Preliminary Biological Studies Research Articles

Complexation by γ-cyclodextrin as a way of improving anticancer potential of sumanene

Biological applications of sumanene buckybowl molecule have been widely discussed over the years yet remain still unexplored experimentally. On the other hand, creating cyclodextrin-containing supramolecular assemblies was demonstrated to be a powerful tool in terms of designing effective systems for medicinal chemistry purposes. Here, we show that sumanene molecule exclusively forms 1:1 host-guest complexes with γ-cyclodextrin (γCD) or (2-hydroxypropyl)-γ-cyclodextrin (HP-γCD), as revealed by extensive spectroscopic studies supported with density functional theory (DFT) computations. Based on our preliminary biological studies, we discovered that the formation of such complexes resulted in the improvement of anticancer properties of sumanene, expressed by high cell viabilities in vitro of healthy human mammary fibroblasts (HMF) together with low viabilities of human breast adenocarcinoma cells (MDA-MB-231). Improved pharmacokinetic (ADME-Tox) properties for sumanene@γCD and sumanene@HP-γCD complexes in comparison to native sumanene were also supported by in sillico modeling studies. This work provides the method how to focus the cytotoxic action of sumanene toward cancer cells using supramolecular assembly strategy, paving the way to the further exploration of biological properties of sumanene-containing supramolecular systems with bioactive features and applications of this buckybowl in general.

A single‐step synthesis of 5,6‐dihydropyrrolo[2,1‐a]isoquinolines and evaluation of their anti‐leukemic activity

AbstractWhile a pharmaceutically intriguing scaffold, 5,6‐dihydropyrrolo[2,1‐a]isoquinoline (DHPIQ), has precedently been prepared from diverse tetrahydroisoquinolines (THIQs) using elaborate conditions, convenient metal‐free methods were discovered from condensation of cyanomethylene‐THIQ (1) and α‐halo‐ketones or aldehydes (1a) to afford 15 DHPIQs (2–16) in moderate yields by employing unique reactivities of the secondary amine and α‐carbon to the nitrile of 1. Preliminary biological studies with chronic myelogenous leukemia K562 and adriamycin‐resistant K562 (K562/ADM) cells exhibited some of the DHPIQs tested were active in the both cell lines. In particular, cyclohexyl‐fused DHPIQ (10) showed GI50 values of 9.79 and 13.60 μM in K562 and K562/ADM cells, respectively. Based on the flow cytometry analysis of 10, the anti‐cancer activity could be from apoptosis‐related mechanisms. Overall, this DHPIQ scaffold may be further optimized to discover clinically meaningful anti‐leukemic agents overcoming adriamycin resistance.

Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment.

Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ-metronidazole; MCZ-miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.

Construction of Highly Functionalized 2-Styrylfurans by N-Heterocyclic Carbene/Brønsted Acid Catalysis.

This research presents an original method for synthesizing styrylfurans using N-heterocyclic carbenes (NHCs) and Brønsted acid catalysis. By exploiting 2,4-dioxoesters as conjugated 1,3-dicarbonyls, we have developed a technique allowing the efficient formation of highly functionalized styrylfurans with interesting photochemical properties, through a NHC-catalyzed cross-benzoin reaction followed by a Brønsted acid-driven Paal-Knorr-like condensation. This approach permits the integration of various substituents on the furan ring, with preliminary biological studies indicating potential as fluorescent dyes.

Influence of nanosecond laser surface patterning on dental 3Y-TZP: Effects on the topography, hydrothermal degradation and cell response

ObjectivesLaser surface micropatterning of dental-grade zirconia (3Y-TZP) was explored with the objective of providing defined linear patterns capable of guiding bone-cell response. MethodsA nanosecond (ns-) laser was employed to fabricate microgrooves on the surface of 3Y-TZP discs, yielding three different groove periodicities (i.e., 30, 50 and 100 µm). The resulting topography and surface damage were characterized by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). X-Ray diffraction (XRD) and Raman spectroscopy techniques were employed to assess the hydrothermal degradation resistance of the modified topographies. Preliminary biological studies were conducted to evaluate adhesion (6 h) of human mesenchymal stem cells (hMSC) to the patterns in terms of cell number and morphology. Finally, Staphylococcus aureus adhesion (4 h) to the microgrooves was investigated. ResultsThe surface analysis showed grooves of approximately 1.8 µm height that exhibited surface damage in the form of pile-up at the edge of the microgrooves, microcracks and cavities. Accelerated aging tests revealed a slight decrease of the hydrothermal degradation resistance after laser patterning, and the Raman mapping showed the presence of monoclinic phase heterogeneously distributed along the patterned surfaces. An increase of the hMSC area was identified on all the microgrooved surfaces, although only the 50 µm periodicity, which is closer to the cell size, significantly favored cell elongation and alignment along the grooves. A decrease in Staphylococcus aureus adhesion was observed on the investigated micropatterns. SignificanceThe study suggests that linear microgrooves of 50 µm periodicity may help in promoting hMSC adhesion and alignment, while reducing bacterial cell attachment.

