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Background
editThe presence of ideas regarding the clustering or formation of structures with high guanine association became apparent in 1960’s, through the identification of gel-like substances associated with guanines.[1] More specifically, this research detailed the four-stranded DNA structures with a high association of guanines, which was later identified in eukaryotic telomeric regions of DNA in the 1980’s.[2] The importance of finding G-quadruplex structure was best hypothesized by the statement, “If G-quadruplexes form so readily in vitro, Nature will have found a way of using them in vivo” - Aaron Klug, Nobel Prize Winner in Chemistry (1982). With the abundance of G-quadruplexes in vivo, these structures hold a biologically relevant role through interactions with the promoter regions of oncogenes and telomeres.
Cancer
editG-quadruplexes are prevalent in eukaryotic cells especially in telomeres and in 5` unsaturated strands. In cancer cells that have mutated helicase these complexes cannot be unwound. This causes replication of damaged and cancerous cells. Stabilizing the G-quadruplexes can inhibit cell growth and replication. This can lead to death of cancer cells.[3]
Along with the association of G-quadruplexes in telomeric regions of DNA, G-quadruplex structures have been identified in various human proto-oncogene promoter regions.[4] Some of these oncogenes include c-KIT, PDGF-A and VEGF, showing the importance of this structure in cancer growth and development. Current therapeutic research has focused on targeting this stabilization of G-quadruplex structures to arrest unregulated cell growth and division.
One particular gene region, the c-myc pathway, plays an integral role in the regulation of a protein product, c-Myc. With this product, the c-Myc protein functions in the processes of apoptosis and cell growth or development and as a transcriptional control on human telomerase reverse transcriptase.[5]
Therapeutics
editTelomeres are generally made up of G quadruplexes. These complexes have a high affinity for porphyrin rings which makes them effective anticancer agents. However TMPyP4 has been limited for used due to its non-selectivity toward cancer cell telomeres and normal double stranded DNA (dsDNA). To address this issue analog of TMPyP4 was synthesized known as 5Me which targets only G quadruplex DNA which inhibits cancer growth more effectively than TMPyP4.[6]
Ligand design and development remains an important field of research into therapeutic reagents due to the abundance of G-quadruplexes and their multiple conformational differences. One type of ligand involving a Quindoline derivative, SYUIQ-05, utilizes the stabilization of promoter region G-quadruplexes to inhibit the production of both the c-Myc protein and the human telomerase reverse transcriptase (hTERT). This main pathway of targeting this region results in the lack of telomerase elongation, leading to arrested cell development. Further research remains necessary for the discovery of a single gene target, to minimize cross reactivity with more efficient antitumor activity.[7]
Ligand Binding
editThe binding of ligands to G-quadruplexes is vital for anti-cancer pursuits because G-quadruplexes are found typically at translocation hot spots. MM41, a ligand that binds selectively for a quadruplex on the BCL-2 promoter, is shaped with a central core and 4 side chains branching sterically out. The shape of the ligand is vital because it closely matches the quadruplex which has stacked quartets and the loops of nucleic acids holding it together. When bound, MM41’s central chromophore is situated on top of the 3’ terminal G-quartet and the side chains of the ligand associate to the loops of the quadruplex. The quartet and the chromophore are bound with a π-π bond while the side chains and loops are not bound but are in close proximity. What makes this binding strong is the fluidity in the position of the loops to better associate with the ligand side chains.[8]
When designing ligands to be bound to quadruplexes it is important to note that the best binding is done in parallel with the ligand and quadruplex. It’s been found that ligands with smaller side chains bind better to the quadruplex because smaller ligands have more concentrated electron density. Also, the hydrogen bonds of ligands with smaller side chains are shorter and therefore stronger. The side chains and the loops of the quadruplexes are mobile and due to this are able to associate strongly when in the proper conformations.[9]
- ^ Gellert, M.; Lipsett, M. N.; Davies, D. R. (1962-12-15). "Helix formation by guanylic acid". Proceedings of the National Academy of Sciences of the United States of America. 48: 2013–2018. ISSN 0027-8424. PMC 221115. PMID 13947099.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Henderson, E.; Hardin, C. C.; Walk, S. K.; Tinoco, I.; Blackburn, E. H. (1987-12-24). "Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine-guanine base pairs". Cell. 51 (6): 899–908. ISSN 0092-8674. PMID 3690664.
- ^ Neidle, Stephen (2016-02-16). "Quadruplex Nucleic Acids as Novel Therapeutic Targets". Journal of Medicinal Chemistry. 59 (13): 5987–6011. doi:10.1021/acs.jmedchem.5b01835. ISSN 0022-2623.
- ^ Chen, Yuwei; Yang, Danzhou (2012-9). "Sequence, stability, and structure of G-quadruplexes and their interactions with drugs". Current Protocols in Nucleic Acid Chemistry. Chapter 17: Unit17.5. doi:10.1002/0471142700.nc1705s50. ISSN 1934-9289. PMC 3463244. PMID 22956454.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ Ou, Tian-Miao; Lin, Jing; Lu, Yu-Jing; Hou, Jin-Qiang; Tan, Jia-Heng; Chen, Shu-Han; Li, Zeng; Li, Yan-Ping; Li, Ding (2011-08-25). "Inhibition of Cell Proliferation by Quindoline Derivative (SYUIQ-05) through its Preferential Interaction withc-mycPromoter G-Quadruplex". Journal of Medicinal Chemistry. 54 (16): 5671–5679. doi:10.1021/jm200062u. ISSN 0022-2623.
- ^ Chilakamarthi, Ushasri; Koteshwar, Devulapally; Jinka, Sudhakar; Vamsi Krishna, Narra; Sridharan, Kathyayani; Nagesh, Narayana; Giribabu, Lingamallu (2018-11-09). "Novel Amphiphilic G-Quadruplex Binding Synthetic Derivative of TMPyP4 and Its Effect on Cancer Cell Proliferation and Apoptosis Induction". Biochemistry. doi:10.1021/acs.biochem.8b00843. ISSN 0006-2960.
- ^ Ou, Tian-Miao; Lin, Jing; Lu, Yu-Jing; Hou, Jin-Qiang; Tan, Jia-Heng; Chen, Shu-Han; Li, Zeng; Li, Yan-Ping; Li, Ding (2011-08-25). "Inhibition of Cell Proliferation by Quindoline Derivative (SYUIQ-05) through its Preferential Interaction withc-mycPromoter G-Quadruplex". Journal of Medicinal Chemistry. 54 (16): 5671–5679. doi:10.1021/jm200062u. ISSN 0022-2623.
- ^ Ohnmacht, Stephan A; Marchetti, Chiara; Gunaratnam, Mekala; Besser, Rachael J; Haider, Shozeb M; Di Vita, Gloria; Lowe, Helen L; Mellinas-Gomez, Maria; Diocou, Seckou (2015-06-16). "A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer". Scientific Reports. 5 (1). doi:10.1038/srep11385. ISSN 2045-2322. PMC 4468576. PMID 26077929.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Collie, Gavin W.; Promontorio, Rossella; Hampel, Sonja M.; Micco, Marialuisa; Neidle, Stephen; Parkinson, Gary N. (2012-01-31). "Structural Basis for Telomeric G-Quadruplex Targeting by Naphthalene Diimide Ligands". Journal of the American Chemical Society. 134 (5): 2723–2731. doi:10.1021/ja2102423. ISSN 0002-7863.