Effect of meso-substituents and medium properties on the photo- and pH-stability, penetration efficiency into bacterial and microscopic fungi cells of terpene-BODIPY conjugates.

In order to expand the arsenal of tools and areas for practical use of BODIPY dyes as bifunctional fluorescent theranostics, we studied the effect of the meso-substituents nature and medium properties on photo- and pH-stability, efficiency of singlet oxygen generation, and affinity to biostructures of terpene-BODIPY conjugates. The BODIPYs fused with myrtenol or thiotherpenoid via carboxylic acid residues exhibit high stability over a wide pH range and the presence of a bulky substituent at the meso-position of BODIPY conjugates increases their photostability two-fold compared to structurally related meso-unsubstituted analogues. Furthermore, the photodegradation rate of the conjugates directly depends on their ability to generate singlet oxygen and the course probability of the corresponding red-ox reactions involving reactive oxygen species. The conjugate of BODIPY with a thiotherpenoid demonstrated high ability to penetrate the membranes of filamentous and yeast-like fungi and bind to membrane of organelles in the fungal cell. At the same time, this compound also had a high ability to penetrate into biofilms of Staphylococcus aureus and Klebsiella pneumoniae and into bacterial cells within the matrix, which makes this compound promising for staining intracellular structures of eukaryotic cells and bacteria embedded into biofilms.

Unraveling the Mechanism of Platelet Aggregation Suppression by Thioterpenoids: Molecular Docking and In Vivo Antiaggregant Activity.

Natural monoterpenes and their derivatives are widely considered the effective ingredients for the design and production of novel biologically active compounds. In this study, by using the molecular docking technique, we examined the effects of two series of "sulfide-sulfoxide-sulfone" thioterpenoids containing different (e.g., bornane and pinane) monoterpene skeletons on the platelet's aggregation. Our data revealed that all the synthesized compounds exhibit inhibitory activities on platelet aggregation. For example, compound 1 effectively inhibited platelet activation and demonstrated direct binding with CD61 integrin, a well-known platelet GPIIb-IIIa receptor on platelets. We further examined the antiaggregant activity of the most active compound, 1, in vivo and compared its activity with that of acetylsalicylic acid and an oral GPIIb-IIIa blocker, orbofiban. We found that compound 1 demonstrates antiaggregant activity in rats when administered per os and its activity was comparable with that of acetylsalicylic acid and orbofiban. Moreover, similarly, tirofiban, a well-known GPIIb-IIIa blocker, compound 1, effectively decreased the expression of P-selectin to the values similar to those of the intact platelets. Collectively, here, we show, for the first time, the potent antiaggregant activity of compound 1 both in vitro and in vivo due to its ability to bind with the GPIIb-IIIa receptor on platelets.

XPS and quantum chemical analysis of 4Me-BODIPY derivatives.

The results of a X-ray photoelectron spectroscopy (XPS) and steady-state absorption spectroscopy study of the electronic structure, and cationic and excited states of a series of 1,3,5,7-tetramethyl-substituted BODIPYs (4Me,2R-BODIPYs) are presented. The experimental data were interpreted using high-level ab initio quantum chemical computations, including the algebraic diagrammatic construction method for the polarization propagator of the second order (ADC(2)), the outer-valence Green's function (OVGF) method, the density functional (DFT) approach, and the time-dependent DFT (TD-DFT) approach. Substitution effects on the XPS and absorption spectra were determined for 2,6-positions of 4Me,2R-BODIPY pyrrole nuclei (R = H, Br, Bu, benzyl). A very satisfactory performance of the DFT Koopmans theorem analogue was demonstrated with respect to the energy intervals between the electronic levels of 4Me,2R-BODIPY above 13 eV (BHHLYP functional) and the values of the HOMO-LUMO energy gap (ωB97X functional).

Increasing the Efficacy of Treatment of Staphylococcus aureus-Candida albicans Mixed Infections with Myrtenol.

