Naphthalene Diimides as Multimodal G-Quadruplex-Selective Ligands

Abstract

G-quadruplexes are four-stranded nucleic acids structures that can form in guanine-rich sequences. Following the observation that G-quadruplexes are particularly abundant in genomic regions related to cancer, such as telomeres and oncogenes promoters, several G-quadruplex-binding molecules have been developed for therapeutic purposes. Among them, naphthalene diimide derivatives have reported versatility, consistent selectivity and high affinity toward the G-quadruplex structures. In this review, we present the chemical features, synthesis and peculiar optoelectronic properties (absorption, emission, redox) that make naphtalene diimides so versatile for biomedical applications. We present the latest developments on naphthalene diimides as G-quadruplex ligands, focusing on their ability to bind G-quadruplexes at telomeres and oncogene promoters with consequent anticancer activity. Their different binding modes (reversible versus irreversible/covalent) towards G-quadruplexes and their additional use as antimicrobial agents are also presented and discussed.

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…Following earlier work examining the potential of quinone methide precursors as general DNA alkylating agents, the group exploited naphthalene diimide (NDI) derivatives to confer G4‐selectivity to this warhead . NDIs have themselves been extensively explored as G4 binding agents, displaying impressive selectivity and, more recently, promising results against in vivo disease models , . Initially, the group reported compound 33 to be capable of alkylating telo22 G4.…”

Dyads of G‐Quadruplex Ligands Triggering DNA Damage Response and Tumour Cell Growth Inhibition at Subnanomolar Concentration

“…and at the end an isocratic flow over 4min. 1 H, 13 CNMR spectra were recorded on aB ruker ADVANCE 300 MHz spectrometer. To reduce the reaction time and by-product formation, the following nucleophilic aromatic substitution (S N Ar) was performed by using am icrowave-assisted protocol.…”

“…[9] Next, two research groupsi ndependentlyr eported the use of G4-specific antibodies that bind with nm affinity to visualiset hese structures in cells by meanso ff luorescencebasedi maging. [13] In fact, their optoelectronic properties can be effectively tuned by substituents on the aromatic core, [14] thus giving origin to absorption and emission in the red spectroscopicw indow, which makes them appealing forf luorescence imaging and photodynamic therapy (PDT). These data are very persuasive of the G4 existence,b iological significance, and potential" drugability" in humanc ells.…”

“…[11,12] In this frame,o ur interestg oes to G4-binding naphthalene diimides (NDIs),w hich are extremelyv ersatile compounds. [13] In fact, their optoelectronic properties can be effectively tuned by substituents on the aromatic core, [14] thus giving origin to absorption and emission in the red spectroscopicw indow, which makes them appealing forf luorescence imaging and photodynamic therapy (PDT). [15,16] Additionally,N DIsh ave been exploiteda sa ppealing scaffold for the designo fG 4l igands, thanks to their chemical accessibility and large planar surface.…”

Trifunctionalized Naphthalene Diimides and Dimeric Analogues as G-Quadruplex-Targeting Anticancer Agents Selected by Affinity Chromatography

“…These compounds exhibited excellent water solubility and cellular entry capability, thus emerging as versatile tools for both therapeutic and diagnostic applications [14,15]. A number of di-, tri-and tetrasubstituted monomeric NDIs were also designed and synthesized, showing telomerase inhibitory activity and antiproliferative effects on different cancer cell lines, as well as the ability to easily access the nucleus [11][12][13][16][17][18]. It is noteworthy that the trisubstituted NDIs proved to be the most cytotoxic compounds in the investigated series, being also the most selective ones on several cancer cell lines over healthy cells and displaying antitumor activity in vivo in human pancreatic ductal adenocarcinoma (PDAC) animal models [19].…”