A Theobromine Derivative with Anticancer Properties Targeting VEGFR‐2: Semisynthesis, in silico and in vitro Studies

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A Theobromine Derivative with Anticancer Properties Targeting VEGFR-2: Semisynthesis, in silico and in vitro Studies

A new theobromine derivative, (T-1-AFPB), was designed as a VEGFR-2 inhibitor. DFT calculations indicated T-1-AFPB’s stability and reactivity. T-1-AFPB’s potential binding and inhibition of VEGFR-2 were indicated by molecular docking, MD simulations, PLIP, MM-GBSA, and PCA studies. T-1-AFPB’s drug likeness was indicated several in silico ADMET investigations. Subsequently, T-1-AFPB was semi-synthesized, and in vitro assays confirmed its potential to inhibit VEGFR-2 and to inhibit the growth of HepG2 and MCF-7 cancer cell lines, displaying very high selectivity indices and inducing apoptosis.


Abstract

A computer-assisted drug design (CADD) approach was utilized to design a new acetamido-N-(para-fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T-1-APFPB), following the pharmacophoric features of VEGFR-2 inhibitors. The stability and reactivity of T-1-AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T-1-AFPB’s potential to bind with and inhibit VEGFR-2. The precise binding of T-1-AFPB against VEGFR-2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM-GBSA, and PCA studies. Then, T-1-AFPB (4-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamido)-N-(4-fluorophenyl)benzamide) was semi-synthesized and the in vitro assays showed its potential to inhibit VEGFR-2 with an IC50 value of 69 nM (sorafenib's IC50 was 56 nM) and to inhibit the growth of HepG2 and MCF-7 cancer cell lines with IC50 values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T-1-AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T-1-AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T-1-APFPB providing it as a promising lead VEGFR-2 inhibitor for further development aiming at cancer therapy.

Exploring the Effects of Various Capping Agents on Zinc Sulfide Quantum Dot Characteristics and In‐vitro Fate

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Exploring the Effects of Various Capping Agents on Zinc Sulfide Quantum Dot Characteristics and In-vitro Fate

The effects of three different commonly employed capping agents; mercaptoethanol (ME), mercaptoacetic acid (MAA), and cysteamine (CA), on the physicochemical and optical characteristics of ZnS QDs, as well as their interactions with cells, were studied. These capping agents were found to have considerable effects on the behavior and properties of ZnS QDs such as stability, cytotoxicity and aggregation. Consequently, it is advisable to select capping agents in accordance with the specific objectives of the research.


Abstract

The choice of capping agents used during the synthesis process of quantum dots (QDs) can significantly influence their fate and fundamental properties. Hence, choosing an appropriate capping agent is a critical step in both synthesis and biomedical application of QDs. In this research, ZnS QDs were synthesized via chemical precipitation process and three commonly employed capping agents, namely mercaptoethanol (ME), mercaptoacetic acid (MAA), and cysteamine (CA), were used to stabilize the QDs. This study was aimed to examine how these capping agents impact the physicochemical and optical characteristics of ZnS QDs, as well as their interactions with biological systems. The findings revealed that the capping agents had considerable effects on the behavior and properties of ZnS QDs. MAA-QD exhibited superior crystal lattice, smaller size, and significant quantum yield (QY). In contrast, CA-QDs demonstrated the lowest QY and the highest tendency for aggregation. ME-QDs exhibited intermediate characteristics, along with an acceptable level of cytotoxicity, rapid uptake by cells, and efficient escape from lysosomes. Consequently, it is advisable to select capping agents in accordance with the specific objectives of the research.

Catalyst‐free Propargylboration of Ketones with Allenyl‐Bpins: Highly Stereoselective Synthesis of tert‐Homopropargyl Alcohols Bearing Vicinal Stereocenters

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A practical and efficient propargylboration of ketones is presented using general allenylboronic acid pinacol esters (allenyl-Bpins) without a catalyst. This reaction is triggered by in-situ activation of stable allenyl-Bpins through the sequential addition of 1.25 equiv. of nBuLi and the prerequisite 2.0 equiv. of TFAA. Under the optimized reaction conditions, the versatile trisubstituted allenyl-Bpins react with various ketones smoothly to afford a wide range of tert-homopropargyl alcohols bearing vicinal stereocenters in high yields with good to excellent diastereoselectivities. Furthermore, propargylboration of ketones with chiral trisubstituted allenyl-Bpins allows for the asymmetric synthesis of chiral tert-homopropargyl alcohols with a full chirality transfer.

Characteristics of the Frustrated Lewis Pairs (FLPs) on the Surface of Albite and the Corresponding Mechanism of H2 Activation

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Characteristics of the Frustrated Lewis Pairs (FLPs) on the Surface of Albite and the Corresponding Mechanism of H2 Activation

In the reaction of H2 activation, the interaction between the HOMO of H2 and the SOMO of LB and the electron acceptance characteristics of LA are the key factors. The activation energy of H2 is the required activation energy from the ground state to the excited state, once the excited state is produced, dissociation adsorption of H2 will occur directly.


Abstract

The characteristics of frustrated Lewis pairs (FLPs) on albite surfaces were analyzed with density functional theory, and the reaction mechanism for H2 activation by the FLPs was studied. The results show that albite is an ideal substrate material with FLPs, and its (001) and (010) surfaces have the typical characteristics of FLPs. In the case of H2 activation, the interaction between the HOMO of H2 and the SOMO of the Lewis base and the electron acceptance characteristics of the Lewis acid are the key factors. In fact, the activation energy of H2 is the required activation energy from the ground state to the excited state, and once the excited state is produced, the dissociative adsorption of H2 will occur directly. This study provides a new ideas and a reference for research on the construction of novel solid FLPs catalysts using ultramicro channel materials.