Infectious diseases caused by various nosocomial microorganisms affect worldwide both immunocompromised and relatively healthy persons. Bacteria and fungi have different tools to evade antimicrobials, such as hydrolysis damaging the drug, efflux systems, and the formation of biofilm that significantly complicates the treatment of the infection. Here, we show that myrtenol potentiates the antimicrobial and biofilm-preventing activity of conventional drugs against S. aureus and C. albicans mono- and dual-species cultures. In our study, the two optical isomers, (-)-myrtenol and (+)-myrtenol, have been tested as either antibacterials, antifungals, or enhancers of conventional drugs. (+)-Myrtenol demonstrated a synergistic effect with amikacin, fluconazole, and benzalkonium chloride on 64-81% of the clinical isolates of S. aureus and C. albicans, including MRSA and fluconazole-resistant fungi, while (-)-myrtenol increased the properties of amikacin and fluconazole to repress biofilm formation in half of the S. aureus and C. albicans isolates. Furthermore, myrtenol was able to potentiate benzalkonium chloride up to sixteen-fold against planktonic cells in an S. aureus-C. albicans mixed culture and repressed the adhesion of S. aureus. The mechanism of both (-)-myrtenol and (+)-myrtenol synergy with conventional drugs was apparently driven by membrane damage since the treatment with both terpenes led to a significant drop in membrane potential similar to the action of benzalkonium chloride. Thus, due to the low toxicity of myrtenol, it seems to be a promising agent to increase the efficiency of the treatment of infections caused by bacteria and be fungi of the genus Candida as well as mixed fungal-bacterial infections, including resistant strains.

Thioterpenoids as Potential Antithrombotic Drugs: Molecular Docking, Antiaggregant, Anticoagulant and Antioxidant Activities.

Natural monoterpenes and their derivatives are widely considered as effective ingredients for the design and production of new biologically active compounds with high antioxidant, antimicrobial and anti-protozoa properties. In this study, we synthesized two series of thiotherpenoids "sulfide-sulfoxide-sulfone", with different bicyclic monoterpene skeleton (bornane and pinane) structures. The effect of the obtained compounds on platelet aggregation was investigated by using the molecular docking technique. The obtained data revealed that all the synthesized compounds may act as potential inhibitors of platelet aggregation. Moreover, the studied sulfides have shown high antioxidant activity as revealed by lipid peroxidation (LPO) process inhibition in a non-cellular substrate containing animal lipids. The sulfides were able to inhibit erythrocyte oxidative hemolysis, to reduce the accumulation of secondary LPO products in cells and to prevent the oxidation of native oxyhemoglobin. Additionally, the corresponding sulfones and sulfoxides exhibited insignificant antioxidant activity. However, the sulfides were found to exhibit significant antiaggregant and anticoagulant effects. These findings suggest as well that the sulfides could serve as a leader compound for future research and possible practical applications.

Dataset for the Synthesis of Boron-Dipyrrin Dyes, their fluorescent properties, their interaction with proteins, Triton-X-based surfactants, and micellar clusterization approaches to validation based on fluorescent dyes.

The data presented here refer to the research article by Aleksei V. Solomonov, Yuriy S. Marfin, Alexander B. Tesler, Dmitry A. Merkushev, Elizaveta A. Bogatyreva, Elena V. Antina, Evgeniy V. Rumyantsev, and Ulyana Shimanovich "Spanning BODIPY fluorescence with self-assembled micellar clusters", Colloids and Surfaces B: Biointerfaces, 216, 2022, 112532. The present article provides details on optical characterization for a set of meso- and tetra-substituted boron-dipyrrin (BODIPY) complexes encapsulated inside of self-assembled Triton-X-based micellar coordination clusters (MCCs), based on Triton-X family surfactants. Changes in the optical properties of the BODIPY complexes upon interaction with bovine serum albumin, in a binary mixture of THF:H2O and titrated with Triton TX-114, were evaluated. The optical properties and the formation kinetics of the BODIPY-based MCCs and the BODIPY-supported micelle chelator aggregates (MCAs) are presented as well. The presented data provide additional insights into the structural and formation aspects of both the traditional and newly obtained micellar coordination clusters for their future optimization, control, and application. The synthetic procedures for the synthesis of a set of meso- and tetra-substituted BODIPY complexes and their optical properties in different media are also presented. The research is related to the paper (Solomonov et al., 2022).

