Abstract
The self-association of DNA formed by Hoogsteen hydrogen bonding comprises several layers of four guanine or G-tetrads or G4s. The distinct feature of G4s, such as the G-tetrads and loops, qualify structure-selective recognition by small molecules and various ligands and can act as potential anticancer therapeutic molecules. The G4 selective ligands can influence gene expression by targeting a nucleic acid structure rather than sequence. Telomere G4 can be targeted for cancer treatment by small molecules inhibiting the telomerase activity, whereas c-MYC is capable of controlling transcription and can be targeted to influence transcription. The k-RAS is one of the most frequently encountered oncogenic driver mutations in pancreatic, colorectal, and lung cancers. The k-RAS oncogene plays an important role in acquiring and increasing drug resistance and can also be directly targeted by small molecules to combat k-RAS mutant tumors. Modular G4 ligands with different functional groups, side chains, and rotatable bonds, as well as conformation, affect the binding affinity/ selectivity in cancer chemotherapeutic interventions. These modular G4 ligands act by targeting the diversity of G4 loops and groves and assist in developing more drug-like compounds with selectivity. In this review, we present the recent research on synthetic G4 DNA-interacting ligands as an approach towards the discovery of target-specific anticancer chemotherapeutic agents.
Keywords: G-Quadruplex, c-MYC, telomerase inhibitors, k-RAS, modular G4 ligand, anticancer G4 ligands.
Graphical Abstract
[http://dx.doi.org/10.1016/j.trechm.2019.07.002] [PMID: 32923997]
[http://dx.doi.org/10.1039/b814576h] [PMID: 18985188]
[http://dx.doi.org/10.1038/nsmb1171] [PMID: 17146462]
[http://dx.doi.org/10.3390/molecules24030429] [PMID: 30682877]
[http://dx.doi.org/10.1039/C6CP04357G] [PMID: 27425864]
[http://dx.doi.org/10.1016/j.tcb.2009.05.002] [PMID: 19589679]
[http://dx.doi.org/10.1016/j.jmb.2003.09.018] [PMID: 14596797]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0941] [PMID: 19010844]
[http://dx.doi.org/10.1093/nar/gkn120] [PMID: 18490377]
[http://dx.doi.org/10.1016/j.bbrc.2006.02.148] [PMID: 16540083]
[http://dx.doi.org/10.1093/nar/gkz179] [PMID: 30892612]
[http://dx.doi.org/10.1093/nar/gkl529] [PMID: 16914419]
[http://dx.doi.org/10.1093/nar/gki609] [PMID: 15914667]
[http://dx.doi.org/10.1093/nar/gkl1057] [PMID: 17169996]
[http://dx.doi.org/10.1093/nar/gki553] [PMID: 15914666]
[http://dx.doi.org/10.1038/nature755] [PMID: 12050675]
[http://dx.doi.org/10.1093/nar/gkl726] [PMID: 17040899]
[http://dx.doi.org/10.1093/nar/gkm706] [PMID: 17895279]
[http://dx.doi.org/10.1111/j.1742-4658.2010.07760.x] [PMID: 20670277]
[http://dx.doi.org/10.1074/jbc.M113.496463] [PMID: 23935105]
[http://dx.doi.org/10.1021/acschembio.9b00475] [PMID: 31532996]
[http://dx.doi.org/10.1016/0969-2126(93)90015-9] [PMID: 8081740]
[http://dx.doi.org/10.1016/j.molmed.2020.05.002] [PMID: 32467069]
[http://dx.doi.org/10.1002/cmdc.201700747] [PMID: 29512884]
[http://dx.doi.org/10.1038/s41580-020-0236-x] [PMID: 32313204]
[http://dx.doi.org/10.1038/s41570-017-0041]
[http://dx.doi.org/10.1093/nar/gky187] [PMID: 29554280]
[http://dx.doi.org/10.1038/nrd793] [PMID: 12120414]
[http://dx.doi.org/10.1021/ja204197d] [PMID: 21702440]
[http://dx.doi.org/10.1021/ja0297988] [PMID: 12670225]
[http://dx.doi.org/10.1098/rstb.2016.0436]
[http://dx.doi.org/10.1016/j.ejmech.2011.10.057] [PMID: 22104971]
[http://dx.doi.org/10.1515/BC.2001.073] [PMID: 11405224]
[http://dx.doi.org/10.3892/ol.2020.11659] [PMID: 32724340]
