Cationic helicenes as selective G4 DNA binders and optical probes for cellular imaging

Summers, Peter A.; Thomas, Ajesh P.; Kench, Timothy; Vannier, Jean‐Baptiste; Kuimova, Marina K.; Vilar, Ramón

doi:10.1039/d1sc04567a

Cited by 16 publications

(13 citation statements)

References 48 publications

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“…[46] This recognition on the extended aromatic surface of G-quartets was consistent with the G-quartet structure (Figure 3,A), as expected from models (Figure 3,D), and many examples in the literature. [35][36][37][38][39][40][41][42][43][44][45][46] Taken together, red-shifted excitation and emission maxima indicated that the flipper probe planarizes upon surface recognition on G-quartets to maximize non-covalent π-stacking interactions, and not by mechanical compression as in lipid bilayer membranes.…”

Section: D)mentioning

confidence: 93%

“…The most promising DNA motif for chemical flipper planarization were G‐quartets 4 ( Figure 3 ,A ) [33–46] . G‐Quartets have important functions in biology, from telomeres to gene expression.…”

Section: Figurementioning

confidence: 99%

“…To elaborate on flipper planarization, cMyc 4p and human telomers hTel22 4a were selected as single‐stranded parallel and antiparallel G‐quartets, respectively ( Figure 4 ,A and 4,B ) [39–42,46] . The sequence of the triple helix 6 was chosen because it is one of the few examples with characterized intercalators ( Figure 4 ,C ) [46,67] .…”

Section: Figurementioning

confidence: 99%

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G‐Quartets, 4‐Way Junctions and Triple Helices but Not DNA Duplexes: Planarization of Twisted Push–Pull Flipper Probes by Surface Recognition Rather Than Physical Compression

Sakai

Assies

Matile

2022

Helvetica Chimica Acta

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Planarizable push-pull flipper probes have been introduced to image order and tension of membranes in living cells. In this report, we show that fluorescent flippers can also be planarized by chemical interactions on DNA architectures rather than by physical forces in biomembranes. Compared to fluorescence in water, the planarization on parallel cMyc G-quartets is characterized by a 100 nm red shift of the excitation maximum and a strong increase in fluorescence intensity. A coinciding 100 nm red shift of the emission maximum compared to planarized flippers in ordered membranes reveals that planarization occurs on the water-accessible surface rather than within the G-quartets. Less relevant for physical compression in the ground state in hydrophobic membranes, this functional relevance of flipper solvatochromism in the excited state, reflected by red shifts in emission rather than excitation, is unprecedented and introduces attractive dual sensing perspectives. With decreasing efficiency, flippers are also planarized by antiparallel hTel22 G-quartets, 4-way junctions and triple helices, while the aromatic surface of B-DNA duplexes is too small for strong enough π stacking. These remarkably consistent results expand the understanding of planarizable push-pull flipper probes and enable applications in new directions.

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Section: D)mentioning

confidence: 93%

Section: Figurementioning

confidence: 99%

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G‐Quartets, 4‐Way Junctions and Triple Helices but Not DNA Duplexes: Planarization of Twisted Push–Pull Flipper Probes by Surface Recognition Rather Than Physical Compression

Sakai

Assies

Matile

2022

Helvetica Chimica Acta

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“…Despite the increasing number of applications for the use of helicenes in synthesis and materials science, these scaffolds are understudied in the area of chemical biology. Given their extended conjugation, there are several examples where the photophysical properties of helicenes have been exploited to enable them to act as dyes for cell imaging or photodynamic activity. ,,− Alternatively, and in analogy to more conventional polyaromatic hydrocarbons (PAHs), the cellular cytotoxicity of helicenes has been investigated in a few examples. − However, there are limited examples of the helicene scaffold interacting specifically and directly with therapeutically relevant biological targets.…”

Section: Introductionmentioning

confidence: 99%

“…The best examples of helicenes designed for medicinal chemistry aim to address DNA topologies, including selective binding of helicenes to B/Z-DNA , and G-quadruplex DNA. ,, It is worth noting, however, that despite simple analogies between the helical form of both DNA and the helicenes, there is a large mismatch in helix dimensions: The helical pitch of [ n ]-helicenes with n = 6–11 is 3.21 vs 33.2 Å for B-DNA . As such, helicene recognition of DNA is likely based on conventional mechanisms of binding, such as intercalation, rather than more specific shape complementarity.…”

Section: Introductionmentioning

confidence: 99%

[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

Rushworth

Thawani

Fajardo-Ruiz

et al. 2022

JACS Au

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Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenesthemselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

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Self‐Assembled Peptidyl Aggregates for the Fluorogenic Recognition of Mitochondrial DNA G‐Quadruplexes

et al. 2022

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The selective monitoring of G-quadruplex (G4) structures in living cells is important to elucidate their functions and reveal their value as diagnostic or therapeutic targets. Here we report a fluorogenic probe (CV2) able to selectively light-up parallel G4 DNA over antiparallel topologies. CV2 was constructed by conjugating the excimer-forming CV dye with a peptide sequence (L-Arg-L-Gly-glutaric acid) that specifically recognizes G4s. CV2 forms self-assembled, red excimeremitting nanoaggregates in aqueous media, but specific binding to G4s triggers its disassembly into rigidified monomeric dyes, leading to a dramatic fluorescence enhancement. Moreover, selective permeation of CV2 stains G4s in mitochondria over the nucleus. CV2 was employed for tracking the folding and unfolding of G4s in living cells, and for monitoring mitochondrial DNA (mtDNA) damage. These properties make CV2 appealing to investigate the possible roles of mtDNA G4s in diseases that involve mitochondrial dysfunction.

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Cationic helicenes as selective G4 DNA binders and optical probes for cellular imaging

Abstract: The important role that G-quadurplex DNA (G4 DNA) structures play in regulating biological processes is becoming widely recognised. These structures have also been proposed to be attractive drug targets. Therefore,...

Cited by 16 publications

References 48 publications

G‐Quartets, 4‐Way Junctions and Triple Helices but Not DNA Duplexes: Planarization of Twisted Push–Pull Flipper Probes by Surface Recognition Rather Than Physical Compression

G‐Quartets, 4‐Way Junctions and Triple Helices but Not DNA Duplexes: Planarization of Twisted Push–Pull Flipper Probes by Surface Recognition Rather Than Physical Compression

[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

Self‐Assembled Peptidyl Aggregates for the Fluorogenic Recognition of Mitochondrial DNA G‐Quadruplexes

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