D,L-Citrullinato-bipyridine Copper Complex: Experimental and Theoretical Characterization

Citrulline is a non-protein amino acid that acts as a metabolic intermediate in the urea cycle and arginine synthesis. It is present in some foods, although its name derives from watermelon (Citrullus vulgaris), from which it was first identified. Under normal conditions, Citrulline exists as a zwitterion in aqueous solutions since its carboxylic and amine groups can act as Lewis donors to chelate metal cations. In addition, Citrulline possesses in the aliphatic chain a terminal ureide group, which could also coordinate. Although Citrulline is comparable to other classical amino acids, its coordination chemistry has yet to be explored. Only two metal complexes have been reported, and the copper complex is a polymeric and insoluble material. As part of our search for active Casiopeina® analogs, we created a more soluble complex by combining 2,2′-Bipyridine into a new mixed material, resulting in the mononuclear complex [Cu(Bipy)(Citr)(H2O)(NO3)]·H2O. Single-crystal X-ray diffraction, spectroscopic methods (FT-IR, UV-Vis, Raman), and mass spectrometry characterized the material. Interestingly, both isomers of Citrulline, R(D), and S(L) are present in the same crystal. In addition, the molecular structure and electronic properties of the complex were calculated using density functional theory (DFT). Non-covalent interactions were characterized using the atoms-in-molecules (AIM) approach and Hirshfeld surface (HS) analysis. This ternary complex containing Citrulline and 2,2′-Bipyridine will be used for docking calculations and preliminary biological studies using calf thymus DNA (CT-DNA) and plasmid pUC19 as a first approximation to cytotoxic activity against cancer cell lines.

One-Pot Three Component Synthesis of Quinazolin-4(3H)-One Derivatives: Investigation of Photophysical Properties and FRET Application toward Protein Lysozyme

A one-pot, three-component reaction between isatoic anhydride, 1,3-diketones, and amines/arylhydrazines catalyzed by a combination of molecular I2 and Et3N in open-air affords a series of quinazolin-4(3H)-one derivatives in good yield. The protocol offers an operationally simple, facile, and cost-effective pathway utilizing easily accessible reagents under mild reaction conditions with significant substrate scope. The results of steady state and time-resolved absorption and emission spectroscopy indicate the potential of quinazolin-4(3H)-one derivatives as a fluorescence probe. They exhibit unique photophysical responses in different solvent environments. In addition, they can also act as FRET acceptors during interaction with protein lysozyme. Preliminary biological studies indicate that quinazolin-4(3H)-ones are cell permeable and can be used as a fluorescent probe for bio-imaging of human cervical cancer (HeLa) cells.

Nanonized carbamazepine for nose-to-brain delivery: pharmaceutical formulation development

Epilepsy is one of the most common neurological disorders in the world. The therapeutic treatment is challenging since conventional drugs have limited efficacy and several side effects that impair patient management. Efforts are being made to find innovative strategies to control epileptic seizures. Intranasal administration provides a convenient route to deliver the drug to the brain. Carbamazepine (CBZ) is an anticonvulsant characterized by poor water solubility, nanonization can improve its bioavailability. Therefore, the design of CBZ nanocrystals (NCs) was assessed to obtain a formulation suitable for nose-to-brain delivery. CBZ NCs were prepared by sonoprecipitation following the Quality by Design approach identifying the impact of process and formulation variables on the critical quality attributes of the final product. The formulation was characterized by a technological point of view (thermotropic behavior, crystallinity, morphology, mucoadhesive strength). Response surface methodology was a reliable tool (error % 2.6) to optimize CBZ NCs with size ≤300 nm. Incubation of CBZ NCs in artificial cerebrospinal fluid at 37 °C did not promote aggregation and degradation phenomena. Preliminary biological studies revealed the biocompatibility of CBZ NCs towards Olfactory Ensheating Cells. The suspension was successfully converted into a powder. The highly concentrated formulation can be obtained, providing the possibility to administer the maximum dose of the drug in the lowest volume.

Organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles via de novo indole formation.

The first organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles based on o-alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5-endo-dig cyclization of new well-designed o-alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N,N'-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N,N'-pyrrolylindoles had a low IC50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N-nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand-substrate dispersion interactions facilitate the axial chirality of the target products.

Numerical Modeling and Computer Simulation of a Meander Line Antenna for Alzheimer's Disease Treatment, a Feasibility Study.

Alzheimer's disease (AD) is a brain disorder that eventually causes memory loss and the ability to perform simple cognitive functions; research efforts within pharmaceuticals and other medical treatments have minimal impact on the disease. Our preliminary biological studies showed that Repeated Electromagnetic Field Stimulation (REFMS) applying an EM frequency of 64 MHz and a specific absorption rate (SAR) of 0.4 - 0.9 W/kg decrease the level of amyloid-β peptides (Aβ), which is the most likely etiology of AD. This study emphasizes uniform E/H field and SAR distribution with adequate penetration depth penetration through multiple human head layers driven with low input power for safety treatments. In this work, we performed numerical modeling and computer simulations of a portable Meander Line antenna (MLA) to achieve the required EMF parameters to treat AD. The MLA device features a low cost, small size, wide bandwidth, and the ability to integrate into a portable system. This study utilized a High-Frequency Simulation System (HFSS) in the design of the MLA with the desired characteristics suited for AD treatment in humans. The team designed a 24-turn antenna with a 60 cm length and 25 cm width and achieved the required resonant frequency of 64 MHz. Here we used two numerical human head phantoms to test the antenna, the MIDA and spherical head phantom with six and seven tissue layers, respectively. The antenna was fed from a 50-Watt input source to obtain the SAR of 0.6 W/kg requirement in the center of the simulated brain tissue layer. We found that the E/H field and SAR distribution produced was not homogeneous; there were areas of high SAR values close to the antenna transmitter, also areas of low SAR value far away from the antenna. This paper details the antenna parameters, the scattering parameters response, the efficiency response, and the E and H field distribution; we presented the computer simulation results and discussed future work for a practical model.

New Route to Glycosylated Porphyrins via Aromatic Nucleophilic Substitution (SNAr)-Synthesis and Cellular Uptake Studies.

Glycoporphyrins are group of compounds of high value for the purpose of photodynamic therapy and other biomedical applications. Despite great progress in the field, new diversity-oriented syntheses of carbohydrate-porphyrin hybrids are increasingly desired. Herein, we present efficient, mild, and metal-free conditions for synthesis of glycoporphyrins. The versatile nature of the SNAr procedure is presented in 16 examples. Preliminary biological studies have been conducted on the cytotoxicity and cellular uptake of the final molecules.

Synthesis of new sulfamate linked 4-hydroxycoumarin conjugates as potent anti-α-amylase agents: In vitro approach coupled with molecular docking, DFT calculation and chemoinformatics prediction

This work describes the design and synthesis of new coumarin-sulfamate derivatives by the action of a series of aliphatic alcohols on (4-hydroxycoumarine-3-carbonyl)sulfamoyl chloride 2, previously prepared by reacting 4-hydroxycoumarine 1 with chlorosulfonyl isocyanate. Different spectroscopic techniques (1H NMR, 13C NMR and ESI-HRMS) were used to confirm their chemical structures. The prepared compounds were tested as α-amylase inhibitors in preliminary biological studies. The majority of compounds, especially 3a, 3e, 3f and 3 h showed good ability to inhibit α-amylase enzyme (IC50 = 0.52–6.01 μg/mL). All the synthesized compounds were theoretically studied using the Density Functional Theory (DFT) method with a B3LYP-D3(BJ)/6–311++G(d,p) basis set to determine structural and some spectroscopic parameters with the HyperChem 8.03 software. Furthermore, they were docked into an α-amylase active site. The strength of intermolecular hydrogen bonding and hydrophobic interactions in ligand-receptor complexes were found to be significant descriptors in explaining the inhibition results. The pharmacokinetic profile of the synthesized derivatives was also predicted. The physicochemical properties determined were found to be within the desired range, and their agreement with Lipinski's rule of five, shows that most compounds are likely to be orally active. The significant results obtained with some of the newly synthesized compounds encourage in vivo anti-α-amylase research in order to reach promising antidiabetic candidates.

