Molecular design and synthesis of methoxy-substitued spiropyrans with photomodulated NIR-fluorescence.

This study focuses on the molecular design and synthesis of salt spiropyrans with near-IR fluorescence. The structure of the obtained compounds was confirmed by NMR, IR and mass spectroscopy. In the course of studying the spectral and photoluminescent characteristics, it was possible to reveal the effect of some substituents in various positions on the properties of spiropyran dyes. Due to the structural similarity of one of the isomers to cyanine dyes, the obtained compounds are of interest as potential fluorescent probes for bioimagimg, in particular, for DNA studies. To reveal their ability of binding to DNA molecules molecular docking was carried out. Toxic effects of compounds demonstrating NIR fluorescence were studied on biofilms, as well as using bacterial lux-biosensors.

Novel Indoline Spiropyrans Based on Human Hormones ß-Estradiol and Estrone: Synthesis, Structure, Chromogenic and Cytotoxic Properties.

The introduction of a switchable function into the structure of a bioactive compound can endow it with unique capabilities for regulating biological activity under the influence of various types of external stimuli, which makes such hybrid compounds promising objects for photopharmacology, targeted drug delivery and bio-imaging. This work is devoted to the synthesis and study of new spirocyclic derivatives of important human hormones-ß-estradiol and estrone-possessing a wide range of biological activities. The obtained hybrid compounds represent an indoline spiropyrans family, a widely known class of organic photochromic compounds. The structure of the compounds was confirmed by 1H and 13C NMR, IR, HRMS and single-crystal X-ray analysis. The intermolecular interactions in the crystals of spiropyran (3) were defined by Hirshfeld surfaces and 2D fingerprint plots, which were successfully acquired from CrystalExplorer (v21.5). All target hybrids demonstrated pronounced activity in the visible region of the spectrum. The mechanisms of thermal isomerization processes of spiropyrans and their protonated merocyanine forms were studied by DFT methods, which revealed the energetic advantage of the protonation process with the formation of a ß-cisoid CCCH conformer at the first stage and its further isomerization to more stable ß-transoid forms. The proposed mechanism of acidochromic transformation was confirmed by the additional NMR study data that allowed for the detecting of the intermediate CCCH isomer. The study of the short-term cytotoxicity of new spirocyclic derivatives of estrogens and their 2-formyl-precursors was performed on the HeLa cell model. The precursors and spiropyrans differed in toxicity, suggesting their variable applicability in novel anti-cancer technologies.

Rational Functionalization of UiO-66 with Pd Nanoparticles: Synthesis and In Situ Fourier-Transform Infrared Monitoring.

Functionalization of metal-organic frameworks (MOFs) with noble metal nanoparticles (NPs) is a challenging task. Conventional impregnation by metals often leads to agglomerates on the surface of MOF crystals. Functional groups on linkers interact with metal precursors and promote the homogeneous distribution of NPs in the pores of MOFs, but their uncontrolled localization can block channels and thus hinder mass transport. To overcome this problem, we created nucleation centers only in the defective pores of the UiO-66 MOF via the postsynthesis exchange. First, we have introduced defects into UiO-66 using benzoic acid as a modulator. Second, the modulator was exchanged for amino-benzoic acid. As a result, amino groups have decorated mainly the defective pores and attracted the Pd precursor after impregnation. The interaction of the metal precursor with amino groups and the growth of NPs were monitored by in situ infrared spectroscopy. Three processes were distinguished: the gaseous HCl release, NH2 reactivation, and growth of extended Pd surfaces. Uniform Pd NPs were located in the pores because of the homogeneous distribution of the precursor and pore diffusion-limited nucleation rate. Our work demonstrates an alternative approach of controlled Pd incorporation into UiO-66 that is of great importance for the rational design of heterogeneous catalysts.

Novel molecular hybrids of indoline spiropyrans and α-lipoic acid as potential photopharmacological agents: Synthesis, structure, photochromic and biological properties.

