Design of Modular G‐quadruplex Ligands

Abstract

Guanine-rich nucleic acid sequences able to form four-stranded structures (G-quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug-like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure-G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.

Binding Studies of Metal–Salphen and Metal–Bipyridine Complexes towards G‐Quadruplex DNA

“…Initially, most G‐quadruplex binding molecules were based on organic heteroaromatic compounds . Subsequently, it was shown that metal complexes can also be excellent G4 DNA binders thanks to their unique electronic and structural features, as has been discussed in detail elsewhere .…”

“…[10,11] Initially,m ost G-quadruplexb inding molecules were based on organic heteroaromatic compounds. [12,13] Subsequently,i t was shown that metal complexesc an also be excellent G4 DNA binderst hanks to their unique electronic and structural features, ash as been discussed in detail elsewhere. [14,15] An example of this, are metal salphen ands alen complexes, which have been extensively studied over the past 10 years (see Figure 1).…”

Combining 1,3‐Ditriazolylbenzene and Quinoline to Discover a New G‐Quadruplex‐Interactive Small Molecule Active against Cancer Stem‐Like Cells

“…[1,7,8] Moreover,t he enrichment of theses tructures in promoter regions of, in particular, proto-oncogenesh as been revealed by informaticsa nalysiso ft he human genome [9] and supported by antibody-based G4 chromatin immunoprecipitation and highthroughput sequencing. [15,16,17] The 1,3-di(1H-1,2,3-triazol-4-yl)benzene system was previously shown by biophysical and molecular modeling studies to provide an efficient central module, able to interact effectively with the 3'-end G-quartet of the human telomeric parallel-stranded G4 structure. [1,3] Strikingly,i th as been shown that G4stabilizing ligands might differentially target humanc ancer stem cells, [11,12] as ubpopulation of cancer cells implied in tumorf ormation, metastases, and recurrence due to their long-lasting properties and resistance to chemotherapy.…”

“…[1,3] Strikingly,i th as been shown that G4stabilizing ligands might differentially target humanc ancer stem cells, [11,12] as ubpopulation of cancer cells implied in tumorf ormation, metastases, and recurrence due to their long-lasting properties and resistance to chemotherapy. [15,20] To furthere xplore triazole and quinoline rings in the design of G4-interactive small molecules with potential anticancer activity,w ed esigned compounds 1a-d with predicted good oral drug-like properties (Table S1 in the Supporting Information). Differences between nucleic acid sequences forming G4s can create diverse G4 topologies that may have major influence on G4-ligandi nteractions.…”

“…The design of flexible nonfused polycyclic G4-interactive smallm olecules that may also target grooves and loops of G4s has emerged as one way to achieve selectivity and also to lead to more drug-like compounds. [15,16,17] The 1,3-di(1H-1,2,3-triazol-4-yl)benzene system was previously shown by biophysical and molecular modeling studies to provide an efficient central module, able to interact effectively with the 3'-end G-quartet of the human telomeric parallel-stranded G4 structure. [18,19] Also, quinolines have been shownt ob ei mportant modules in the design of several potent G4 ligands.…”