Zinc-Chelating Compounds as Inhibitors of Human and Bacterial Zinc Metalloproteases

Inhibition of bacterial virulence is believed to be a new treatment option for bacterial infections. In the present study, we tested dipicolylamine (DPA), tripicolylamine (TPA), tris pyridine ethylene diamine (TPED), pyridine and thiophene derivatives as putative inhibitors of the bacterial virulence factors thermolysin (TLN), pseudolysin (PLN) and aureolysin (ALN) and the human zinc metalloproteases, matrix metalloprotease-9 (MMP-9) and matrix metalloprotease-14 (MMP-14). These compounds have nitrogen or sulfur as putative donor atoms for zinc chelation. In general, the compounds showed stronger inhibition of MMP-14 and PLN than of the other enzymes, with Ki values in the lower μM range. Except for DPA, none of the compounds showed significantly stronger inhibition of the virulence factors than of the human zinc metalloproteases. TPA and Zn230 were the only compounds that inhibited all five zinc metalloproteinases with a Ki value in the lower μM range. The thiophene compounds gave weak or no inhibition. Docking indicated that some of the compounds coordinated zinc by one oxygen atom from a hydroxyl or carbonyl group, or by oxygen atoms both from a hydroxyl group and a carbonyl group, and not by pyridine nitrogen as in DPA and TPA.

Influence of Inorganic Metal (Ag, Cu) Nanoparticles on Biological Activity and Biochemical Properties of Brassica napus Rhizosphere Soil

Two separate forms of application of silver and copper nanoparticles (AgNP and CuNP in a nanocolloidal suspension) to winter oilseed rape seeds were used: (1) seed soaking (S) for 1 h at 20 °C in a NP suspension and (2) additional seed soaking and spraying plants 21-day-old seedlings (SP) with NP. The AgNP and CuNP colloidal suspensions in sterile distilled water were applied in three different NP concentrations (50, 100, 150 mg L−1). However, the changes in the biology and biochemistry of the Brassica napus rhizospheric soil after the application of CuNPs and AgNPs are not considerable, although mostly statistically significant, and the application of CuNPs is more beneficial for this activity than the application of AgNPs. The number of CFUs (colony–forming units) of the tested groups of culturable microorganisms (fungi and copiotrophic, oligotrophic, and siderophore-producing bacteria) indicates the following trend: the abundance of all the tested groups was slightly positively correlated with CuNPs and clearly negatively correlated with AgNPs in each version of application. The soil pH value and tested biochemical soil parameters (IAA: indole-3-acetic acid, PhC: phenolic compounds, FeCC: Fe–chelating compounds) were negatively correlated with AgNPs applied to the seeds (S) at all the tested concentrations and to the seeds and plants (SP) at the concentration of 50 mg L−1. In turn, these parameters were strongly positively correlated with CuNPs applied to the S and SP groups at the concentration of 50 mg L−1 as well as Ag applied to SP at 100 mg L−1. Decrease in dehydrogenase activity (DHA) was lower after the application of CuNPs and AgNPs in S than in the SP way, and the DHA activity was equal to the activity in the control sample after the CuNP application in 100 and 150 mg L−1 concentrations.

Changing the Nature of the Chelating Ligand of Tetracoordinate Boron-Containing PAH Multi-resonant Thermally Activated Delayed Fluorescence Emitters Tunes the Emission from Green to Deep Red

Multi-resonant thermally activated delayed fluorescence (MR-TADF) materials have attracted considerable attention recently. The molecular design frequently incorporates cycloboration. However, to the best of our knowledge MR-TADF compounds containing nitrogen chelation to boron is still unknown. Reported herein is a new class of tetracoordinate boron-containing MR-TADF emitters bearing a C^N^C- and N^N^N-chelating ligands. We demonstrate that the replacement of B−C covalent bond in C^N^C-chelating ligand by B−N covalent bond affords a regioisomer, which dramatically influences the optoelectronic properties of the molecule. The resulting N^N^N-chelating compounds show bathochromically shifted absorption and emission spectra relative to C^N^C-chelating compounds. The incorporation of tert-butylcarbazole group to the 4-position of the pyridine significantly enhances both the thermal stability and the reverse intersystem crossing rate, yet has a negligible effect on the emission properties. Consequently, high-performance hyperfluorescence organic light-emitting diodes (HF-OLEDs) that utilize these molecules as green and yellow-green emitters show maximum external quantum efficiency (ηext) of 11.5% and 25.1%, and a suppressed efficiency roll-off with ηext of 10.2% and 18.7% at a luminance of 1000 cd m−2, respectively.

Towards the synthesis of photobactin: methodology and metal binding aspects

Siderophores are metal-typically iron-chelating compounds that have received countless attention in research, as they can play a role in medicine intended for drug delivery and iron overload treatment. The synthesis of Photobactin has been of interest as it has been previously isolated (<10 mg) from Photorhabdus luminescence and has not once been synthesized. This thesis examined the preparation of Photobactin using a multi-step approach: synthesizing two building blocks individually and coupling them together with an amide coupling reagent. Both building blocks were synthesized successfully. However, the deprotection of the ester group on one of the building blocks has been uncooperative, and therefore the total synthesis of Photobactin was not achieved. Moreover, DFT computation calculations were performed to study Photobactin binding properties with Fe3+. According to the results, iron (Fe3+) is likely to form a hexadentate (6-coordinate ligand) or a tetradentate (4-coordinate ligand) complex with Photobactin. Each of the compounds leading to Photobactin was characterized using 1H and 13C-NMR. Some compounds were characterized using elemental analysis and performing 2D-NMR (COSY, HMBC, and HSQC) to make final assignments.

