scholarly journals The Use of Ruthenium Complexes as Molecular Probes for Non-Canonical DNA

2022 ◽  
Author(s):  
Eleni Sullivan
Keyword(s):  
Transcription Initiation ◽  
Ruthenium Complex ◽  
Telomerase Activity ◽  
Molecular Probes ◽  
Telomeric Region ◽  
Base Pairs ◽  
Ruthenium Polypyridyl ◽  
Living Things ◽  
G Quadruplex ◽  
High Binding Affinity

This study considered the preparation of a new DNA binding Ruthenium polypyridyl complex possessing an infrared active nitrile group. The binding abilities of a novel Ruthenium complex, [Ru(TMP)2DPPZ-10-CN], to various forms of DNA—both canonical and non-canonical—were examined by performing multiple DNA titrations. DNA is of great interest as it is the carrier of genetic information for all living things. Damage to DNA can have drastically detrimental effects, so the study of its structure and replication is of great importance. Two non-canonical structures that are important are the G-quadruplex and i-motif which form at the telomeric and regulatory regions of genes, respectively, and have the ability to block telomerase activity and influence transcription. The complex was synthesized by microwave irradiation and purified using a silica column and an ion exchange with Amberlite 402. Six titrations were, then, performed with salmon sperm dsDNA, guanine monophosphate (GMP), G4T4G4, human telomere G-quadruplex, i-motif C5T3, and i-motif C30. The complex was found to favor non-canonical structures, particularly the G-quadruplex structure, because of its high [bp]/[Ru] concentrations. The higher concentration of base pairs or structures per Ruthenium molecule indicated that the complex had a high binding affinity for that particular DNA structure. These results support the notion that Ruthenium metal complexes can be used for theragnostic purposes and can be used to target the telomeric region of genes where G-quadruplex structures can be found and influence transcription initiation and inhibit telomerase activity.

scholarly journals The Use of Ruthenium Complexes as Molecular Probes for Non-Canonical DNA” by Eleni Sullivan

2022 ◽  
Author(s):  
Eleni Sullivan
Keyword(s):  
Transcription Initiation ◽  
Ruthenium Complex ◽  
Telomerase Activity ◽  
Molecular Probes ◽  
Telomeric Region ◽  
Base Pairs ◽  
Ruthenium Polypyridyl ◽  
Living Things ◽  
G Quadruplex ◽  
High Binding Affinity

This study considered the preparation of a new DNA binding Ruthenium polypyridyl complex possessing an infrared active nitrile group. The binding abilities of a novel Ruthenium complex, [Ru(TMP)2DPPZ-10-CN], to various forms of DNA—both canonical and non-canonical—were examined by performing multiple DNA titrations. DNA is of great interest as it is the carrier of genetic information for all living things. Damage to DNA can have drastically detrimental effects, so the study of its structure and replication is of great importance. Two non-canonical structures that are important are the G-quadruplex and i-motif which form at the telomeric and regulatory regions of genes, respectively, and have the ability to block telomerase activity and influence transcription. The complex was synthesized by microwave irradiation and purified using a silica column and an ion exchange with Amberlite 402. Six titrations were, then, performed with salmon sperm dsDNA, guanine monophosphate (GMP), G4T4G4, human telomere G-quadruplex, i-motif C5T3, and i-motif C30. The complex was found to favor non-canonical structures, particularly the G-quadruplex structure, because of its high [bp]/[Ru] concentrations. The higher concentration of base pairs or structures per Ruthenium molecule indicated that the complex had a high binding affinity for that particular DNA structure. These results support the notion that Ruthenium metal complexes can be used for theragnostic purposes and can be used to target the telomeric region of genes where G-quadruplex structures can be found and influence transcription initiation and inhibit telomerase activity.

scholarly journals A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent

2019 ◽  
Author(s):  
Anna Notaro ◽  
Marta Jakubaszek ◽  
Severin Koch ◽  
Riccardo Rubbiani ◽  
Orsolya Dömötör ◽  
...  
Keyword(s):  
Ligand Exchange ◽  
Causes Of Death ◽  
Anticancer Agent ◽  
Chemotherapeutic Agent ◽  
Ruthenium Complex ◽  
Ruthenium Polypyridyl ◽  
Biological Investigation ◽  
Tumour Spheroids

