Corking and Uncorking Carbon Nanotubes by Metal Nanoparticles Bearing pH-Cleavable Hydrazone Linkers. Theoretical Analysis Based on Molecular Dynamics Simulations

In this work we determine and discuss free-energy barriers associated with the detachment of metal (gold) nanoparticles covered by an organic shell from carbon nanotubes functionalized by hydrazide segments. At neutral pH, both compounds can form hydrazone bonds which in turn lead to the chemically corked form of the nanotube. At slightly acidic pH, the hydrazone bonds undergo hydrolysis, leading to chemically unbonded nanotube and gold nanoparticles. We found that at this state the dispersion interactions between the nanotube and gold nanoparticles are still very strong and spontaneous detachment of gold nanoparticles does not occur. Therefore, the uncorked state of the nanotube cannot be realized at normal conditions. The presence of guest molecules (cisplatin) in the inner cavity of the nanotube affects the energetic balance of the system, and spontaneous uncorking can occur with some small activation barrier. However, the uncorking is in this case related to the shift of the nanoparticle from the nanotube tip to its sidewall. That model system can thus realize the mechanism of pH-controlled drug release from the inner cavities of carbon nanotubes. Determination of the free-energy barriers in the considered systems architectures required a special treatment. Standard application of the weighted histogram analysis of biased probability distributions turned out to be totally ineffective. Therefore, we developed a special version of that method which tolerates weak overlapping of the probability histograms. This method may be useful for fast survey of free-energy barriers in any other system architectures

Discovery and Investigation of Anticancer Ruthenium–Arene Schiff-Base Complexes via Water-Promoted Combinatorial Three-Component Assembly

The structural diversity of metal scaffolds makes them a viable alternative to traditional organic scaffolds for drug design. Combinatorial chemistry and multicomponent reactions, coupled with high-throughput screening, are useful techniques in drug discovery, but they are rarely used in metal-based drug design. We report the optimization and validation of a new combinatorial, metal-based, three-component assembly reaction for the synthesis of a library of 442 Ru–arene Schiff-base (RAS) complexes. These RAS complexes were synthesized in a one-pot, on-a-plate format using commercially available starting materials under aqueous conditions. The library was screened for their anticancer activity, and several cytotoxic lead compounds were identified. In particular, [(η⁶-1,3,5-triisopropylbenzene)­RuCl­(4-methoxy-<i>N</i>-(2-quinolinylmethylene)­aniline)]Cl (<b>4</b>) displayed low micromolar IC₅₀ values in ovarian cancers (A2780, A2780cisR), breast cancer (MCF7), and colorectal cancer (HCT116, SW480). The absence of p53 activation or changes in IC₅₀ value between p53^+/+ and p53^–/– cells suggests that <b>4</b> and possibly the other lead compounds may act independently of the p53 tumor suppressor gene frequently mutated in cancer

Gene Detection in Complex Biological Media Using Semiconductor Nanorods within an Integrated Microfluidic Device

The salient optical properties of highly luminescent semiconductor nanocrystals render them ideal fluorophores for clinical diagnostics, therapeutics, and highly sensitive biochip applications. Microfluidic systems allow miniaturization and integration of multiple biochemical processes in a single device and do not require sophisticated diagnostic tools. Herein, we describe a microfluidic system that integrates RNA extraction, reverse transcription to cDNA, amplification and detection within one integrated device to detect histidine decarboxylase (HDC) gene directly from human white blood cells samples. When anisotropic semiconductor nanorods (NRs) were used as the fluorescent probes, the detection limit was found to be 0.4 ng of total RNA, which was much lower than that obtained using spherical quantum dots (QDs) or organic dyes. This was attributed to the large action cross-section of NRs and their high probability of target capture in a pull-down detection scheme. The combination of large scale integrated microfluidics with highly fluorescent semiconductor NRs may find widespread utility in point-of-care devices and multitarget diagnostics

Exploring the Directionality of 5‑Substitutions in a New Series of 5‑Alkylaminopyrazolo[4,3‑<i>e</i>]1,2,4-triazolo[1,5‑<i>c</i>]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.

The structure–activity relationship (SAR) of new 5-alkylaminopyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidines as antagonists of the A₃ adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A₃ AR. All the synthesized compounds showed affinity for the hA₃ AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (<i>S</i>) α-phenylethylamino moiety at the 5 position (<b>26</b>, <i>K</i>_i hA₃ = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N⁵ position toward the extracellular environment

Exploring the Directionality of 5‑Substitutions in a New Series of 5‑Alkylaminopyrazolo[4,3‑<i>e</i>]1,2,4-triazolo[1,5‑<i>c</i>]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.

