Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core
G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative <b>1</b> was synthesiz...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/9/2791 |
| _version_ | 1797503761848991744 |
|---|---|
| author | Stefania Mazzini Salvatore Princiotto Loana Musso Daniele Passarella Giovanni Luca Beretta Paola Perego Sabrina Dallavalle |
| author_facet | Stefania Mazzini Salvatore Princiotto Loana Musso Daniele Passarella Giovanni Luca Beretta Paola Perego Sabrina Dallavalle |
| author_sort | Stefania Mazzini |
| collection | DOAJ |
| description | G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative <b>1</b> was synthesized and found to share the structural features typical of G-quadruplex binders. Herein, structural modifications were conducted on this scaffold in order to assist the binding with a G-quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active compound, compound <b>9,</b> was analyzed with NMR spectrometry in order to investigate its binding mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere d(TTAGGGT)<sub>4</sub> showed a stable, although not strong, interaction at the 3′-end of the nucleotidic sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external phosphate groups. Overall, this work can be considered a platform for the development of a new class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex grooves and loops. |
| first_indexed | 2024-03-10T03:54:57Z |
| format | Article |
| id | doaj.art-bd178e875e9142b2a9856e3ab67fe0f5 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:54:57Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-bd178e875e9142b2a9856e3ab67fe0f52023-11-23T08:49:41ZengMDPI AGMolecules1420-30492022-04-01279279110.3390/molecules27092791Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione CoreStefania Mazzini0Salvatore Princiotto1Loana Musso2Daniele Passarella3Giovanni Luca Beretta4Paola Perego5Sabrina Dallavalle6Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, ItalyDepartment of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, ItalyDepartment of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, ItalyDepartment of Chemistry, University of Milan, 20133 Milan, ItalyMolecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, ItalyMolecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, ItalyDepartment of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, ItalyG-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative <b>1</b> was synthesized and found to share the structural features typical of G-quadruplex binders. Herein, structural modifications were conducted on this scaffold in order to assist the binding with a G-quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active compound, compound <b>9,</b> was analyzed with NMR spectrometry in order to investigate its binding mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere d(TTAGGGT)<sub>4</sub> showed a stable, although not strong, interaction at the 3′-end of the nucleotidic sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external phosphate groups. Overall, this work can be considered a platform for the development of a new class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex grooves and loops.https://www.mdpi.com/1420-3049/27/9/2791kynurenic acidKYNAG-quadruplexDNAstabilizationcytotoxicity |
| spellingShingle | Stefania Mazzini Salvatore Princiotto Loana Musso Daniele Passarella Giovanni Luca Beretta Paola Perego Sabrina Dallavalle Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core Molecules kynurenic acid KYNA G-quadruplex DNA stabilization cytotoxicity |
| title | Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core |
| title_full | Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core |
| title_fullStr | Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core |
| title_full_unstemmed | Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core |
| title_short | Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core |
| title_sort | synthesis and investigation of the g quadruplex binding properties of kynurenic acid derivatives with a dihydroimidazoquinoline 3 5 dione core |
| topic | kynurenic acid KYNA G-quadruplex DNA stabilization cytotoxicity |
| url | https://www.mdpi.com/1420-3049/27/9/2791 |
| work_keys_str_mv | AT stefaniamazzini synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore AT salvatoreprinciotto synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore AT loanamusso synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore AT danielepassarella synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore AT giovannilucaberetta synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore AT paolaperego synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore AT sabrinadallavalle synthesisandinvestigationofthegquadruplexbindingpropertiesofkynurenicacidderivativeswithadihydroimidazoquinoline35dionecore |