[2+1] Cycloaddition Affording Methylene‐ and Vinylidenecyclopropane Derivatives: A Journey around the Reactivity of Metal‐Phosphinito–Phosphinous Acid Complexes

Metal–phosphinito–phosphinous acid complexes are interesting catalysts exhibiting unique reactivities. In this account, we intend to provide a clear overview of palladium– and platinum–phosphinito–phosphinous acid complexes, their preparation from secondary phosphine oxides, and their applications in catalysis. They have been mainly used to develop [2+1] cycloadditions to afford methylenecyclopropane derivatives using norbornenes and various alkynes as partners. As a function of the catalyst, the reaction conditions, or the nature of the reagents, different synthetic transformations have been observed: [2+1] cycloadditions, giving rise to either alkylidenecyclopropanes or vinylidenecyclopropanes; tandem [2+1]/[3+2] cycloadditions, and so forth. The mechanisms of these reactions have been studied to rationalize the different reactivities observed.     

Tetracyclines as a potential antiviral therapy against Crimean Congo hemorrhagic fever virus: Docking and molecular dynamic studies

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is one of the deadliest human diseases with mortality rate near 50%. Special attention should be paid to this virus since there is no approved treatment for it. On the other hand, the recent outbreak of Ebola virus which is a member of hemorrhagic fever viruses shows this group of viruses can be extremely dangerous. Previous studies have indicated that nucleoprotein of CCHFV, a pivotal protein in virus replication, is an appropriate target for antiviral drug development. The aim of this study is finding inhibitor(s) of this protein. Herein, a virtual screening procedure employing docking followed by molecular dynamic was used to identify small molecule inhibitors of the nucleoprotein from FDA-approved drugs. Regarding CCHFV, using in-silico method is a safe way to achieve its inhibitor(s) since this virus is categorized as a World Health Organization (WHO) biosafety level 4 pathogen and therefore investigation in general laboratories is restricted. In conclusion, considering docking and molecular dynamic results alongside with bioavailability of FDA-approved drugs, doxycycline and minocycline are proposed as potential inhibitors of CCHFV nucleoprotein. There is hope, this study encourage other research groups for in-vitro and in-vivo studies about the efficacy of those two medicines in CCHFV treatment.     

Disruption of redox catalytic functions of peroxiredoxin-thioredoxin complex in Mycobacterium tuberculosis H37Rv using small interface binding molecules

Mycobacterium tuberculosis has distinctive ability to detoxify various microbicidal superoxides and hydroperoxides via a redox catalytic cycle involving thiol reductants of peroxiredoxin (Prx) and thioredoxin (Trx) systems which has conferred on it resistance against oxidative killing and survivability within host. We have used computational approach to disrupt catalytic functions of Prx-Trx complex which can possibly render the pathogen vulnerable to oxidative killing in the host. Using protein–protein docking method, we have successfully constructed the Prx-Trx complex. Statistics of interface region revealed contact area of each monomer less than 1500 Å² and enriched in polar amino acids indicating transient interaction between Prx and Trx. We have identified ZINC40139449 as a potent interface binding molecule through virtual screening of drug-like compounds from ZINC database. Molecular dynamics (MD) simulation studies showed differences in structural properties of Prx-Trx complex both in apo and ligand bound states with regard to root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuations (RMSF), solvent accessible surface area (SASA) and number of hydrogen bonds (NHBs). Interestingly, we found stability of two conserved catalytic residues Cys61 and Cys174 of Prx and conserved catalytic motif, WCXXC of Trx upon binding of ZINC40139449. The time dependent displacement study reveals that the compound is quite stable in the interface binding region till 30 ns of MD simulation. The structural properties were further validated by principal component analysis (PCA). We report ZINC40139449 as promising lead which can be further evaluated by in vitro or in vivo enzyme inhibition assays.     