[http://dx.doi.org/10.1515/cclm-2017-0870] [PMID: 29494336]
[http://dx.doi.org/10.1093/aje/kwm380] [PMID: 18270372]
[http://dx.doi.org/10.15252/embj.2018100492] [PMID: 30737259]
[http://dx.doi.org/10.1111/j.1742-4658.2009.07464.x] [PMID: 19951353]
[http://dx.doi.org/10.1038/s41576-019-0099-1] [PMID: 30760854]
[http://dx.doi.org/10.1080/15476286.2015.1094596] [PMID: 26400640]
[http://dx.doi.org/10.1038/nrc2275] [PMID: 18256617]
[http://dx.doi.org/10.1021/ja005780q] [PMID: 11456694]
[http://dx.doi.org/10.1093/nar/gkr1308] [PMID: 22266651]
[http://dx.doi.org/10.1016/bs.armc.2020.04.005]
[http://dx.doi.org/10.1016/S0959-440X(03)00072-1] [PMID: 12831878]
[http://dx.doi.org/10.1002/anie.200300589] [PMID: 14755695]
[http://dx.doi.org/10.1016/j.biopha.2021.111550] [PMID: 33831835]
[http://dx.doi.org/10.1021/ja807503g] [PMID: 19271707]
[http://dx.doi.org/10.3109/1061186X.2012.669384] [PMID: 22424091]
[http://dx.doi.org/10.1016/j.biochi.2007.07.011] [PMID: 17822826]
[http://dx.doi.org/10.1016/j.cbpa.2009.04.637] [PMID: 19515602]
[http://dx.doi.org/10.1038/srep09696] [PMID: 25853628]
[http://dx.doi.org/10.1016/j.drudis.2010.05.012] [PMID: 20594936]
[http://dx.doi.org/10.1200/JCO.2008.18.7286] [PMID: 18757341]
[http://dx.doi.org/10.1016/j.cell.2012.08.026] [PMID: 23021215]
[http://dx.doi.org/10.1038/nrc2819] [PMID: 20332779]
[http://dx.doi.org/10.1016/j.semcancer.2006.07.014]
[http://dx.doi.org/10.1101/gad.1066903] [PMID: 12695332]
[http://dx.doi.org/10.1101/gad.1067003] [PMID: 12695333]
[http://dx.doi.org/10.1074/jbc.M210462200] [PMID: 12529326]
[http://dx.doi.org/10.1101/cshperspect.a014357] [PMID: 24384812]
[http://dx.doi.org/10.1074/jbc.M207441200] [PMID: 12177005]
[http://dx.doi.org/10.1038/sj.onc.1206800] [PMID: 12944920]
[http://dx.doi.org/10.1038/sj.emboj.7600509] [PMID: 15616584]
[http://dx.doi.org/10.1146/annurev.pharmtox.48.113006.094649] [PMID: 19922264]
[http://dx.doi.org/10.1038/nrm1703] [PMID: 16064138]
[http://dx.doi.org/10.1016/j.cell.2012.03.003] [PMID: 22464321]
[http://dx.doi.org/10.1038/nrd3428] [PMID: 21455236]
[http://dx.doi.org/10.1177/1947601910377493] [PMID: 21113409]
[http://dx.doi.org/10.1038/nrc2733] [PMID: 19907434]
[http://dx.doi.org/10.1073/pnas.182256799] [PMID: 12195017]
[http://dx.doi.org/10.7554/eLife.46793] [PMID: 31287417]
[http://dx.doi.org/10.1021/jacs.0c01879] [PMID: 32267689]
[http://dx.doi.org/10.1021/ja017308q] [PMID: 11878947]
[http://dx.doi.org/10.1111/cbdd.13910] [PMID: 34148284]
[http://dx.doi.org/10.1021/ja310251r] [PMID: 23521617]
[http://dx.doi.org/10.1021/ja805615w] [PMID: 18975896]
[http://dx.doi.org/10.1021/ja067352b] [PMID: 17260991]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2910] [PMID: 15735037]
[http://dx.doi.org/10.1002/anie.200801235] [PMID: 18563772]
[http://dx.doi.org/10.1002/cbic.200800563] [PMID: 19140143]
[http://dx.doi.org/10.1021/acschembio.9b00934] [PMID: 32216326]
[http://dx.doi.org/10.1038/ncomms16103] [PMID: 28706243]
[http://dx.doi.org/10.1039/c1cs15117g] [PMID: 21720638]
[http://dx.doi.org/10.1021/ja8046552] [PMID: 18980309]
[http://dx.doi.org/10.1039/b718854d] [PMID: 18338058]
[http://dx.doi.org/10.1002/anie.201103422] [PMID: 21812083]
[http://dx.doi.org/10.1016/j.bbagen.2016.11.024] [PMID: 27865994]
[http://dx.doi.org/10.1016/j.bmcl.2012.07.065] [PMID: 22892119]
[http://dx.doi.org/10.1016/j.bmcl.2013.07.057] [PMID: 23972440]
[http://dx.doi.org/10.1016/j.tet.2011.10.066]
[http://dx.doi.org/10.1073/pnas.052698099] [PMID: 11854467]
[http://dx.doi.org/10.1038/sj.onc.1208468] [PMID: 15735722]
[http://dx.doi.org/10.1039/b806042h] [PMID: 18688346]
[http://dx.doi.org/10.1002/chem.201102556] [PMID: 22161991]