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic ones and gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported a ruthenium complex ([Ru(DIP)2(sq)](PF6), where DIP is 4,7- diphenyl-1,10-phenantroline and sq is the semiquinonate), with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)2(mal)](PF6), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)2(mal)](PF6), its stability in solutions and in conditions which resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity compared to the approved drug cisplatin, inspiring further tests. [Ru(DIP)2(mal)](PF6) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism. <br>

scholarly journals A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent

2019 ◽  
Author(s):  
Anna Notaro ◽  
Marta Jakubaszek ◽  
Severin Koch ◽  
Riccardo Rubbiani ◽  
Orsolya Dömötör ◽  
...  
Keyword(s):  
Ligand Exchange ◽  
Causes Of Death ◽  
Anticancer Agent ◽  
Chemotherapeutic Agent ◽  
Ruthenium Complex ◽  
Ruthenium Polypyridyl ◽  
Biological Investigation ◽  
Tumour Spheroids

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic ones and gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported a ruthenium complex ([Ru(DIP)2(sq)](PF6), where DIP is 4,7- diphenyl-1,10-phenantroline and sq is the semiquinonate), with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)2(mal)](PF6), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)2(mal)](PF6), its stability in solutions and in conditions which resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity compared to the approved drug cisplatin, inspiring further tests. [Ru(DIP)2(mal)](PF6) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism. <br>

scholarly journals Negative regulation of the human epsilon-globin gene by transcriptional interference: role of an Alu repetitive element.

1990 ◽  
Vol 10 (3) ◽  
pp. 1209-1216 ◽  
Author(s):  
J Wu ◽  
G J Grindlay ◽  
P Bushel ◽  
L Mendelsohn ◽  
M Allan
Keyword(s):  
Transcription Initiation ◽  
Repetitive Element ◽  
Globin Gene ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Transcriptional Interference ◽  
Base Pairs ◽  
Transient Expression Assay ◽  
Down Regulation ◽  
Alternative Transcription

The human epsilon-globin gene has a number of alternative transcription initiation sites which correspond with regions of DNase I hypersensitivity upstream of the canonical cap site. Transcripts originating from the promoters located -4.3/-4.5 and -1.48 kilobase pairs (kbp) and -900 and -200 base pairs (bp) upstream of the major epsilon-globin cap site can, at certain stages of erythroid differentiation, extend through the gene and are polyadenylated. The 350-bp PolIII transcripts, originating within the Alu repetitive element -2.2 kbp upstream of the cap site, extend in the opposite direction from the gene, are nonpolyadenylated, nucleus confined, and are detectable only in mature K562 cells or mature embryonic red blood cells where the epsilon-globin major cap site is maximally transcribed. Fragments containing the promoters located between -4.5 and -4.3 kbp upstream of the gene down regulate transcription from the epsilon-globin gene 20- to 30-fold in a transient expression assay in which both erythroid and nonerythroid cell lines were used. This occurs only when the direction of transcription from the -4.3/-4.5-kbp promoters is towards the gene, and we hypothesize that down regulation is caused by transcriptional interference. Fragments containing the Alu repetitive element -2.2 kbp upstream of the gene can overcome down regulation of the epsilon-globin gene by the -4.5-kbp element when interposed in the direct orientation between this element and the epsilon-globin gene.

Determination by 1H NMR of a Slow Conformational Transition and Hydration Change in the Consensus TATAAT Prsbnow Box

1997 ◽  
Author(s):  
C. Milhé
Keyword(s):  
Rna Polymerase ◽  
Rate Constant ◽  
Transcription Initiation ◽  
Conformational Transition ◽  
Bound Water ◽  
Order Rate Constant ◽  
Minor Groove ◽  
Base Pairs ◽  
Proton Resonances ◽  
Pribnow Box

