Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology

Abstract

A pyridinium-decorated photoresponsive dithienylethene selectively targets G-quadruplex DNA, allowing binding mode and toxicity to be controlled exclusively with visible light.

Light-inducedin situchemical activation of a fluorescent probe for monitoring intracellular G-quadruplex structures

“…While a large number of organic and metal-organic compounds have been reported to target duplex and G4 structures with different levels of selectivity, there are very few reports of small-molecules that can bind to DNA only after activation by an external stimulus. [6][7][8][9][10][11][12] Prominent recent examples of such active and dynamic G4-binders include a metal salphen complex that is activated in the presence of bio-reductants 11 and a metal-mediated conformational switching of a G4-binder based on a pyridodicarboxamide unit. 6 Among the various possible triggers, photon irradiation offers distinct advantages because of its higher spatiotemporal precision, tunable energetic resolution, remote action and absence of waste chemical products.…”

“…6 Among the various possible triggers, photon irradiation offers distinct advantages because of its higher spatiotemporal precision, tunable energetic resolution, remote action and absence of waste chemical products. Yet, the development of photoresponsive G4-ligands has received scant attention to date: a molecular photoswitch based-on an azobenzene unit 7 , a stiff-stilbene-and dithienylethene-derived ligands 12,13 and (photo)caged G4binders 9,10 constitute rare examples of such molecules and translation of their activity into relevant physiological media has been rarely reported. 10,12 In a recent series of papers, we have described a low-cost and high-yielding, gram-scale synthetic procedure that afforded enantiopure binaphthol-like compounds featuring extended quinoline moieties, a motif quite commonly found in bioactive molecules.…”

“…Yet, the development of photoresponsive G4-ligands has received scant attention to date: a molecular photoswitch based-on an azobenzene unit 7 , a stiff-stilbene-and dithienylethene-derived ligands 12,13 and (photo)caged G4binders 9,10 constitute rare examples of such molecules and translation of their activity into relevant physiological media has been rarely reported. 10,12 In a recent series of papers, we have described a low-cost and high-yielding, gram-scale synthetic procedure that afforded enantiopure binaphthol-like compounds featuring extended quinoline moieties, a motif quite commonly found in bioactive molecules. [14][15][16] In the present paper, we describe how, upon UV light irradiation of 1, selective conversion to a new emissive photoproduct 2 is achieved where the intramolecular macrocyclization of the individual quinoline moieties occur with significant extension of the aromatic skeleton of the molecule (Scheme 1 and Fig.…”

Spectroscopic Properties of Two 5′-(4-Dimethylamino)Azobenzene Conjugated G-Quadruplex Forming Oligonucleotides

“…As a consequence, in alkaline medium, the trans-to-cis conversion should be detectable, as had occurred for double helices incorporating DMAzo analogues [ 17 , 56 , 57 ]. In addition, the dye was not functionalized with specific substituents able to support the stacking on the G-quartet by additional interactions [ 65 , 66 , 67 , 68 , 69 , 70 ]. Based on these observations, we hypothesized that such interactions between the dye and the Qs can stabilize a specific tautomer of the protonated dye, thus accelerating or hampering the trans-cis conversion also using alkaline pH [ 51 , 52 , 53 , 54 , 55 ].…”

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

“… 1728 Additionally, visible-light triggered switching of the G-quadruplex ligand binding mode and G-tetrad structure formation using a pyridinium-substituted dithienylethene has been demonstrated under physiologically relevant conditions. 1729 …”