Copper-Catalyzed Glutathione Oxidation is Accelerated by the Anticancer Thiosemicarbazone Dp44mT and Further Boosted at Lower pH

Glutathione (GSH) is the most abundant thiol in mammalian cells and plays a crucial role in maintaining redox cellular homeostasis. The thiols of two GSH molecules can be oxidized to the disulfide GSSG. The cytosolic GSH/GSSG ratio is very high (>100), and its reduction can lead to apoptosis or necrosis, which are of interest in cancer research. CuII ions are very efficient oxidants of thiols, but with an excess of GSH, CuIn(GS)m clusters are formed, in which CuI is very slowly reoxidized by O2 at pH 7.4 and even more slowly at lower pH. Here, the aerobic oxidation of GSH by CuII was investigated at different pH values in the presence of the anticancer thiosemicarbazone Dp44mT, which accumulates in lysosomes and induces lysosomal membrane permeabilization in a Cu-dependent manner. The results showed that CuII-Dp44mT catalyzes GSH oxidation faster than CuII alone at pH 7.4 and hence accelerates the production of very reactive hydroxyl radicals. Moreover, GSH oxidation and hydroxyl radical production by CuII-Dp44mT were accelerated at the acidic pH found in lysosomes. To decipher this unusually faster thiol oxidation at lower pH, density functional theory (DFT) calculations, electrochemical and spectroscopic studies were performed. The results suggest that the acceleration is due to the protonation of CuII-Dp44mT on the hydrazinic nitrogen, which favors the rate-limiting reduction step without subsequent dissociation of the CuI intermediate. Furthermore, preliminary biological studies in cell culture using the proton pump inhibitor bafilomycin A1 indicated that the lysosomal pH plays a role in the activity of CuII-Dp44mT.

Organocatalytic discrimination of non-directing aryl and heteroaryl groups: enantioselective synthesis of bioactive indole-containing triarylmethanes.

Despite the enormous developments in asymmetric catalysis, the basis for asymmetric induction is largely limited to the spatial interaction between the substrate and catalyst. Consequently, asymmetric discrimination between two sterically similar groups remains a challenge. This is particularly formidable for enantiodifferentiation between two aryl groups without a directing group or electronic manipulation. Here we address this challenge by using a robust organocatalytic system leading to excellent enantioselection between aryl and heteroaryl groups. With versatile 2-indole imine methide as the platform, an excellent combination of a superb chiral phosphoric acid and the optimal hydride source provided efficient access to a range of highly enantioenriched indole-containing triarylmethanes. Control experiments and kinetic studies provided important insights into the mechanism. DFT calculations also indicated that while hydrogen bonding is important for activation, the key interaction for discrimination of the two aryl groups is mainly π–π stacking. Preliminary biological studies also demonstrated the great potential of these triarylmethanes for anticancer and antiviral drug development.

EMF Antenna Exposure on a Multilayer Human Head Simulation for Alzheimer Disease Treatments.

In this paper, we follow up with our preliminary biological studies that showed that Repeated electromagnetic field stimulation (REMFS) decreased the toxic amyloid-beta (Aβ) levels, which is considered to be the cause of Alzheimer’s disease (AD). The REMFS parameters of these exposures were a frequency of 64 MHz and a Specific absorption rate (SAR) of 0.4 to 0.9 W/Kg in primary human neuronal cultures. In this work, an electromagnetic field (EMF) model was simulated using high-frequency simulation system (HFSS/EMPro) software. Our goal was to achieve the EM parameters (EMF Frequency and SAR) required to decrease the toxic Aβ levels in our biological studies in a simulated human head. The simulations performed here will potentially lead to the successful development of an exposure system to treat Alzheimer’s disease patients. A popular VFH (very high frequency) patch microstrip antenna system was considered in the study. The selection was based on simple and easy construction and appropriateness to the VHF applications. The evaluation of the SAR and temperature distribution on the various head layers, including skin, fat, dura, the cerebrospinal (CSF), and grey matter, brain tissues, were determined for efficacy SAR and safety temperature increase on a simulated human head. Based on a current pulse of 1 A peak current fed to the antenna feeder, a maximum SAR of 0.6 W/Kg was achieved. A range of 0.4 to 0.6 SAR was observed over the various layers of the simulated human head. The initial design of the antenna indicated an antenna size in the order of 1 m in length and width, suggesting a stationary practical model for AD therapy. Future direction is given for wearable antenna and exposure system, featuring high efficiency and patient comfort.

