha6Denise Francisco7Miguel Prudncio8Marta Martins9Catarina Soeiro10Sílvia A. Sousa11Jorge H. Leitão12Tnia S. Morais13Ins Bártolo14Nuno Taveira15Joana F. Guerreiro16Fernanda Marques17CNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université Rennes, F-35000 Rennes, FranceCNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université Rennes, F-35000 Rennes, FranceCNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université Rennes, F-35000 Rennes, FranceCNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université Rennes, F-35000 Rennes, FranceCNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université Rennes, F-35000 Rennes, FranceCNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Université Rennes, F-35000 Rennes, FranceInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, PortugalInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, PortugaliBB-Institute for Bioengineering and Biosciences, Departmento de Bioengenharia, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, PortugaliBB-Institute for Bioengineering and Biosciences, Departmento de Bioengenharia, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, PortugaliBB-Institute for Bioengineering and Biosciences, Departmento de Bioengenharia, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, PortugalCentro de Química Estrutural and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, PortugaliMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Avenida das Forças Armadas, 1600-083 Lisboa, PortugaliMed.ULisboa, Faculdade de Farmácia da Universidade de Lisboa, Avenida das Forças Armadas, 1600-083 Lisboa, PortugalCentro de Ciências e Tecnologias Nucleares and Departamento de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, PortugalCentro de Ciências e Tecnologias Nucleares and Departamento de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, PortugalThe biological properties of sixteen structurally related monoanionic gold (III) bis(dithiolene/ diselenolene) complexes were evaluated. The complexes differ in the nature of the heteroatom connected to the gold atom (AuS for dithiolene, AuSe for diselenolene), the substituent on the nitrogen atom of the thiazoline ring (Me, Et, Pr, iPr and Bu), the nature of the exocyclic atom or group of atoms (O, S, Se, C(CN)<sub>2</sub>) and the counter-ion (Ph<sub>4</sub>P<sup>+</sup> or Et<sub>4</sub>N<sup>+</sup>). The anticancer and antimicrobial activities of all the complexes were investigated, while the anti-HIV activity was evaluated only for selected complexes. Most complexes showed relevant anticancer activities against Cisplatin-sensitive and Cisplatin-resistant ovarian cancer cells A2780 and OVCAR8, respectively. After 48 h of incubation, the IC<sub>50</sub> values ranged from 0.1–8 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>M (A2780) and 0.8–29 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>M (OVCAR8). The complexes with the Ph<sub>4</sub>P<sup>+</sup> ([<span style="color: #ff1b00;"><b>P</b></span>]) counter-ion are in general more active than their Et<sub>4</sub>N<sup>+</sup> ([<span style="color: #2dc26b;"><b>N</b></span>]) analogues, presenting IC<sub>50</sub> values in the same order of magnitude or even lower than Auranofin. Studies in the zebrafish embryo model further showed that, despite their marked anticancer effect, the complexes with [<span style="color: #ff1b00;"><b>P</b></span>] counter-ion exhibited low in vivo toxicity. In general, the exocyclic exchange of sulfur by oxygen or ylidenemalononitrile (C(CN)<sub>2</sub>) enhanced the compounds toxicity. Most complexes containing the [<span style="color: #ff1b00;"><b>P</b></span>] counter ion exhibited exceptional antiplasmodial activity against the <i>Plasmodium berghei</i> parasite liver stages, with submicromolar IC<sub>50</sub> values ranging from 400–700 nM. In contrast, antibacterial/fungi activities were highest for most complexes with the [<span style="color: #2dc26b;"><b>N</b></span>] counter-ion. Auranofin and two selected complexes [<span style="color: #ff1b00;"><b>P</b></span>][AuSBu(=S)] and [<span style="color: #ff1b00;"><b>P</b></span>][AuSEt(=S)] did not present anti-HIV activity in TZM-bl cells. Mechanistic studies for selected complexes support the idea that thioredoxin reductase, but not DNA, is a possible target for some of these complexes. The complexes [<span style="color: #ff1b00;"><b>P</b></span>] [AuSBu(=S)], [<span style="color: #ff1b00;"><b>P</b></span>] [AuSEt(=S)], [<span style="color: #ff1b00;"><b>P</b></span>] [AuSEt(=Se)] and [<span style="color: #ff1b00;"><b>P</b></span>] [AuSeiPr(=S)] displayed a strong quenching of the fluorescence intensity of human serum albumin (HSA), which indicates a strong interaction with this protein. Overall, the results highlight the promising biological activities of these complexes, warranting their further evaluation as future drug candidates with clinical applicability.https://www.mdpi.com/1422-0067/23/13/7146gold bis(dithiolene) complexesdiselenolenestructural modificationanticancer activityantimicrobial activityHSA interaction |
| spellingShingle | Yann Le Gal Agathe Filatre-Furcate Dominique Lorcy Olivier Jeannin Thierry Roisnel Vincent Dorcet Diana Fontinha Denise Francisco Miguel Prudncio Marta Martins Catarina Soeiro Sílvia A. Sousa Jorge H. Leitão Tnia S. Morais Ins Bártolo Nuno Taveira Joana F. Guerreiro Fernanda Marques Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes International Journal of Molecular Sciences gold bis(dithiolene) complexes diselenolene structural modification anticancer activity antimicrobial activity HSA interaction |
| title | Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes |
| title_full | Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes |
| title_fullStr | Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes |
| title_full_unstemmed | Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes |
| title_short | Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes |
| title_sort | broad spectrum functional activity of structurally related monoanionic au iii bis dithiolene complexes |
| topic | gold bis(dithiolene) complexes diselenolene structural modification anticancer activity antimicrobial activity HSA interaction |
| url | https://www.mdpi.com/1422-0067/23/13/7146 |
| work_keys_str_mv | AT yannlegal broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT agathefilatrefurcate broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT dominiquelorcy broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT olivierjeannin broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT thierryroisnel broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT vincentdorcet broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT dianafontinha broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT denisefrancisco broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT miguelprudncio broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT martamartins broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT catarinasoeiro broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT silviaasousa broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT jorgehleitao broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT tniasmorais broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT insbartolo broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT nunotaveira broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT joanafguerreiro broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes AT fernandamarques broadspectrumfunctionalactivityofstructurallyrelatedmonoanionicauiiibisdithiolenecomplexes |