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Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
Further interplay between DNA repair, oxidatively generated 8-oxodG and transcriptional activity has been documented in mammalian genes, with Fleming et al. (2017a) demonstrating that DNA damage in G-quadruplex-forming sequences (PQS) of a promoter can lead to a 300% increase in gene expression. This suggests that 8-oxodG represents an epigenetic-like modification, while G-quadruplex-forming sequences serve as sensors of oxidative stress. G-quadruplexes are G-rich sequences that can fold in DNA structures and comprise four or more continuous runs of oligo-G (specific sites that are optimally reactive toward one-electron oxidation), interspersed with one or more loops between the G run nucleotides. The GGG runs in one strand of DNA duplex can fold, forming layers in G-tetrads, and are exposed sites for G oxidation by a one-electron mechanism. The carbonate radical anion () is a potent one-electron oxidant formed from carbon dioxide and peroxynitrite, and also directly from bicarbonate; muscle bicarbonate concentration can rise multiple fold during high-intensity exercise. While (pKa < 0) is more selective and less oxidising than (E0 = 1.78 V vs. 2.3 V at pH 7.0), it can initiate many damaging reactions in a biological system (Medinas et al., 2007; Di Meo and Venditti, 2020).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Until recently, there has been controversy as to whether quadruplex structures are artifacts that occur only in isolated DNA under laboratory conditions, or whether they occur in genomic DNA in cells. Although four-stranded G-quadruplex structures have high thermodynamic stability under near-physiological conditions in the laboratory suggesting that they could form in cells, no firm experimental evidence existed until 2013 when Balasubramanian and co-workers at Cambridge University (UK) reported that they had used an engineered, labeled, structure-specific antibody to quantitatively visualize DNA G-quadruplex structures in human cells. Using this approach, they showed that G-quadruplex formation in DNA is modulated during cell-cycle progression, and that endogenous G-quadruplex DNA structures could be stabilized by a small-molecule ligand. These findings provided substantive evidence for the formation of G-quadruplex structures in the genome of mammalian cells. An algorithm (available on-line) is now available to predict sequences of DNA that have the capacity to form quadruplexes involving a simple matching pattern: d(G3+N1-7G3+N1-7G3+N1-7G3+), where N is any base (including guanine).
Modern Pharmacognostic Investigation of Harmal
Published in Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen, Harmal, 2017
Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen
G-quadruplexes are secondary three-dimensional structures of DNA that also involve anomalous, base interactions irregular to the Watson and Crick canon. They are now an intensive subject of research as essential genome regulators, and so, highly relevant for cutting edge cancer research (Valton and Prioleau 2016). Because of their general resistance to being victims of drug resistance by the host, and relative profile of higher safety than synthetic chemical agents, natural products are an attractive repository for prospecting after new drugs.
Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Jean Guillon, Anita Cohen, Clotilde Boudot, Alessandra Valle, Vittoria Milano, Rabindra Nath Das, Aurore Guédin, Stéphane Moreau, Luisa Ronga, Solène Savrimoutou, Maxime Demourgues, Elodie Reviriego, Sandra Rubio, Sandie Ferriez, Patrice Agnamey, Cécile Pauc, Serge Moukha, Pascale Dozolme, Sophie Da Nascimento, Pierre Laumaillé, Anne Bouchut, Nadine Azas, Jean-Louis Mergny, Catherine Mullié, Pascal Sonnet, Bertrand Courtioux
In addition, the in vitro cytotoxicity of our new bis[(substituted-aminomethyl)phenyl]quinoline-like derivatives was assessed in human HepG2 cells, and an index of selectivity, the ratio of cytotoxic to antiparasitic activity, was determined for each derivative. The telomeres of the different protozoa could constitute attractive drug targets36–39 and telomerase activity is detected in gametocytes and during the transition to the erythrocytic stage of P. falciparum40. The telomeric 3′G-overhang region of P. falciparum is a repetition of degenerate unit 5′-GGGTTYA-3′ (where Y could be T or C)41 which can fold into intramolecular G-quadruplex42. This difference between parasitic and human (5′-GGGTTA-3′) G-quadruplexes is also observed with L. spp and T. brucei brucei, which augurs the possibility of developing antiparasitic ligands targeting G-quadruplexes found in these protozoal species. Thus, we investigated whether these derivatives could stabilise some parasitic telomeric DNA G-quadruplex structures. Consequently, potential stabilisation of P. falciparum and T. brucei brucei telomeric G-quadruplexes was evaluated using a FRET melting assay.
The use of a 2-aminopurine-containing split G-quadruplex for sequence-specific DNA detection
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Sung Hyun Hwang, Woo Young Kwon, Hyunmin Eun, Sehan Jeong, Jun Seok Park, Kwang Jin Kim, Hyung Joo Kim, Sang Hyun Lee, Kyungmoon Park, Jeong-Jun Yoon, Yung-Hun Yang, Ki Soo Park
The aim of the investigation described below was to explore a simple detection strategy that utilizes a system in which one component of a split G-quadruplex contains an emission silent 2-AP. In addition, the split G-quadruplex components each contain a specific overhang sequence for recognition of the target DNA. In this manner, the G-quadruplex is only formed from the components in the presence of target DNA. Moreover, G-quadruplex formation is associated with a simultaneous enhancement in fluorescence intensity of the 2-AP fluorophore [23]. To maximize the efficiency of a sensor based on this strategy, the effect of the G-quadruplex sequence and split ratios on the fluorescence enhancement of the 2-AP-containing split G-quadruplex was investigated [24]. Finally, to demonstrate its utility in biological applications, the sensor developed in this effort was used for sequence-specific detection of the target DNA, Chlamydia trachomatis, one of the most common bacteria that causes a sexually transmitted disease (STD). Importantly, this effort represents the first systematic investigation leading to the development and application of a 2-AP-containing split G-quadruplex-based sensor.
Asymmetric triplex metallohelices stabilise DNA G-quadruplexes in promoter oncogene sequences and efficiently reduce their expression in cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Jaroslav Malina, Hana Kostrhunova, Hualong Song, Peter Scott, Viktor Brabec
In addition to the canonical double helix, DNA can also fold into alternative higher-order structures that are believed to participate in controlling essential genetic processes such as transcription, replication, and telomere maintenance1–3 and are involved in the development of many human pathologies4. DNA G-quadruplexes (G4s) formed by guanine-rich sequences that assemble into G-quartets stabilised by Hoogsteen hydrogen bonds and monovalent cations5 are highly stable tetra-stranded structures, and their formation has been confirmed in human telomeres and several key genome regions; available evidence suggests that their stabilisation downregulates gene expression6. Hence G-quadruplexes have attracted growing attention as possible drug targets also because they are predominantly formed in promoters of oncogenes, such as c-MYC7, c-KIT8, k-RAS9, BCL210, or VEGF11. Remarkably, the c-MYC and k-RAS oncogenes are overexpressed in 70%12 and 30% of all human cancers, respectively, and as it has been demonstrated, small-molecule stabilization13 of G4s located in their promoter regions downregulated c-MYC14 and k-RAS13 expression. The c-KIT oncogene, as another example, is implicated in the progression of several types of cancer, mainly gastrointestinal stromal tumours15. It contains in its promoter region two G4-forming sequences; stabilisation of G-quadruplexes formed in these sequences by appropriate ligands inhibits the expression of c-KIT16.