Synthesis, biological evaluation and cellular localization study of fluorescent derivatives of Jiyuan Oridonin A

Jiyuan Oridonin A (JOA) is a naturally occurring ent-kaurane diterpenoid that exhibits significant potential in the field of anti-tumor drug development. However, its detailed anti-cancer mechanism of action has not been fully understood. In order to investigate its anticancer mode of action, two series of novel fluorescent derivatives of JOA conjugated with naphthalimide dyes were synthesized, and their antitumor activity against five selected cancer cell lines (MGC-803, SW1990, PC-3, TE-1 and HGC-27) was evaluated. Compared with JOA, the anti-tumor activity of the vast majority of compounds were improved. Among them, B12 exhibited promising anti-proliferative activity against HGC-27 cells with IC50 value of 0.39 ± 0.09 μM. Fluorescence imaging studies demonstrated that probe B12 could enter HGC-27 cells in a dose-dependent and time-dependent manner and was mainly accumulated in mitochondria. Preliminary biological mechanism studies indicated that B12 was able to inhibit cell cloning and migration. Further studies suggested that B12-induced apoptosis was related to the mitochondrial pathway. Overall, our results provide new approaches to explore the molecular mechanism of the natural product JOA, which would contribute to its further development as an antitumor agent.

The two faces of platinum hydrospirophosphorane complexes—Not only relevant catalysts but cytotoxic compounds as well

AbstractPlatinum complexes [PtCl2(L)] L = L1, L2 with symmetrical HP (OCH2CMe2NH)2 (L1) and unsymmetrical HP(OCMe2CMe2O)(OCH2CMe2NH) (L2) hydrospirophosphorane (HSP) ligands were demonstrated to play a dual role of catalysts and cytotoxic compounds as well. The structure of new complex [PtCl2(L2)] was confirmed by physicochemical and spectroscopic methods, as well as single X‐ray diffraction studies for [PtCl2{P (OCMe2CMe2O)(OCH2CMe2NH2)}]. HSP ligand coordinated to the platinum center in bidentate κ2‐P,NH2 chelating mode of fashion. Both complexes were found to exhibit catalytic activity for Heck cross‐coupling reactions of iodobenzene with substituted styrenes, with good conversion and yield of stilbenes. Moreover, complexes have been applied as excellent catalysts for highly regioselective hydrosilylation of aromatic and aliphatic terminal olefins, and acetylenes terminal and internal as well. On the other hand, the preliminary biological studies revealed that in the presence of foretinib, drug candidate in clinical trials for the treatment of cancer, platinum complexes revealed increased synergistic effect and efficiently decreased the number of viable cells of triple negative breast cancer MDA‐MB‐231 cell line.

Molecular salts of the isoniazid derivatives. Expanding the scope of sulfonate-pyridinium synthon to design materials

Understanding the intermolecular interactions is central to crystal engineering and is pivotal in designing of the new materials. Of recent we have reported sulfonate-pyridinium interaction as robust synthon and herein we utilize the interaction to develop molecular complexes: [(ISN–I3C–H)+(5-SSA-H)ˉ] (1), [(ISN-pV-H)+(5-SSA-H)ˉ.MeOH·H2O] (2), and [(ISN-oV-H)+(5-SSA-H)ˉ.H2O] (3). 1–3 have been obtained by reaction of isoniazid derivatives: ((1H-indol-3-yl)methylene)isonicotinohydrazide (ISN–I3C), isonicotinic acid (4-hydroxy-3-methoxy-benzylidene)-hydrazide (ISN-pV) and isonicotinic acid (2-hydroxy-3-methoxy-benzylidene)-hydrazide (ISN-oV) with 5-sulfosalicylic acid (5-SSA-2H). Molecular salts 1 and 2 manifest direct charge assisted sulfonate-pyridinium interaction, while, in 3, the synthon is masked by lattice water. The Schiff base cations in 1 and 2 stack together through strong π-interactions forming 2-dimensional layers and 1-dimensional tapes, respectively, which, in turn, are bridged by the organo-sulfonate anions into a 3-dimensional ionic solids. While the crystal formers in 3, the hydrogen bonds are utilized to form three molecule thick sheets, which aggregate through C–H⋯O and π-π interactions to form a 3-dimensional supramolecule. Hirshfeld studies corroborate with structural studies and validate that reciprocal O–H/H–O interactions are the chief intermolecular interactions in these oxygen rich compounds while weak dispersive H–H contacts are the second dominant interactions responsible for the molecular packing. Framework energy, as well as individual contribution of columbic, potential and dispersive forces towards molecular packing, are visualized through framework energy analyses of 1–3, which also substantiate that very robust sulfonate-pyridinium contact is not the strongest intermolecular contact. The resultant multi-component crystals exhibit enhanced optical properties, which are attributed to proton transfer and/or π-stacking interactions. The band gap values of 1–3 observed in the Tauc plots corroborate with charge transfer interactions. The products also exhibit enhanced solubility in methanol, higher than the isoniazid derivatives, and the thermal stability up to 240 ​°C. The molecular salts have also been screened for preliminary biological studies.