The conformational dynamics and hydration of a DNA 14-mer containing the consensus Pribnow box sequence TATAAT have been measured using rotating frame T1 measurements and NOESY and ROESY in water. The H2 proton resonances of adenines show fast intermediate exchange behavior which can be attributed to a conformational transition that affects the distances between H2 protons of neighboring adenine residues, both sequential and cross-strand. The relaxation rate constant of the transition was measured at 4000s-1 at 25°C. Bound water close to the H2 proton of adenines was observed with residence times of >lns. At low temperature (5°C), the Pribnow box is in a closed state in which hydration water in the minor groove is tightly bound. At higher temperatures, the conformation opens up as judged by the increase in separation between sequential H2 protons of adenines and water exchanges freely from the minor groove. The conformational transition and the altered hydration pattern may be related to promoter function. The control of gene expression in procaryotes depends on the specific recognition by RNA polymerase of a six base-pair sequence (consensus: TTGACA) located at -35 from the transcription site, and a second one, named the Pribnow box (consensus: TATAAT) at about 10 base-pairs upstream the initiation site (Rosenberg and Court, 1979). It has been shown (Hawley and McClure, 1983) that strong promoters exhibit a high degree of homology with the consensus sequences, separated by an optimum consensus spacer length of 17 base pairs. The strength of a promoter depends on, among other thing, the rate of the initiation of transcription. This rate depends on the product between the thermodynamic and kinetic constants KB and k2 (McClure, 1980). The initial binding of RNA polymerase to the promoter results in the formation of a transcriptionally inactive ‘closed’ complex, characterized by the association constant KB. Isomerization to the active ‘open’ complex then occurs, and is characterized by the first order rate constant k2. Hence, the frequency of transcription initiation depends both on the strength of the polymerase-promoter interaction, and the ease with which this complex can isomerize to the productive state. Both of these events are likely to depend on the physical properties of the promoter.

scholarly journals Effects of deficient of the Hoogsteen base-pairs on the G-quadruplex stabilization and binding mode of a cationic porphyrin

2015 ◽  
Vol 2 ◽  
pp. 29-35 ◽  
Author(s):  
Jihye Moon ◽  
Ji Hoon Han ◽  
Da Young Kim ◽  
Maeng-joon Jung ◽  
Seog K. Kim
Keyword(s):  
Binding Mode ◽  
Base Pairs ◽  
Cationic Porphyrin ◽  
G Quadruplex

Spectroelectrochemical studies of a ruthenium complex containing the pH sensitive 4,4′-dihydroxy-2,2′-bipyridine ligand

2018 ◽  
Vol 47 (12) ◽  
pp. 4149-4161 ◽  
Author(s):  
Erin J. Viere ◽  
Ashley E. Kuhn ◽  
Margaret H. Roeder ◽  
Nicholas A. Piro ◽  
W. Scott Kassel ◽  
...  
Keyword(s):  
Electronic Properties ◽  
Ruthenium Complex ◽  
Ph Sensitive ◽  
Ruthenium Polypyridyl ◽  
Polypyridyl Complex ◽  
Structural And Electronic Properties ◽  
Bipyridine Ligand

The effects of oxidation by one electron on the structural and electronic properties of a ruthenium polypyridyl complex with a pH sensitive ligand is detailed.

scholarly journals A DNA G-quadruplex/i-motif hybrid

2019 ◽  
Author(s):  
Betty Chu ◽  
Daoning Zhang ◽  
Paul J Paukstelis
Keyword(s):  
Tandem Repeats ◽  
Double Helix ◽  
Structural Diversity ◽  
Hybrid Structure ◽  
Structural Motif ◽  
Base Pairs ◽  
Independent Sequence ◽  
Solution Studies ◽  
G Quadruplex

Abstract DNA can form many structures beyond the canonical Watson–Crick double helix. It is now clear that noncanonical structures are present in genomic DNA and have biological functions. G-rich G-quadruplexes and C-rich i-motifs are the most well-characterized noncanonical DNA motifs that have been detected in vivo with either proscribed or postulated biological roles. Because of their independent sequence requirements, these structures have largely been considered distinct types of quadruplexes. Here, we describe the crystal structure of the DNA oligonucleotide, d(CCAGGCTGCAA), that self-associates to form a quadruplex structure containing two central antiparallel G-tetrads and six i-motif C–C+ base pairs. Solution studies suggest a robust structural motif capable of assembling as a tetramer of individual strands or as a dimer when composed of tandem repeats. This hybrid structure highlights the growing structural diversity of DNA and suggests that biological systems may harbor many functionally important non-duplex structures.

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