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.

Accurate prediction of 11B NMR chemical shift of BODIPYs via machine learning.

In this article, we present the results of developing a model based on an RFR machine learning method using the ISIDA fragment descriptors for predicting the 11B NMR chemical shift of BODIPYs. The model is freely available at https://ochem.eu/article/146458. The model demonstrates the high quality of predicting the 11B NMR chemical shift (RMSE, 5CV (FINALE training set) = 0.40 ppm, RMSE (TEST set) = 0.14 ppm). In addition, we compared the "cost" and the user-friendliness for calculations using the quantum-chemical model with the DFT/GIAO approach. The 11B NMR chemical shift prediction accuracy (RMSE) of the model considered is more than three times higher and tremendously faster than the DFT/GIAO calculations. As a result, we provide a convenient tool and database that we collected for all researchers, that allows them to predict the 11B NMR chemical shift of boron-containing dyes. We believe that the new model will make it easier for researchers to correctly interpret the 11B NMR chemical shifts experimentally determined and to select more optimal conditions to perform an NMR experiment.

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).

Donor-Acceptor Complexes of (5,10,15,20-Tetra(4-methylphenyl)porphyrinato)cobalt(II) with Fullerenes C60: Self-Assembly, Spectral, Electrochemical and Photophysical Properties.

The noncovalent interactions of (5,10,15,20-tetra(4-methylphenyl)porphinato)cobalt(II) (CoTTP) with C60 and 1-N-methyl-2-(pyridin-4-yl)-3,4-fullero[60]pyrrolidine (PyC60) were studied in toluene using absorption and fluorescence titration methods. The self-assembly in the 2:1 complexes (the triads) (C60)2CoTTP and (PyC60)2CoTTP was established. The bonding constants for (C60)2CoTTP and (PyC60)2CoTTP are defined to be (3.47 ± 0.69) × 109 and (1.47 ± 0.28) × 1010 M-2, respectively. 1H NMR, IR spectroscopy, thermogravimetric analysis and cyclic voltammetry data have provided very good support in favor of efficient complex formation in the ground state between fullerenes and CoTTP. PyC60/C60 fluorescence quenching in the PyC60/C60-CoTTP systems was studied and the fluorescence lifetime with various CoTTP additions was determined. The singlet oxygen quantum yield was determined for PyC60 and the intensity decrease in the 1O2 phosphorescence for C60 and PyC60 with the CoTTP addition leading to the low efficiency of intercombination conversion for the formation of the 3C60* triplet excited state was found. Using femtosecond transient absorption measurements in toluene, the photoinduced electron transfer from the CoTTP in the excited singlet state to fullerene moiety was established. Quantum chemical calculations were used for the determination of molecular structure, stability and the HOMO/LUMO energy levels of the triads as well as to predict the localization of frontier orbitals in the triads.

Amine-Reactive BODIPY Dye: Spectral Properties and Application for Protein Labeling.

A boron-dipyrromethene (BODIPY) derivative reactive towards amino groups of proteins (NHS-Ph-BODIPY) was synthesized. Spectroscopic and photophysical properties of amine-reactive NHS-Ph-BODIPY and its non-reactive precursor (COOH-Ph-BODIPY) in a number of organic solvents were investigated. Both fluorescent dyes were characterized by green absorption (521-532 nm) and fluorescence (538-552 nm) and medium molar absorption coefficients (46,500-118,500 M-1·cm-1) and fluorescence quantum yields (0.32 - 0.73). Solvent polarizability and dipolarity were found to play a crucial role in solvent effects on COOH-Ph-BODIPY and NHS-Ph-BODIPY absorption and emission bands maxima. Quantum-chemical calculations were used to show why solvent polarizability and dipolarity are important as well as to understand how the nature of the substituent affects spectroscopic properties of the fluorescent dyes. NHS-Ph-BODIPY was used for fluorescent labeling of a number of proteins. Conjugation of NHS-Ph-BODIPY with bovine serum albumin (BSA) resulted in bathochromic shifts of absorption and emission bands and noticeable fluorescence quenching (about 1.5 times). It was demonstrated that the sensitivity of BSA detection with NHS-Ph-BODIPY was up to eight times higher than with Coomassie brilliant blue while the sensitivity of PII-like protein PotN (PotN) detection with NHS-Ph-BODIPY and Coomassie brilliant blue was almost the same. On the basis of the molecular docking results, the most probable binding sites of NHS-Ph-BODIPY in BSA and PotN and the corresponding binding free energies were estimated.

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.

Can machine learning methods accurately predict the molar absorption coefficient of different classes of dyes?

In this article, we provide a convenient tool for all researchers to predict the value of the molar absorption coefficient for a wide number of dyes without any computer costs. The new model is based on RFR method (ALogPS, OEstate + Fragmentor + QNPR) and is able to predict the molar absorption coefficient with an accuracy (5-fold cross-validation RMSE) of 0.26 log unit. This accuracy was achieved due to the fact that the model was trained on data for more than 20,000 unique dye molecules. To our knowledge, this is the first model for predicting the molar absorption coefficient trained on such a large and diverse set of dyes. The model is available at https://ochem.eu/article/145413. We hope that the new model will allow researchers to predict dyes with practically significant spectral characteristics and verify existing experimental data.

Diclofenac Ion Hydration: Experimental and Theoretical Search for Anion Pairs.

Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium.

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.

Deep neural network model for highly accurate prediction of BODIPYs absorption.

A possibility to accurately predict the absorption maximum wavelength of BODIPYs was investigated. We found that previously reported models had a low accuracy (40-57 nm) to predict BODIPYs due to the limited dataset sizes and/or number of BODIPYs (few hundreds). New models developed in this study were based on data of 6000-plus fluorescent dyes (including 4000-plus BODIPYs) and the deep neural network architecture. The high prediction accuracy (five-fold cross-validation room mean squared error (RMSE) of 18.4 nm) was obtained using a consensus model, which was more accurate than individual models. This model provided the excellent accuracy (RMSE of 8 nm) for molecules previously synthesized in our laboratory as well as for prospective validation of three new BODIPYs. We found that solvent properties did not significantly influence the model accuracy since only few BODIPYs exhibited solvatochromism. The analysis of large prediction errors suggested that compounds able to have intermolecular interactions with solvent or salts were likely to be incorrectly predicted. The consensus model is freely available at https://ochem.eu/article/134921 and can help the other researchers to accelerate design of new dyes with desired properties.

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.

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+.