Organic photochromic compounds are attracting great interest as photoswitchable components of various bioconjugates for using in photopharmacology, targeted drug delivery and bio-imaging. Here we report on the synthesis of two novel molecular hybrids of indoline spiropyrans and alpha-lipoic acid via an esterification reaction. Preliminary photochemical studies revealed photochromic activity of 5-methoxy-substituted spirocompounds in their acetonitrile solutions. Both hybrid spiropyrans along with their parent substances in the hybrids were tested for the short-term cytotoxicity on HeLa cell cultures. The results of cytotoxicity studies showed unpredictable biocompatibility of the hybrids in comparison with the parent hydroxyl-substituted spiropyrans and α-lipoic acid, especially at the relatively high concentration of 2 mM. Using flow cytometry, we demonstrated that the both hybrids induced antioxidant response in the model cells. After the 24 h treatment, the hybrids administered at lower (500 µM) concentration caused suppressed cytosolic ROS and/or induced cellular thiols. At higher concentration, one of the hybrids demonstrated properties qualitatively similar to alpha-lipoic acid, yet far more strong. Together, flow cytometry results suggested that both hybrids of spiropyrans possess emergent biochemical and signaling antioxidant properties, exceeding those of alpha-lipoic acid.

Meta-stable state photoacid containing ß-estradiol fragment with photomodulated biological activity and anti-cancer stem cells properties.

Photopharmacology is a young and rapidly developing field of research that offers significant potential for new insights into targeted therapy. While it primarily focuses on cancer treatment, it also holds promise for other diseases. The key feature of photopharmacological agents is the presence of a photosensitive and biologically active component in the same molecule. In our current study, we synthesized a spiropyran-based meta-stable state photoacid containing a fragment of ß-estradiol. This compound exhibits negative photochromism and photocontrolled fluorescence under visible-light irradiation due to the initial stabilization of its self-protonated form in solution. We conducted comprehensive biological studies on the HeLa cells model to assess the short- and long-term cytotoxicity of the photoacid, its metabolic effects, its influence on signaling and epithelial-mesenchymal transition super-system pathways, and the proportion of the population enriched with cancer stem cells. Our findings reveal that this derivative demonstrates low cytotoxicity to HeLa cells, yet it is capable of dramatically reducing malignant cells side population enriched in cancer stem cells. Additionally, appropriate structural modification lead to an increase in some other biological effects compared to ß-estradiol. In particular, our substance possesses rare properties of AP-1 suppression and demonstrates some pro-oxidant and metabolic effects, which can be regulated by visible light irradiation. As a result, the new estradiol-based photoacid may be considered a promising multi-acting photopharmacological agent for the next-generation anti-cancer research & development.

A Modern Look at Spiropyrans: From Single Molecules to Smart Materials.

Photochromic compounds of the spiropyran family have two main isomers capable of inter-switching with UV or visible light. In the current review, we discuss recent advances in the synthesis, investigation of properties, and applications of spiropyran derivatives. Spiropyrans of the indoline series are in focus as the most promising representatives of multi-sensitive spirocyclic compounds, which can be switched by a number of external stimuli, including light, temperature, pH, presence of metal ions, and mechanical stress. Particular attention is paid to the structural features of molecules, their influence on photochromic properties, and the reactions taking place during isomerization, as the understanding of the structure-property relationships will rationalize the synthesis of compounds with predetermined characteristics. The main prospects for applications of spiropyrans in such fields as smart material production, molecular electronics and nanomachinery, sensing of environmental and biological molecules, and photopharmacology are also discussed.

New cationic spiropyrans with photoswitchable NIR fluorescence.

Visible-light-mediated photochromic compounds with NIR absorption and fluorescence are of great interest for use in different biomedical applications. In this work, new representatives of spiropyrans with conjugated cationic 3H-indolium substituents in different positions of 2H-chromene moiety were synthesized. The electron-donating methoxy groups were introduced in the uncharged indoline and charged indolium cycles to form the effective conjugation chain between the hetarene moiety and the cationic fragment for reaching NIR absorption and fluorescence. The molecular structure and the effects of cationic fragment position on the mutual stability of the spirocyclic and merocyanine forms of compounds were carefully studied in the solutions and solid state by NMR, IR, HRMS, single-crystal XRD, and quantum chemical calculations. It was found that the obtained spiropyrans demonstrate positive or negative photochromism depending on the cationic fragment's position. One of spiropyrans has shown bidirectional photochromic properties induced exclusively by visible light of different wavelengths in both directions. The photoinduced merocyanine forms of compounds possessed far-red shifted absorption maxima and NIR fluorescence, which makes them prospective fluorescent probes for bioimaging.

