Photochromic derivatives of indigo: historical overview of development, challenges and applications.

The importance of indigo dyes is constantly increasing with the evolution of novel textile materials and photochromic material technologies. The aim of this review article is to provide a comprehensive overview of the development of photochromic indigo derivatives from the first report on the photochromic N,N'-diacetylindigo in 1954 until now. We begin with the list of historical milestones in the development of photochromic indigo derivatives. Further, we provide a brief description of the synthetic procedures utilised to obtain indigo and its derivatives, outline the structural peculiarities, photophysical and photochemical properties of indigo and proceed with the detailed discussion of the photochromic indigo derivatives. Finally, we highlight the photochromism of the structural isomers of indigo (isoindigo and indirubin) and provide an overview of prospective applications of indigo photoswitches.

Aurones: Unexplored Visible-Light Photoswitches for Aqueous Medium.

The development of synthetically accessible photoswitches showing an efficient performance in aqueous medium has recently become an urgent task due to the rapid progress of photopharmacology and novel biomedical applications. In response to this challenge, in this work, aurone derivatives are introduced as a novel class of efficient visible-light photoswitches for aqueous medium. In general, aurones exhibit superior performance in water, including significantly higher quantum yields, compared with other indigoid photoswitches (hemithioindigo and hemiindigo). Especially remarkable are the half-lives of the photoinduced E-isomers of aurones in water, reaching up to 7 years. Further modification of the aurone scaffold with substituents that increase water solubility does not affect most of the photoswitching characteristics and even improves some them. The highly advantageous property profile of the aurone photoswitches make them a perfect novel platform for the design of light-controllable systems in the areas requiring photoswitching in aqueous medium.

Design of Aurone-Based Dual-State Emissive (DSE) Fluorophores.

The development of dual-state emissive (DSE) fluorophores, i. e. organic molecules showing balanced emission in both solution and as molecular solids, has recently become an emerging approach in material science, biology, sensing, and optoelectronics. However, the majority of existing DSE fluorophores represents structural modifications of the scaffolds known for their aggregation-induced emission (AIE) properties, e. g., tetraphenylethylenes (TFE), triphenylamines (TFA), and others. In this study, we introduce aurones as an easily accessible scaffold for the construction of DSE fluorophores and describe the main design principles allowing to achieve the balanced emission in both solution and solid state. Herein, we present the solid-state fluorescence in a systematic series of aurone derivatives for the first time. We propose that the newly found DSE properties of aurones in combination with their established biological activity can be applied efficiently in biomedical studies and diagnostic tools.

Fused Bis(hemi-indigo): Broad-Range Wavelength-Independent Photoswitches.

Wavelength-independent conversion of organic photoswitches in the photostationary state is a rare phenomenon that opens up a way for many practical applications. In this work, three fused bis(hemi-indigo) derivatives with different substitution patterns were synthesized and their photoswitching was investigated by optical spectroscopy, real-time NMR spectroscopy and TD-DFT calculations. We disclosed that the Z-E photoisomerization of the meta-bis(hemi-indigo) derivative was remarkably independent of the irradiation wavelength from UV up to yellow light. The wavelength-independent forward photoswitching together with the inhibited backward photoisomerization, high thermal stability of the photoinduced isomers as well as significant overlap between the photoswitch absorption and the solar spectrum allows to suggest bis(hemi-indigo) derivatives as promising candidates for molecular solar thermal energy storage (MOST) systems.

Photoswitches for controllable RNA binding: a future approach in the RNA-targeting therapy.

RNA is an emerging drug target that opens new perspectives in the treatment of viral and bacterial infections, cancer and a range of so far incurable genetic diseases. Among the various strategies towards the design and development of selective and efficient ligands for targeting and detection of therapeutically relevant RNA, photoswitchable RNA binders represent a very promising approach due to the possibility to control the ligand-RNA and protein-RNA interactions by light with high spatiotemporal resolution. However, the field of photoswitchable RNA binders still remains underexplored due to challenging design of lead structures that should combine high RNA binding selectivity with efficient photochemical performance. The aim of this highlight article is to describe the development of photoswitchable noncovalent RNA binders and to outline the current situation and perspectives of this emerging interdisciplinary field.