Discovery of potential inhibitor against human acetylcholinesterase: a molecular docking and molecular dynamics investigation

Alzheimer’s disease (AD) is a progressive neurodegenerative disease of central nervous system among elderly people. Human acetylcholinesterase (hAChE), an important enzyme in neuronal signaling, is responsible for the degradation of acetylcholine which in turn prevents the post synaptic signal transmissions. hAChE has been an attractive target of drug discovery for the search of therapeutics against AD. In the recent past hAChE has become hot target for the investigation of new potential therapeutics. We performed virtual screening of entire database against hAChE. Further, the extra precision molecular docking was carried out to refine the docking results and the best complex was passed for molecular dynamics simulations in order of understanding the hAChE dynamics and its behavior in complex with the ligand which corroborate the outcomes of virtual screening. This also provides binding free energy data that establishes the ligands efficiency for inhibiting hAChE. The computational findings discussed in this paper provide initial information of inhibitory effects of ligand, (drugbank entry DB00983), over hAChE.     

Thioether‐derived Macrocycle for Peptide Secondary Structure Fixation

Recently, we developed methods to stabilize peptides into various secondary structures, including α‐helix, type III turn and β‐hairpin via proper thioether based macrocyclization. These conformationally constrained peptidomimetics confer enhanced biophysical properties and provide a valuable avenue towards clinically‐relevant therapeutic molecules. In this personal account, thioether‐derived macrocyclization methods developed by our group for stabilization of α‐helix, type‐III β turn and β‐hairpin conformations are discussed.     

Aptamer‐functionalized Fe3O4 magnetic nanoparticles as a solid‐phase extraction adsorbent for the selective extraction of berberine from Cortex phellodendri

The extraction adsorbent was fabricated by immobilizing the highly specific recognition and binding of aptamer onto the surface of Fe₃O₄ magnetic nanoparticles, which not only acted as recognition elements to recognize and capture the target molecule berberine from the extract of Cortex phellodendri , but also could favor the rapid separation and purification of the bound berberine by using an external magnet. The developed solid‐phase extraction method in this work was useful for the selective extraction and determination of berberine in Cortex phellodendri extracts. Various conditions such as the amount of aptamer‐functionalized Fe₃O₄ magnetic nanoparticles, extraction time, temperature, pH value, Mg²⁺ concentration, elution time and solvent were optimized for the solid‐phase extraction of berberine. Under optimal conditions, the purity of berberine extracted from Cortex phellodendri was as high as 98.7% compared with that of 4.85% in the extract, indicating that aptamer‐functionalized Fe₃O₄ magnetic nanoparticles‐based solid‐phase extraction method was very effective for berberine enrichment and separation from a complex herb extract. The applicability and reliability of the developed solid‐phase extraction method were demonstrated by separating berberine from nine different concentrations of one Cortex phellodendri extract. The relative recoveries of the spiked solutions of all the samples were between 95.4 and 111.3%, with relative standard deviations ranging between 0.57 and 1.85%.     

Identification and quantitative analysis of physalin D and its metabolites in rat urine and feces by liquid chromatography with triple quadrupole time‐of‐flight mass spectrometry

Physalin D is known to show extensive bioactivities. However, no excretion study has elucidated the excretion of physalin D and its metabolites. This study investigates the excretion of physalin D and its metabolites in rats. Metabolites in rat urine and feces were separated and identified by liquid chromatography with triple quadrupole time‐of‐flight mass spectrometry. Furthermore, a validated high‐performance liquid chromatography with tandem mass spectrometry method was developed to quantify physalin D, physalin D glucuronide, and physalin D sulfate in rat feces and urine after the intragastric administration of physalin D. The analyte showed good linearity over a wide concentration range (r  > 0.995), and the lower limit of quantification was 0.0532 μg/mL and 0.226 μg/g for urine and feces, respectively. Nine metabolites, including five phase I and four phase II metabolites, were identified and clarified after dosing in vivo. Only 4.0% of the gavaged dose, including physalin D and its phase II metabolites, was excreted in urine, whereas 10.8% was found in feces in the unchanged form. The results indicate that the extensive and rapid metabolism may be the main factors leading to the short half‐life of physalin D. These results can provide a basis for further studies on the structural modification and pharmacology of physalin D.     

