Screening of Scaffolds for the Design of G-Quadruplex Ligands
In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) he...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Applied Sciences |
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| Online Access: | https://www.mdpi.com/2076-3417/12/4/2170 |
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| author | Joana Figueiredo David Peitinho Maria Paula Cabral Campello Maria Cristina Oliveira António Paulo Jean-Louis Mergny Carla Cruz |
| author_facet | Joana Figueiredo David Peitinho Maria Paula Cabral Campello Maria Cristina Oliveira António Paulo Jean-Louis Mergny Carla Cruz |
| author_sort | Joana Figueiredo |
| collection | DOAJ |
| description | In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C<sub>5</sub>NH<sub>2</sub> has the most favorable cytotoxic profile in terms of cell selectivity. |
| first_indexed | 2024-03-09T22:40:45Z |
| format | Article |
| id | doaj.art-92e84548499c4b5e8bd4134eed4f3ae2 |
| institution | Directory Open Access Journal |
| issn | 2076-3417 |
| language | English |
| last_indexed | 2024-03-09T22:40:45Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Applied Sciences |
| spelling | doaj.art-92e84548499c4b5e8bd4134eed4f3ae22023-11-23T18:40:26ZengMDPI AGApplied Sciences2076-34172022-02-01124217010.3390/app12042170Screening of Scaffolds for the Design of G-Quadruplex LigandsJoana Figueiredo0David Peitinho1Maria Paula Cabral Campello2Maria Cristina Oliveira3António Paulo4Jean-Louis Mergny5Carla Cruz6Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, PortugalCentro 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, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, PortugalCentro 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, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139.7), 2695-066 Bobadela, PortugalInstitute of Biophysics of the CAS, v.v.i., Královopolská 135, 612 65 Brno, Czech RepublicCentro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, PortugalIn the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C<sub>5</sub>NH<sub>2</sub> has the most favorable cytotoxic profile in terms of cell selectivity.https://www.mdpi.com/2076-3417/12/4/2170G-quadruplexheterocycle compoundsscaffoldsdrug-design |
| spellingShingle | Joana Figueiredo David Peitinho Maria Paula Cabral Campello Maria Cristina Oliveira António Paulo Jean-Louis Mergny Carla Cruz Screening of Scaffolds for the Design of G-Quadruplex Ligands Applied Sciences G-quadruplex heterocycle compounds scaffolds drug-design |
| title | Screening of Scaffolds for the Design of G-Quadruplex Ligands |
| title_full | Screening of Scaffolds for the Design of G-Quadruplex Ligands |
| title_fullStr | Screening of Scaffolds for the Design of G-Quadruplex Ligands |
| title_full_unstemmed | Screening of Scaffolds for the Design of G-Quadruplex Ligands |
| title_short | Screening of Scaffolds for the Design of G-Quadruplex Ligands |
| title_sort | screening of scaffolds for the design of g quadruplex ligands |
| topic | G-quadruplex heterocycle compounds scaffolds drug-design |
| url | https://www.mdpi.com/2076-3417/12/4/2170 |
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