Spanning BODIPY fluorescence with self-assembled micellar clusters.

BODIPY dyes possess favorable optical properties for a variety of applications including in vivo and in vitro diagnostics. However, their utilization might be limited by their water insolubility and incompatibility with chemical modifications, resulting in low aggregation stability. Here, we outline the route for addressing this issue. We have demonstrated two approaches, based on dye entrapment in micellar coordination clusters (MCCs); this provides a general solution for water solubility as well as aggregation stability of the seven BODIPY derivatives. These derivatives have various bulky aromatic substituents in the 2,3,5,6- and meso-positions and can rotate relative to a dipyrrin core, which also provides molecular rotor properties. The molecular structural features and the presence of aromatic groups allows BODIPY dyes to be used as "supporting molecules", thus promoting micelle-micelle interaction and micellar network stabilization. In the second approach, self-micellization, following BODIPY use, leads to MCC formation without the use of any mediators, including chelators and/or metal ions. In both approaches, BODIPY exhibits an excellent optical response, at a concentration beyond its solubilization limit in aqueous media and without undesired crystallization. The suggested approaches represent systems used to encapsulate BODIPY in a capsule-based surfactant environment, enabling one to track the aggregation of BODIPY; these approaches represent an alternative system to study and apply BODIPY's molecular rotor properties. The stabilized compounds, i.e., the BODIPY-loaded MCCs, provide a unique feature of permeability to hydrophilic ligand-switching proteins such as BSA; they exhibit a bright "turn-on" fluorescence signal within the clusters via macromolecular complexation, thus expanding the possibilities of water-soluble BODIPY-loaded MCCs utilization for functional indicators.

Design, Spectral Characteristics, Photostability, and Possibilities for Practical Application of BODIPY FL-Labeled Thioterpenoid.

This paper presents the design and a comparative analysis of the structural and solvation factors on the spectral and biological properties of the BODIPY biomarker with a thioterpene fragment. Covalent binding of the thioterpene moiety to the butanoic acid residue of meso-substituted BODIPY was carried out to find out the membranotropic effect of conjugate to erythrocytes, and to assess the possibilities of its practical application in bioimaging. The molecular structure of the conjugate was confirmed via X-ray, UV/vis-, NMR-, and MS-spectra. It was found that dye demonstrates high photostability and high fluorescence quantum yield (to ~100%) at 514-519 nm. In addition, the marker was shown to effectively penetrate the erythrocytes membrane in the absence of erythrotoxicity. The conjugation of BODIPY with thioterpenoid is an excellent way to increase affinity dyes to biostructures, including blood components.

Aggregation behavior and spectroscopic properties of red-emitting distyryl-BODIPY in aqueous solution, Langmuir-Schaefer films and Pluoronic® F127 micelles.

Red-emitting distyryl substituted BODIPY dyes are among the most promising luminophors for bioimaging and optics applications. However, the practical application of BODIPYs is limited due to their high hydrophobicity and tendency to aggregate in aqueous organic solutions and solid phase. In this article, we propose an elegant solution to this problem. To this end, we carried out the detailed experimental and quantum-chemical study of the structural and spectral features of BF2-ms-phenyl-5,5'-bis(4-dimethylaminostyryl)-3,3'-dimethyl-2,2'-dipyrromethene (distyryl-BDP). The particular attention was paid to analysis of high sensitivity of the distyryl-BDP spectral characteristics to the solvent properties, and also the aggregation behavior features both in water-organic media and in mono- and multilayer Langmuir-Schaefer films. We selected the best conditions to obtain the hydrophilic micellar structures of distyryl-BDP with Pluronic® F127 having a high efficiency of dye solubilization. This method increasing the solubility improves the distyryl-BDP transport efficiency in physiological aqueous media. The aqueous solutions of distyryl-BDP-Pl micelles show the intense fluorescence in the phototherapy window region (λfl = 739 nm).