Towards the synthesis of photobactin: methodology and metal binding aspects

Siderophores are metal-typically iron-chelating compounds that have received countless attention in research, as they can play a role in medicine intended for drug delivery and iron overload treatment. The synthesis of Photobactin has been of interest as it has been previously isolated (<10 mg) from Photorhabdus luminescence and has not once been synthesized. This thesis examined the preparation of Photobactin using a multi-step approach: synthesizing two building blocks individually and coupling them together with an amide coupling reagent. Both building blocks were synthesized successfully. However, the deprotection of the ester group on one of the building blocks has been uncooperative, and therefore the total synthesis of Photobactin was not achieved. Moreover, DFT computation calculations were performed to study Photobactin binding properties with Fe3+. According to the results, iron (Fe3+) is likely to form a hexadentate (6-coordinate ligand) or a tetradentate (4-coordinate ligand) complex with Photobactin. Each of the compounds leading to Photobactin was characterized using 1H and 13C-NMR. Some compounds were characterized using elemental analysis and performing 2D-NMR (COSY, HMBC, and HSQC) to make final assignments.

Neutral Metal-Chelating Compounds with High 64Cu Affinity for PET Imaging Applications in Alzheimer’s Disease

<div> <p>Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer’s disease (AD). The development of longer-lived radiolabeled compounds is essential for further expanding the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as ⁶⁴Cu (t_1/2 = 12.7 h, β⁺ = 17%, β^- = 39%, EC = 43%, E_max = 0.656 MeV) are capable of accomplishing this. One limitation of ⁶⁴Cu PET agents is that they could release free radioactive Cu ions from the metal complexes, which decreases the signal to noise ratio and accuracy of imaging. Herein, a series of 1,4,7-triazacyclononane (TACN) and 2,11-diaza[3.3]-(2,6)pyridinophane (N4)-based <a>metal-chelating compounds with pyridine arms were designed and synthesized by incorporating Aβ-interacting fragments into metal-binding ligands, which allows for excellent Cu chelation without diminishing their Aβ-binding affinity. </a>The crystal structures of the corresponding Cu complexes confirmed the pyridine N atoms are involved in binding to Cu. Radiolabeling and autoradiopraphy studies show that <a>the compounds efficiently chelate ⁶⁴Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections vs. WT controls.</a></p> </div> <br>

Neutral Metal-Chelating Compounds with High 64Cu Affinity for PET Imaging Applications in Alzheimer’s Disease

<div> <p>Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer’s disease (AD). The development of longer-lived radiolabeled compounds is essential for further expanding the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as ⁶⁴Cu (t_1/2 = 12.7 h, β⁺ = 17%, β^- = 39%, EC = 43%, E_max = 0.656 MeV) are capable of accomplishing this. One limitation of ⁶⁴Cu PET agents is that they could release free radioactive Cu ions from the metal complexes, which decreases the signal to noise ratio and accuracy of imaging. Herein, a series of 1,4,7-triazacyclononane (TACN) and 2,11-diaza[3.3]-(2,6)pyridinophane (N4)-based <a>metal-chelating compounds with pyridine arms were designed and synthesized by incorporating Aβ-interacting fragments into metal-binding ligands, which allows for excellent Cu chelation without diminishing their Aβ-binding affinity. </a>The crystal structures of the corresponding Cu complexes confirmed the pyridine N atoms are involved in binding to Cu. Radiolabeling and autoradiopraphy studies show that <a>the compounds efficiently chelate ⁶⁴Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections vs. WT controls.</a></p> </div> <br>

Irreversible Inhibition of BoNT/A Protease: Unique Warhead Reactivity and Function Contingent upon a Bifunctional Approach

We describe a comprehensive screening campaign of warheads, linked to a hydroxamate chelating anchor, for the modification of Cys165 within the BoNT/A protease. <div>Engaging thorough enzyme kinetics, we detail a remarkable proximity-driven covalent bond with an epoxide warhead, a weak electrophile; yet, one that possessed superior irreversible inhibition, and pharmacological properties, when compared to intrinsically higher reactive warheads. This directed, selective covalent bond was contingent upon the crucial hydroxamate-Zn²⁺chelating interaction as exemplified by examining non-chelating compounds. </div><div>We discuss previous approaches using non-target selective cysteine-reactive warheads to modify the BoNT/A protease of which none present any therapeutic potential – our bifunctional strategy allows the use of intrinsically less reactive warheads to intercept the cysteine, which will allow for less off-target modifications of such inhibitors. Moreover, we also broach that this bifunctional approach is not a one-off strategy that we believe can be broadly translated to other metalloproteases that possess non-catalytic, yet, nucleophilic residues within the enzymes catalytic sphere. </div>