Role and Perspective of Molecular Simulation-Based Investigation of RNA-Ligand Interaction: From Small Molecules and Peptides to Photoswitchable RNA Binding.

Aberrant RNA-protein complexes are formed in a variety of diseases. Identifying the ligands that interfere with their formation is a valuable therapeutic strategy. Molecular simulation, validated against experimental data, has recently emerged as a powerful tool to predict both the pose and energetics of such ligands. Thus, the use of molecular simulation may provide insight into aberrant molecular interactions in diseases and, from a drug design perspective, may allow for the employment of less wet lab resources than traditional in vitro compound screening approaches. With regard to basic research questions, molecular simulation can support the understanding of the exact molecular interaction and binding mode. Here, we focus on examples targeting RNA-protein complexes in neurodegenerative diseases and viral infections. These examples illustrate that the strategy is rather general and could be applied to different pharmacologically relevant approaches. We close this study by outlining one of these approaches, namely the light-controllable association of small molecules with RNA, as an emerging approach in RNA-targeting therapy.

Modification of an NMR probe for monitoring of photoreactions.

We describe a modified NMR probe for the in situ irradiation studies of photochemical reactions in solution-state NMR. To build up this setup, we designed an irradiation insert that brings eight light-emitting diodes (LEDs) into the NMR probe in the immediate proximity of the sample. The inserts with LEDs of different wavelengths are easily exchangeable within minutes. A tunable power supply allows to adjust the light intensity to optimize the irradiation conditions.

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives.

A small series of five novel berberine derivatives was synthesized by the Cu-catalyzed click reaction of 9-propargyladenine with 9-O-(azidoalkyl)berberine derivatives. The association of the resulting berberine-adenine conjugates with representative quadruplex-forming oligonucleotides 22AG dA(G3TTA)3G3 and a2 d(ACAG4TGTG4)2 was examined with photometric and fluorimetric titrations, thermal DNA denaturation analysis, and CD spectroscopy. The results from the spectrometric titrations indicated the formation of 2:1 or 1:1 complexes (ligand:G4-DNA) with log K b values of 10-11 (2:1) and 5-6 (1:1), which are typical for berberine derivatives. Notably, a clear relationship between the binding affinity of the ligands with the length of the alkyl linker chain, n, was not observed. However, depending on the structure, the ligands exhibited different effects when bound to the G4-DNA, such as fluorescent light-up effects and formation of ICD bands, which are mostly pronounced with a linker length of n = 4 (with a2) and n = 5 (with 22AG), thus indicating that each ligand-G4-DNA complex has a specific structure with respect to relative alignment and conformational flexibility of the ligand in the binding site. It was shown exemplarily with one representative ligand from the series that such berberine-adenine conjugates exhibit a selective binding, specifically a selectivity to quadruplex DNA in competition with duplex DNA, and a preferential thermal stabilization of the G4-DNA forms 22AG and KRAS. Notably, the experimental data do not provide evidence for a significant effect of the adenine unit on the binding affinity of the ligands, for example, by additional association with the loops, presumably because the adenine residue is sterically shielded by the neighboring triazole unit.

Cucurbiturils in nucleic acids research.

During the past ten years, the importance of cucurbiturils (CB[n]) as macrocyclic hosts in supramolecular assemblies with various types of natural and synthetic nucleic acids (NAs) has increased explosively. As a component of such systems, CB[n] macrocycles can play a wide spectrum of roles from drug and gene delivery vehicles to catalysts/inhibitors of biochemical reactions and even building blocks for NA-based materials. The aim of this highlight article is to describe the development of the CB[n] applications in nucleic acids research and to outline the current situation and perspectives of this fascinating synergistic combination of supramolecular chemistry of CB[n] and NAs.

