Design, synthesis and evaluation of 4,7-diamino-1,10-phenanthroline G-quadruplex ligands

Design, Synthesis, and Evaluation of 2,9‐Bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline Derivatives as G‐Quadruplex Ligands

“…A large number of small heterocyclic molecules have been synthesized and evaluated for their ability to interact with G‐quadruplexes . Among them are the 1,10‐phenanthroline derivatives, such as PhenDC3 and its structural analogues I , tetraaminophenanthroline II , K35, and phenanthroline‐2,9‐bistriazole III (Figure ) . These compounds have been investigated for their capacity to bind and stabilize various G4 topologies and for their selectivity for G‐quadruplex versus duplex structures.…”

“…[16] Among them are the 1,10-phenanthroline derivatives, such as PhenDC3 and its structurala nalogues I,t etraaminophenanthroline II,K 35, and phenanthroline-2,9-bistriazole III (Figure 1). [17][18][19][20][21][22][23][24][25][26][27][28] These compounds have been investigated for their capacity to bind and stabilize various G4 topologies and for their selectivity for G-quadruplex versus duplexs tructures.…”

Solution Structure of a G‐quadruplex Bound to the Bisquinolinium Compound Phen‐DC3

“…This feature could be one of the underlying reasons for the strong binding affinity of Phen-DC 3 (the dissociation constant is in the submicromolar to nanomolar range) for many DNA and RNA G-quadruplexes. [25,41] It was previously hypothesized that the crescent shape imposed by the central core (pyridine dicarboxamide or phenanthroline dicarboxamide) contributes to the exceptional G-quadruplex recognition properties of the bisquinolinium compounds. [18,42] This hypothesis was supported by the fact that G-quadruplex binding is considerably reduced for analogues exhibiting a more flexible core, such as a bipyridine core, [18] or even lost when the amide connectivity is inverted, thus leading to a linear conformation (see Figure S12 and Table S2).…”

“…Follow-up studies involving analogues containing a different central aromatic core (see Figure S13) or additional cationic side chains (see Figure S14) also further emphasized the importance of the crescent shape of the central core (see Table S2). [25,26,41,[43][44][45][46][47] The importance of the crescent-shaped core can be now rationalized in terms of a large p-overlap between Phen-DC 3 and the top G-tetrad.…”

Selective recognition of specific G-quadruplex vs. duplex DNA by a phenanthroline derivative

“…Recently, several structures containing 1,10-phenanthrolines have been shown as G-quadruplex ligands, for example, the 2,9-disubstituted derivatives [36][37][38][39][40][41][42][43], the 4,7-diamino derivatives [44], a neomycin-capped structure [45,46], and complexes with platinum, ruthenium, and other transition metals [47][48][49]. Although, the phenanthroline bisquinolinium derivatives show highly efficient recognition of G-quadruplex by introducing two cationic side-arms together with accurate match of these structures to quadruplex.…”