Surface Modification of Carbon Nanofibers to Improve Their Biocompatibility in Contact with Osteoblast and Chondrocytes Cell Lines.

The goal of this study is to investigate the influence of different types of modifiers, such as sodium hyaluronate (NaH), graphene oxide (GO), silica oxycarbide (SiOC) and oxidation process (ox) on physicochemical, morphological, and biological properties of electrospun carbon nanofibers (eCNFs). Scanning electron microscopy, X-ray photoelectron spectroscopy and infrared spectroscopy (FTIR) were used to evaluate the microstructure and chemistry of as-prepared and modified CNFs. The electrical properties of CNFs scaffolds were examined using a four-point probe method to evaluate the influence of modifiers on the volume conductivity and surface resistivity of the obtained samples. The wettability of the surfaces of modified and unmodified CNFs scaffolds was also tested by contact angle measurement. During the in vitro study all samples were put into direct contact with human chondrocyte CHON-001 cells and human osteosarcoma MG-63 cells. Their viability was analysed after 72 h in culture. Moreover, the cell morphology and cell area in contact with CNFs was observed by means of fluorescence microscopy. The obtained results show great potential for the modification of CNFs with polymer, ceramic and carbon modifiers, which do not change the fiber form of the substrate but significantly affect their surface and volume properties. Preliminary biological studies have shown that the type of modification of CNFs affects either the rate of increase in the number of cells or the degree of spreading in relation to the unmodified sample. More hydrophilic and low electrically conductive samples such as CNF_ox and CNF_NaH significantly increase cell proliferation, while other GO and SiOC modified samples have an effect on cell adhesion and thus cell spreading. From the point of view of further research and the possibility of combining the electrical properties of modified CNF scaffolds with electrical stimulation, where these scaffolds would be able to transport electrical signals to cells and thus affect cell adhesion, spreading, and consequently tissue regeneration, samples CNF_GO and CNF_SiOC would be the most desirable.

Design, synthesis, stereochemical determination, molecular docking study, in silico pre-ADMET prediction and anti-proliferative activities of indole-pyrimidine derivatives as Mcl-1 inhibitors

In this study, fourteen novel indole-pyrimidine hybrids were designed and synthesized. Their chemical structures were confirmed using different spectroscopic techniques (1H NMR, 13C NMR, IR and mass). Their (E) stereochemical configuration was determined theoretically (MM2 property) and experimentally using 2D NMR technique (NOESY experiment). The prepared compounds were subjected to preliminary biological studies as Mcl-1 inhibitors. Most of the compounds exhibited good abilities for targeting Mcl-1 protein, especially, 7d, 7e, 7i and 7k (Ki = 11.19–15.21 nM). These derivatives were further evaluated against Bcl-XL and Bcl-2 proteins. Some compounds were found to have dual Mcl-1/Bcl-XL such as 7i, or Bcl-XL/Bcl-2 inhibitory activity as 7d.The most potent derivatives as Mcl-1 inhibitors were chosen as representative examples for determination of in-vitro anti-proliferative activity against PC-3, K-562 and MDA-MB-231 cell lines. They possessed excellent to good anti-proliferative activities. All of the synthesized compounds were docked into Mcl-1 active site. Drug-likeness properties and in silico pre-ADMET characters were also predicted.