Encapsulation-Controlled Photoisomerization of a Styryl Derivative: Stereoselective Formation of the Anti Z-Isomer in the Cucurbit[7]uril Cavity.

The photochemical isomerization of a styrylpyridinium dye (SP) bearing an unsymmetrically attached benzo-15-crown-5 ether has been studied in aqueous solution in the absence and presence of cucurbit[7]uril (CB[7]). The detailed analysis of the UV/Vis and NMR spectra showes that the isomeric composition of the photostationary mixtures of SP can be modulated by the host-guest complexation with CB[7]. It was found that steric hindrance caused by encapsulation of SP in the host cavity induces the exclusive formation of the anti conformer of Z-SP in contrast with the mixture of both anti and syn conformers obtained during photoisomerization of the dye without CB[7]. Remarkably, the displacement of anti Z-SP from CB[7] does not lead to the transformation of the anti Z-isomer into the syn Z-isomer pointing out the conformational memory of the system. The results provide an interesting example of the supramolecular stereorecognition by the achiral CB[7] host.

Design, synthesis and investigation of water-soluble hemi-indigo photoswitches for bioapplications.

A series of hemi-indigo derivatives was synthesized and their photoswitching properties in aqueous medium were studied. The dimethoxy hemi-indigo derivative with the best photochromic performance in water was identified as a promising platform for the development of photoswitchable binders for biomolecules. The synthetic approach towards the introduction of the alkylamino pendant to the dimethoxy hemi-indigo core was developed that allowed to obtain an RNA-binding hemi-indigo derivative with photoswitchable fluorescent properties.

Visible-range hemi-indigo photoswitch: ON-OFF fluorescent binder for HIV-1 RNA.

A proof-of-principle for the application of hemi-indigo derivatives as RNA binders with photocontrollable fluorescence is presented. The photoswitch binds to the human immunodeficiency virus type 1 (HIV-1) RNA with a significant light-up effect. The fluorescence of the RNA-bound ligand can be reversibly switched ON and OFF by light without destroying the ligand-RNA associates.

Governing the DNA-binding mode of styryl dyes by the length of their alkyl substituents - from intercalation to major groove binding.

A series of monomeric and homodimeric 4-alkoxystyryl(pyridinium) dyes was synthesized and their DNA-binding properties were investigated. We found that the length of the alkyl substituent has a crucial influence on the binding mode of the dyes, although the structure of the DNA-binding unit is the same for all compounds. Remarkably, mono- and bis-styryl derivatives comprising an oxodecyl chain represent the rare examples of small molecules that bind to the major groove of DNA. We have also demonstrated that the dyes, except the monostyryl dye with a bromopropyl substituent, form chiral aggregates in the presence of double-stranded DNA.

Protonation-Gated Dual Photochromism of a Chromene-Styryl Dye Hybrid.

A novel hybrid bisphotochromic system involving a chromene residue and a styryl dye fragment is described. Initially, the compound shows almost no photochromism due to intramolecular energy and electron transfer between the chromophores. Protonation of the hybrid system blocks the transfer processes and unlocks a dual photochromic activity that includes ring opening of the chromene fragment and E-Z-isomerization of the styryl dye residue. Deprotonation of any photoinduced form resets the system to the initial photoinactive form.

Light-induced piston nanoengines: ultrafast shuttling of a styryl dye inside cucurbit[7]uril.

The combination of photoactive styryl(pyridinium) dyes and cucurbit[7]uril (CB[7]) in an integrated supramolecular system allowed us to design a novel high speed molecular machine based on the fully reversible shuttling motion of the dye inside the CB[7] host cavity. The driving force of this movement is the electrostatic potential change after the occurrence of intramolecular charge transfer in the excited state of the dye molecule that can be externally controlled by light. Steady-state and time-resolved optical spectroscopy as well as DFT calculations provided an unambiguous evidence for the ultrafast piston-like movement of the system between two states. The shuttling process occurs in the picosecond timescale and its bistability depends on the strength of the dye donor fragment.