Targeted Tumor Therapy Based on Nanodiamonds Decorated with Doxorubicin and Folic Acid

The fabrication of nanodiamond (ND)‐based drug carriers for tumor‐targeted drug delivery is described. The ND clusters with an average size of 52.84 nm are fabricated using a simple fluidic device combined with a precipitation method and then conjugated with folic acid (FA) and doxorubicin (Dox) via carbodiimide chemistry to obtain FA/Dox‐modified ND (FA/Dox‐ND) clusters. Cell culture experiments revealed that KB (folate receptor‐positive) cells are preferentially ablated by FA/Dox‐ND clusters compared to A549 (folate receptor‐negative) cells. In vivo results revealed that FA/Dox‐ND clusters are specifically accumulated in tumor tissues after intravenous injection into tumor‐bearing mice, effectively reducing the volume of tumor. Based on these results, this study suggests that FA/Dox‐ND clusters can be a good candidate as tumor‐targeted nanovehicles for delivery of antitumor drug.

     

d‐Fructose‐Decorated Poly(ethylene imine) for Human Breast Cancer Cell Targeting

The high affinity of GLUT5 transporter for d ‐fructose in breast cancer cells has been discussed intensely. In this contribution, high molar mass linear poly(ethylene imine) (LPEI) is functionalized with d ‐fructose moieties to combine the selectivity for the GLUT5 transporter with the delivery potential of PEI for genetic material. The four‐step synthesis of a thiol‐group bearing d ‐fructose enables the decoration of a cationic polymer backbone with d ‐fructose via thiol‐ene photoaddition. The functionalization of LPEI is confirmed by 2D NMR techniques, elemental analysis, and size exclusion chromatography. Importantly, a d ‐fructose decoration of 16% renders the polymers water‐soluble and eliminates the cytotoxicity of PEI in noncancer L929 cells, accompanied by a reduced unspecific cellular uptake of the genetic material. In contrast, the cytotoxicity as well as the cell specific uptake is increased for triple negative MDA‐MB‐231 breast cancer cells. Therefore, the introduction of d ‐fructose shows superior potential for cell targeting, which can be assumed to be GLUT5 dependent.

     

Aligned Poly(ε‐caprolactone) Nanofibers Guide the Orientation and Migration of Human Pluripotent Stem Cell‐Derived Neurons,Astrocytes, and Oligodendrocyte Precursor Cells In Vitro

Stem cell transplantations for spinal cord injury (SCI) have been studied extensively for the past decade in order to replace the damaged tissue with human pluripotent stem cell (hPSC)‐derived neural cells. Transplanted cells may, however, benefit from supporting and guiding structures or scaffolds in order to remain viable and integrate into the host tissue. Biomaterials can be used as supporting scaffolds, as they mimic the characteristics of the natural cellular environment. In this study, hPSC‐derived neurons, astrocytes, and oligodendrocyte precursor cells (OPCs) are cultured on aligned poly(ε‐caprolactone) nanofiber platforms, which guide cell orientation to resemble that of spinal cord in vivo. All cell types are shown to efficiently spread over the nanofiber platform and orient according to the fiber alignment. Human neurons and astrocytes require extracellular matrix molecule coating for the nanofibers, but OPCs grow on nanofibers without additional treatment. Furthermore, the nanofiber platform is combined with a 3D hydrogel scaffold with controlled thickness, and nanofiber‐mediated orientation of hPSC‐derived neurons is also demonstrated in a 3D environment. In this work, clinically relevant materials and substrates for nanofibers, fiber coatings, and hydrogel scaffolds are used and combined with cells suitable for developing functional cell grafts for SCI repair.