The structure–activity relationship (SAR) of new 5-alkylaminopyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidines as antagonists of the A₃ adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A₃ AR. All the synthesized compounds showed affinity for the hA₃ AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (<i>S</i>) α-phenylethylamino moiety at the 5 position (<b>26</b>, <i>K</i>_i hA₃ = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N⁵ position toward the extracellular environment

Scaffold Decoration at Positions 5 and 8 of 1,2,4-Triazolo[1,5‑<i>c</i>]Pyrimidines to Explore the Antagonist Profiling on Adenosine Receptors: A Preliminary Structure–Activity Relationship Study

The structure–activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA_2A and hA₃ ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA_2A antagonists (compound <b>12</b>: hA_2A AR <i>K</i>_i = 3.32 nM; hA₁/hA_2A = 55.6; hA_2A/hA₃ = 0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA₃ AR (compound <b>23</b>: hA₃ AR <i>K</i>_i = 4.14 nM, hA₁/hA₃ = 236; hA_2A/hA₃ = 25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR

Exploring the Directionality of 5‑Substitutions in a New Series of 5‑Alkylaminopyrazolo[4,3‑<i>e</i>]1,2,4-triazolo[1,5‑<i>c</i>]pyrimidine as a Strategy To Design Novel Human A₃ Adenosine Receptor Antagonists.

The structure–activity relationship (SAR) of new 5-alkylaminopyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidines as antagonists of the A₃ adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5-substitutions inside the orthosteric binding site of the A₃ AR. All the synthesized compounds showed affinity for the hA₃ AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (<i>S</i>) α-phenylethylamino moiety at the 5 position (<b>26</b>, <i>K</i>_i hA₃ = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo­[4,3-<i>e</i>]­1,2,4-triazolo­[1,5-<i>c</i>]­pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N⁵ position toward the extracellular environment

Iron Oxide Filled Magnetic Carbon Nanotube–Enzyme Conjugates for Recycling of Amyloglucosidase: Toward Useful Applications in Biofuel Production Process

Biofuels are fast advancing as a new research area to provide alternative sources of sustainable and clean energy. Recent advances in nanotechnology have sought to improve the efficiency of biofuel production, enhancing energy security. In this study, we have incorporated iron oxide nanoparticles into single-walled carbon nanotubes (SWCNTs) to produce magnetic single-walled carbon nanotubes (mSWCNTs). Our objective is to bridge both nanotechnology and biofuel production by immobilizing the enzyme, Amyloglucosidase (AMG), onto mSWCNTs using physical adsorption and covalent immobilization, with the aim of recycling the immobilized enzyme, toward useful applications in biofuel production processes. We have demonstrated that the enzyme retains a certain percentage of its catalytic efficiency (up to 40%) in starch prototype biomass hydrolysis when used repeatedly (up to ten cycles) after immobilization on mSWCNTs, since the nanotubes can be easily separated from the reaction mixture using a simple magnet. The enzyme loading, activity, and structural changes after immobilization onto mSWCNTs were also studied. In addition, we have demonstrated that the immobilized enzyme retains its activity when stored at 4 °C for at least one month. These results, combined with the unique intrinsic properties of the nanotubes, pave the way for greater efficiency in carbon nanotube–enzyme bioreactors and reduced capital costs in industrial enzyme systems

Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A_2A and dopamine D₂ receptors for Parkinson's disease treatment - Fig 5

<p>Dose-response curves of compound <b>5</b> (A), compound <b>6</b> (B) and (±)-PPHT.HCl (C) in D₂R-proteopolymersomes-based fluorescence polarisation (FP) competition assay with BODIPY-NAPS. The non-binding control (D) was achieved by denaturing the D₂R-proteopolymersomes with heat, resulting in a curve that fluorescence intensity did not decrease much when the concentration of (±)-PPHT.HCl increased. For the highest concentrations, experiments were repeated only in duplicate due to solubility issues.</p

Survival percentages of mutant LRRK2 G2019S flies after 7 days, 10 days and 17 days of treatment with various concentrations (50 μM, 100 μM, 200 μM) of compound 5.

<p>Survival percentages of mutant LRRK2 G2019S flies after 7 days, 10 days and 17 days of treatment with various concentrations (50 μM, 100 μM, 200 μM) of compound 5.</p