Cyclic Naphthalene Diimide with a Ferrocene Moiety as a Redox‐Active Tetraplex‐DNA Ligand

Abstract

Cyclic naphthalene diimides (cNDIs), with a ferrocene moiety (cFNDs) and different linker lengths between the ferrocene and cNDI moieties, were designed and synthesized as redox‐active, tetraplex‐DNA ligands. Intramolecular stacking was observed between ferrocene and the NDI planes, which could affect the binding properties for G‐quadruplexes. Interestingly, the circular dichroism spectrum of one of these compounds clearly shows new Cotton effects around 320–380 and 240 nm, which can be considered a direct evidence of intramolecular stacking of ferrocene and the NDI. Regarding recognition of hybrid G‐quadruplexes, the less rigid structures (longer linkers) show higher binding affinity (106 m−1 order of magnitude). All new compounds show higher selectivity for G4 during electrochemical detection than noncyclic FND derivatives, which further identifies the redox‐active potentiality of the cFNDs. Two of the three compounds tested even show preferential inhibition of cell growth in cancer cells over normal cells in a low concentration range, highlighting the potential for bioapplications of these cFNDs.

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

“…Since till now various NDI derivatives were applied for binding and sensing different types of DNA/RNA constructs, including G-quartets [ 55 – 57 ], and other, more complex sequences, the herein presented amino acid–NDI conjugates may in future also be investigated for such applications, either directly or incorporated in peptidoid constructs. Indeed, the colourful and fluorescent NDIs 3a and 3b are ideal for use in peptide-backbone constructed multichromophores targeting FRET-based sensing [ 14 , 26 , 58 ].…”

Disentangling the Structure–Activity Relationships of Naphthalene Diimides as Anticancer G-Quadruplex-Targeting Drugs

“…CD analysis allowed insights into the conformational changes induced by the studied NDI on the target. Increase of the 290 nm band and decrease of the 240 nm band were observed for hybrid monomeric (with disubstituted 2 , 30 , 32 , and 39 ; trisubstituted 43 , 46 , 55 , 80 , 83 , 84 , and 93 ; tetrasubstituted 159 , 160 , and 162 ; core-extended 175 and 179 ; dimeric 185 , 186 , 188 , 189 , and 190 ; and cyclic 202 , 203 , 209 , and 213 ) and dimeric G-quadruplexes (with trisubstituted 46 and cyclic 204 , 214 , 215 , and 216 ). ,,− ,− As far as parallel G-quadruplexes are concerned, a reduction of both the 260 and 240 nm bands was observed (with trisubstituted 46 and 93 ; tetrasubstituted 159 , 160 , and 162 ; core-extended 165 and 175 ; and cyclic 202 and 203 ). ,,,− Conformational changes upon NDI interaction were produced also on duplex structures: increases of both the maximum at 280 nm and the minimum at 250 nm were observed for trisubstituted 46 ; dimeric 185 , 186 , 188 , 189 , and 190 ; and cyclic 209 . ,, Notably, cyclic 200 , 201 , and 202 were studied in their interaction with telomeric and c-myc G-quadruplexes under both dilute and molecular crowding conditions by CD . The studied telomeric G-quadruplex adopted hybrid or parallel topologies in dilute or molecular crowding conditions, respectively, while c-myc G-quadruplex folded in parallel topologies in both conditions.…”

“…On the other hand, some differences were found in the entropic contribution, mainly due to the different ability of the substituents on the NDI core to displace water molecules on binding the target. A negative entropic contribution was obtained for 30 , 32 , 39 , 200 , 201 , and 202 , suggesting that the resulting G-quadruplex/NDI complexes were less flexible than the free G-quadruplexes. ,,, In contrast, a positive Δ S contribution was found for disubstituted 2 , trisubstituted 46 , and cyclic 204 . ,, Notably, the entropic factor proved to be the main driving force for the formation of cyclic 205 – 207 /G-quadruplex complexes …”

Application of naphthalene diimide in biotechnology

“…Takenaka's group synthesized cFND (Table 1, Fig. 3a) and demonstrated an improved preference for the DNA tetraplex, with a binding constant on the order of 10 6 M −1 , and successfully achieved electrochemical detection of the DNA tetraplex [52].…”