Unraveling the Mechanism of Platelet Aggregation Suppression by Monoterpenoids.

Platelet aggregation causes various diseases and therefore challenges the development of novel antiaggregatory drugs. In this study, we report the possible mechanism of platelet aggregation suppression by newly synthesized myrtenol-derived monoterpenoids carrying different heteroatoms (sulphur, oxygen, or nitrogen). Despite all tested compounds suppressed the platelet aggregation in vitro, the most significant effect was observed for the S-containing compounds. The molecular docking confirmed the putative interaction of all tested compounds with the platelet's P2Y12 receptor suggesting that the anti-aggregation properties of monoterpenoids are implemented by blocking the P2Y12 function. The calculated binding force depended on heteroatom in monoterpenoids and significantly decreased with the exchanging of the sulphur atom with oxygen or nitrogen. On the other hand, in NMR studies on dodecyl phosphocholine (DPC) as a membrane model, only S-containing compound was found to be bound with DPC micelles surface. Meanwhile, no stable complexes between DPC micelles with either O- or N-containing compounds were observed. The binding of S-containing compound with cellular membrane reinforces the mechanical properties of the latter, thereby preventing its destabilization and subsequent clot formation on the phospholipid surface. Taken together, our data demonstrate that S-containing myrtenol-derived monoterpenoid suppresses the platelet aggregation in vitro via both membrane stabilization and blocking the P2Y12 receptor and, thus, appears as a promising agent for hemostasis control.

Effects of ms-aryl substitution on the structure and spectral properties of new CH(Ar)-bis(BODIPY) luminophores.

In this article, we present synthesis, spectral characteristics, and results of DFT calculations of new CH(R)-bis(BODIPY) 1-3. They are characterized by the conformational mobility and sensitivity of fluorescence to polarity, proton-, electron donor ability and viscosity of the solvation environment. It is shown that fluorescence intensity of 1-3 increases in the homologous series of alcohols (ethanol, 1-propanol, 1-butanol, 1-octanol, 1-decanol) mainly due to decrease of medium acidic properties. The viscosity of the medium effects on the 1-3 fluorescence in a lesser degree. Compared to 1 and 2, the 3 is the most sensitive towards viscosity both in low-viscosity homologous alcohols and in high-viscosity ethanol-glycerol mixtures. In this regard, the sensitivity of fluorescence of CH(MeOPh)-bis(BODIPY) (compound 3) to the viscosity was studied in binary mixtures of polar DMF and low-polarity toluene with castor and vaseline oils, as well as to the macroviscosity of the solvate environment in mixtures of toluene with polystyrene. Prospects of the practical application of CH(R)-bis(BODIPY)s are proposed for the analysis of polarity, proton-donor properties and viscosity of the medium.

Conjugate of meso-carboxysubstituted-BODIPY with thioterpenoid as an effective fluorescent probe: Synthesis, structure, spectral characteristics, and molecular docking.

This paper is devoted to the design of a fluorescent probe based on meso-carboxysubstituted-BODIPY with a thioterpene fragment. The functional replacement of the methoxy group in the BODIPY molecule on a thioterpene fragment was carried out in order to find out the antiplatelet and anticoagulant action mechanisms of thioterpenoids and to assess the membrane and receptor factors contributions. The molecular structure of the conjugate was confirmed via UV/vis-, NMR- and MS-spectra. It is found that the probe is a high fluorescence quantum yield (to âˆ¼ 100%) in the blue-green region at 509-516 nm. Molecular docking of all studied molecules showed that the BODIPY with terpenoid conjugation is an excellent way to increase their affinity to platelet receptor P2Y12.

A New «off-on¼ Fluorescence Zinc Ion Sensors Based on Iodo- and Bromosubstituted Dipyrromethenes.