Interactions between photoacidic 3-hydroxynaphtho[1,2-b]quinolizinium and cucurbit[7]uril: Influence on acidity in the ground and excited state.

3-Hydroxynaphtho[1,2-b]quinolizinium was synthesized by cyclodehydration route and its optical properties in different media were investigated. The absorption and emission spectra of this compound depend on the pH of the solution. Thus, at higher pH values the deprotonation yields a merocyanine-type dye that exhibits significantly red-shifted absorption bands and causes a dual emisson, i.e., a combination of emission bands of the hydroxyquinolizinium and its deprotonated form. Whereas this compound is a weak acid in the ground state (pKa = 7.9), it has a strongly increased acidity in the excited state (pKa* = 0.4). As a result, the blue-shifted fluorescence of the hydroxyquinolizinium becomes dominant only under strongly acidic conditions. In addition, it is shown that 3-hydroxynaphtho[1,2-b]quinolizinium binds to cucurbit[7]uril (CB[7]) with moderate affinity (Kb = 1.8 × 104 M-1, pH 5) and that the pKa and pKa* values of this ligand increase by about two to three orders of magnitude, respectively, when bound to CB[7].

Regiospecific Photocyclization of Mono- and Bis-Styryl-Substituted N-Heterocycles: A Synthesis of DNA-Binding Benzo[c]quinolizinium Derivatives.

Regiospecific C-N photocyclization of mono- and bis-styryl-substituted N-heterocycles was investigated. We demonstrated that the C-N regiospecificity of the photoinduced electrocyclization is a general feature of ortho-styryl-substituted N-heterocycles comprising one and two nitrogen atoms. This phototransformation provides a straightforward synthesis of the pharmaceutically important benzo[c]quinolizinium cation and its aza-analogues. Noticeably, bis-styryl derivatives undergo only one-fold cyclization with the second styryl fragment remaining uninvolved in the cyclization process. Photocyclization products of monostyryl derivativatives intercalate into calf thymus DNA (ct DNA), whereas photocyclization products of bis-styryl derivativatives possess a mixed binding mechanism with ct DNA. The results can be used for development of novel DNA-targeting chemotherapeutics based on benzo[c]quinolizinium derivatives.

Photoinduced formation of stable Ag-nanoparticles from a ternary ligand-DNA-Ag(+) complex.

The combination of (i) the light-harvesting nature and excited-state redox reactivity of a cationic DNA intercalator, (ii) a conjugated Ag(+)-binding crown ether, and (iii) the stabilizing effect of DNA on AgNPs in one integral ternary complex enables the mild photoinduced formation of Ag nanoparticles.

DNA-ligand interactions gained and lost: light-induced ligand redistribution in a supramolecular cascade.

A supramolecular five-component cascade is presented that enables light-controlled transport of an in situ modified ligand between three host systems based on the different complexation preferences of cyclodextrin, cucurbituril, and double-stranded DNA. The results point out novel approaches for the control of drug-DNA interactions in DNA-targeting therapy.

Interaction of crown ether-annelated styryl dyes with double-stranded DNA.

DNA-binding properties of 15-crown-5-derived mono- and bis-styryl dyes were investigated in the presence of calf thymus DNA. To access the factors that influence the DNA association in the series of these ligands, the structure of the molecules was varied by either changing size of the heterocyclic moiety or altering the position of the styryl substituents. The major binding mode for the monostyryl dyes is intercalation. Notably, binding of the dyes to the nucleic acids leads to a fluorescence enhancement by a factor of up to 54. Therefore, these cationic styryl derivatives may be applied as fluorescent "light-up" probes for DNA detection.