The Influence of Large Pendent Groups on Chain Anisotropy and Electrical Energy Loss of Polyimides at High Frequency through All‐Atomic Molecular Simulation

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Polyimide is a potential material for high-performance printed circuit boards because of its chemical stability and excellent thermal and mechanical properties. Flexible printed circuit boards must have a low static dielectric constant and dielectric loss to reduce signal loss in high-speed communication devices. Engineering the molecular structure of polyimides with large pendant groups is a strategy to reduce their dielectric constant. However, there is no systematic study on how the large pendant groups influence electrical energy loss. We integrated all-atomic molecular dynamics and semi-empirical quantum mechanical calculations to examine the influence of pendant groups on polymer chain anisotropy and electrical energy loss at high frequencies. We analyzed the radius of gyration, relative shape anisotropy, dipole moment, and degree of polarization of the selected polyimides (TPAHF, TmBPHF, TpBPHF, MPDA, TriPMPDA, m-PDA, and m-TFPDA). The simulation results show that anisotropy perpendicular to chain direction and local chain rigidity correlate to electrical energy loss rather than dipole moment magnitudes. Polyimides with anisotropic pendant groups and significant local chain rigidity reduce electrical energy loss. The degree of polarization correlated well with the dielectric loss with a moderate computational cost, and difficulties in directly calculating the dielectric loss were circumvented.

Shedding Light on Highly Emissive 1,4‐Dihydropyrrolo[3,2‐b]pyrrole Derivatives: Synthesis and Aggregate‐Dependent Emission

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Three tetraaryl-1,4-dihydropyrrolo[3,2-b]pyrrole derivatives containing different number of long alkoxy chains (2, 4 and 6) were synthesized, characterized and applied in Organic Light Emitting Diodes (OLEDs). The compounds showed good emission properties with Photoluminescence Quantum Yields (PLQYs) higher than 80% in solution and 50% in solid state (thin film). The solvatochromism results revealed a pronounced vibronic emission in methylcyclohexane and toluene, characterized by two distinct sharp emission peaks and a small redshift in the following order: methylcyclohexane > toluene > dichloromethane > tetrahydrofuran > acetonitrile. Also, the compounds formed aggregates with redshifted emission, which can be attributed to excimer formation. This phenomenon was observed in solutions containing 90% water and with the concentration variation in methylcyclohexane (MCH). Compounds with a greater number of peripheral chains showed the capacity to keep hexagonal columnar organization in films after fast cooling from liquid state. OLEDs fabricated with these compounds showed turn-on voltages lower than 4.0 V, with luminance higher than 1400 cd.m2, electroluminescence spectra with Full Width at Half Maximum lower than 70 nm and maximum External Quantum Efficiency between 7.2% and 4.3%. Overall, this shows that the 1,4-dihydropyrrolo[3,2-b]pyrrole moiety is promising for applications where luminescence is paramount, as in organic light-emitting devices

Integrating Electron Paramagnetic Resonance Spectroscopy and Computational Modeling to Measure Protein Structure and Dynamics

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Electron paramagnetic resonance (EPR) has become a powerful probe of conformational heterogeneity and dynamics of biomolecules. In this review, we discuss different computational modeling techniques that enrich the interpretation of EPR measurements of dynamics or distance restraints. A variety of spin labels are surveyed to provide a background for the discussion of modeling tools. Molecular dynamics (MD) simulations of models containing spin labels provide dynamical properties of biomolecules and their labels. These simulations can be used to predict EPR spectra, sample stable conformations and sample rotameric preferences of label sidechains. For molecular motions longer than milliseconds, enhanced sampling strategies and de novo prediction software incorporating or validated by EPR measurements are able to efficiently refine or predict protein conformations, respectively. To sample large-amplitude conformational transition, a coarse-grained or an atomistic weighted ensemble (WE) strategy can be guided with EPR insights. Looking forward, we anticipate an integrative strategy for efficient sampling of alternate conformations by de novo predictions, followed by validations by systematic EPR measurements and MD simulations. Continuous pathways between alternate states can be further sampled by WE-MD including all intermediate states.

High throughput selection of organic cathode materials

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High throughput selection of organic cathode materials

To discover new organic cathode materials, 86 million organic structures were screened. Two thousand three hundred six materials are predicted to have a monoelectronic reduction potential higher than 4 V (vs. Li/Li+), while 626 materials reached an energy density higher than 800 Whkg−1. Successful materials were sorted in families, some of them never proposed before.


Abstract

Efficient and affordable batteries require the design of novel organic electrode materials to overcome the drawbacks of the traditionally used inorganic materials, and the computational screening of potential candidates is a very efficient way to identify prospective solutions and minimize experimental testing. Here we present a DFT high-throughput computational screening where 86 million molecules contained in the PUBCHEM database have been analyzed and classified according to their estimated electrochemical features. The 5445 top-performing candidates were identified, and among them, 2306 are expected to have a one-electron reduction potential higher than 4 V versus (Li/Li+). Analogously, one-electron energy densities higher than 800 Whkg−1 have been predicted for 626 molecules. Explicit calculations performed for certain materials show that at least 69 candidates with a two-electron energy density higher than 1300 Whkg−1. Successful molecules were sorted into several families, some of them already commonly used electrode materials, and others still experimentally untested. Most of them are small systems containing conjugated CO, NN, or NC functional groups. Our selected molecules form a valuable starting point for experimentalists exploring new materials for organic electrodes.