Monoiodo- and dibromsubstituted dipyrromethenes HL1 - HL3 were described as a highly sensitive and selective «Off-On¼ fluorescent chemosensor for Zn2+ based on the chelation-enhanced fluorescence (CHEF) effect. Сoordination reactions of HL1 - HL3 with Zn2+ cations are accompanied by a significant (124 to 215-fold) increase in fluorescence intensity against the background of other metal ions in the binary propanol-1/cyclohexane mixture (1:30). The fluorometric detection limit of Zn2+ ions using HL1 - HL3 sensors is from 3.0∙10-8 to 3.3·10-9 mol/L. The presence of Na+, K+, Ca2+, Mg2+, Mn2+, Ni2+, Co2+, Pb2+ cations does not interfere with the detection of Zn2+. Complexation reactions are accompanied by a visual change in the color of the solution from yellow-orange to pink-raspberry so that the HL1 - HL3 ligands can also be used as a «naked-eye¼ indicators of the presence of Zn2+ ions.

Design, Spectral Characteristics, and Possibilities for Practical Application of BODIPY FL-Labeled Monoterpenoid.

This article describes the design and biological properties of a BODIPY FL-labeled monoterpenoid BF2-meso-(4-((1″R)-6″,6″-dimethylbicyclo[3.1.1]hept-2″-ene-2″)yl-methoxycarbonylpropyl)-3,3',5,5'-tetramethyl-2,2'-dipyrromethene conjugate (BODIPYmyrt). The fluorophore was characterized using X-ray, NMR, MS, and UV/vis spectroscopy. The conjugate exhibits a high quantum yield (to ∼100%) in the region 515-518 nm. BODIPYmyrt effectively penetrates the membranes of the bacterial and fungal cells and therefore can be used to examine the features of a broad spectrum of Gram-positive and Gram-negative bacteria and pathogenic fungi as well. Moreover, BODIPYmyrt exhibits a moderate tropism to the subcellular structures in mammalian cells (e.g., mitochondria), thereby providing an attractive scaffold for fluorophores to examine these particular organelles.

Effect of Aryl-, Halogen-, and Ms-Aza-Substitution on the Luminescent Properties and Photostability of Difluoroborates of 2,2'-Dipyrrometenes.

Boron(III) complexes with alkyl-, phenyl-, and halogen-substituted 2,2'-dipyrromethenes (BODIPY) and meso-aza-dipyrrometenes (ms-aza-BODIPY) were synthesized. The structure relationship of the obtained coordination compounds with their luminescent characteristics is analyzed. Arylated BODIPY, in contrast to alkyl-substituted analogs, is more sensitive to interparticle interactions with a solvent, causing a decrease in the quantum yield by up to 40%. The introduction of phenyl substituents into the BODIPY molecule shifts the first absorption band bathochromic, significantly (32-37 nm) increases the Stokes shift in the emission spectrum, but reduces the probability of the S0 → S1 electronic transition as compared to alkylated complexes. Replacing the methine carbon atom with nitrogen leads to quenching of ms-aza-BODIPY fluorescence compared to BODIPY up to 5-20%. The stability of 2,2'-dipyrromethenes difluoroborates to oxidative destruction under the influence of UV irradiation in cyclohexane solutions was evaluated. It has been shown that symmetric aryl substitution in pyrrole cycles of dipyrromethene significantly increases the photostability of the corresponding compounds as compared to alkyl-substituted analogs and is an effective method of obtaining boron (III) dipyrromethenates with practically useful properties. It has been established that the replacement of the methin ms-spacer of dipyrromethene by a nitrogen atom significantly reduces the photostability of ms-aza-dipyrromethenates of boron. Halogenation of ß-positions of pyrrole cycles by a factor of 5-8 reduces the photostability of difluoroborates ms-aza-dipyrromethenes in comparison with a non-halogenated analogue.

Luminescent properties of new 2,2-, 2,3- and 3,3-CH2-bis(BODIPY)s dyes: Structural and solvation effects.