Reaction of quinaldine with 4,6-di(tert-butyl)-3-nitro-1,2-benzoquinone. Dependence of the outcome on the reaction conditions and a deeper insight into the mechanism.

Condensation of quinaldine with 4,6-di (tert-butyl)-3-nitro-1,2-benzoquinone results in the formation of 5,7-di (tert-butyl)-2-(quinoline-2-yl)-1,3-tropolone, 5,7-di (tert-butyl)-4-nitro-2-(quinoline-2-yl)-1,3-tropolone, 3,3-dimethyl-2-(5-hydroxy-4-nitro-3-tert-butyl-6-quinoline-2-yl-pyridine-2-yl)butanoic acid, 6-(2,2-dimethylprop-3-yl)-5-tert-butyl-4-nitro-2-(quinoline-2-yl)-pyridine-3-ol, 1,7-di (tert-butyl)-3-(quinoline-2-yl)-2-azabicyclo-[3.3.0]octa-2,7-diene-4,6-dione-N-oxide. The formation of 1,3-tropolone and pyridine-2-yl butanoic acid derivatives proceeds through a ring expansion and 2-azabicyclo [3.3.0]octa-2,7-diene-4,6-dione-N-oxide via the contraction of the o-quinone ring. The structure of the heterocyclic compounds obtained was justified by X-ray diffraction analysis, NMR spectroscopy, IR- and HRMS-spectrometry, and the proposed mechanisms of their formation include the participation of an intermediate product of the expansion reaction of the o-quinone cycle - 5,7-di (tert-butyl)-4-nitro-2-(quinoline-2-yl)-cyclohepta-1,3,5-triene-1,3-diol, which was first isolated preparatively. The DFT/B3LYP/6-311++G** methods were used to determine the thermodynamic stability of tautomeric forms of intermediate products, as well as the relative stability of NH and OH tautomers of 5,7-di (tert-butyl)-2-(quinolin-2-yl)-1,3-tropolone and 5,7-di (tert-butyl)-4-nitro-2-(quinolin-2-yl)-1,3-tropolone.

Immobilization of UiO-67 with photochromic spiropyrans: a quantum chemical study.

Post-synthetic modification of MOFs allows tuning the properties according to desired applications. The incorporation of photoactive molecules introduces sensitivity to radiation properties to the matrix of MOFs. We report on the theoretical analysis of possible ways of construction photoactive MOFs from UiO-67 and spiropyran molecules containing different carbonyl substituents. Large-scale computer modeling with the use of density functional theory method allowed us to select the most energy-efficient schemes of design. It was revealed that the most preferred way of immobilization of UiO-67 is the interaction with the carboxylic group in the indoline fragment of spiropyran. These results are promising for the application of MOFs modified in this way as photoactive sensors. Graphical abstract.

Visible to near-IR molecular switches based on photochromic indoline spiropyrans with a conjugated cationic fragment.

Photochromic molecules which can absorb and emit light within the "biological window" (650-1450 nm) are of great interest for using in various important biomedical applications such as bio-imaging, photopharmacology, targeted drug delivery, etc. Here we present three new indoline spiropyrans containing conjugated cationic fragments and halogen substituents in the 2H-chromene moiety which were synthesized by a simple one-pot method. The molecular structure of the obtained compounds was confirmed by FT-IR, 1H and 13C NMR spectroscopy (including 2D methods), HRMS, elemental and single crystal X-ray analysis. Photochemical studies revealed the photochromic activity of spiropyrans at room temperature which caused photoswitchable fluorescence in the near-IR region after UV-irradiation. While the spirocyclic forms of compounds demonstrated absorption bands in the UV-Vis spectra with maxima in the visible region at about 445 nm and were not fluorescent, the photogenerated merocyanine isomers absorbed in the near-IR range at 708-738 nm and emitted at 768-791 nm. It was found that compound 1a with fluorine substituent possesses the most red-shifted absorption and emission bands of merocyanine form among all the known photochromic spiropyrans with maxima at 738 and 791 nm correspondingly. TD DFT calculations have shown that the longest wavelength absorption maxima of the merocyanine forms correspond to S0-S1 transitions of the isomers with at least one trans-trans-trans-configured vinylindolium fragment which brings them closer to cyanine-like structure and causes an appearance of the absorption and emission bands in the near-IR region.