In this paper the synthesis and spectral properties of three new dimeric bis(BODIPY)s with two indacene domains connected by a methylene (-CH2-) spacer at 2,2-, 2,3- or 3,3- positions were reported. It was found bis(BODIPY)s exhibit a high sensitivity of fluorescence to the medium properties. To interpret solvatochromic effects of bis(BODIPY)s, a multilinear correlation analysis of bis(BODIPY)s fluorescence quantum yields with respect to solvent different parameters was carried out. To understand the features of the spectral properties of bis(BODIPY)s, we carried out a thorough quantum-chemical analysis of the structural, conformational, and spectral characteristics of bis(BODIPY)s. The obtained bis(BODIPY)s have a high potential for application as sensors of medium polarity.

Novel Zinc(II) Bis(Dipyrromethenate)-Doped Ethyl Cellulose Sensors for Acetone Vapor Fluorescence Detection.

In this paper, we report on the results of spectrofluorimetric study of new fluorescent sensor based on [Zn2L2] doped in ethyl cellulose. The sensor optical signal is based on the rapid fluorescence quenching in the presence of acetone vapor. The acetone vapor detection limit in a gas mixture by means of sensor based on [Zn2L2] doped in ethyl cellulose is 1.68 ppb. Being highly sensitive to the acetone acetone presence, instant in response and easy to use, the sensor can find an application for the noninvasive diagnostics of diabetes as well as for the monitoring of the content of acetone acetone in the air at industrial and laboratory facilities. Graphical Abstract.

Synthesis and Photochemical Properties of 2,3;5,6-bis(cyclohexano)-BODIPY.

The boron-dipyrromethene (BODIPY) dye containing an annelated cyclohexyl rings at the 2,3 and 5,6-positions of pyrroles has been synthesized and characterized. Photochemical properties of the obtained compound have been investigated in different individual solvents. 2,3;5,6-Bis(cyclohexano)-BODIPY exhibits intense chromophore properties with maximum of S o → S 1 band in the 543-549 nm (A from 66000 to 96000 L/mol·cm). The complex is a fluorophore with a quantum yield up to ~ 100%. The influence of solvent polarity on the spectral properties was evaluated. To better understand the spectroscopic results, quantum chemical calculations were carried out. Photostability of dye was studied.Graphical Abstract.

Influence of structural and solvation factors on the spectral-fluorescent properties of alkyl-substituted BODIPYs in solutions.

The spectral-fluorescent properties of alkyl-substituted BODIPYs 1-5 in organic solvents were investigated. The alkyl-substituted BODIPYs 1-5 exhibit intense chromophoric properties (lgε=4.60-5.00). Relative fluorescence quantum yield of studied compounds reaches 66-100% and weakly dependent on the structural and solvation effects. Introduction of methyl, propyl, amyl and heptyl substituents in the 2,6-positions of the pyrroles the results in a significant red shift (22-29nm) in the electronic absorption and fluorescence spectra.

A New Sensitive and Selective Off-On Fluorescent Zn2+ Chemosensor Based on 3,3',5,5'-Tetraphenylsubstituted Dipyrromethene.

3,3',5,5'-Tetraphenyl-2,2'-dipyrromethene was described as a highly sensitive and selective Off-on fluorescent colorimetric chemosensor for Zn2+ based on the chelation-enhanced fluorescence (CHEF) effect. The reaction of dipyrromethene ligand with Zn2+ induces the formation of the [ZnL2] complex, which exhibits the increasing fluorescence in 120 fold compared with ligand in the propanol-1/cyclohexane (1:30) binary mixture. The Zn2+ detection limit was 1.4 × 10-7 М. The UV-Vis and fluorescence spectroscopic studies demonstrated that the dipyrromethene sensor was highly selective toward Zn2+ cations over other metal ions (Na+, Mg2+, Co2+, Ni2+, Fe3+, Cu2+, Mn2+, Cd2+ and Pb2+), excluding Hg2+.