Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[11C]YH132: Application in Drug Development and Neurodegenerative Diseases

Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)-[11C]YH132: Application in Drug Development and Neurodegenerative Diseases

(R)-[11C]YH132 is a specific and selective PET tracer for MAGL brain imaging. It has the potential to accelerate MAGL drug discovery and may be used to stage neurodegenerative diseases.


Abstract

Monoacylglycerol lipase (MAGL) plays a crucial role in the degradation of 2-arachidonoylglycerol (2-AG), one of the major endocannabinoids in the brain. Inhibiting MAGL could lead to increased levels of 2-AG, which showed beneficial effects on pain management, anxiety, inflammation, and neuroprotection. In the current study, we report the characterization of an enantiomerically pure (R)-[11C]YH132 as a novel MAGL PET tracer. It demonstrates an improved pharmacokinetic profile compared to its racemate. High in vitro MAGL specificity of (R)-[11C]YH132 was confirmed by autoradiography studies using mouse and rat brain sections. In vivo, (R)-[11C]YH132 displayed a high brain penetration, and high specificity and selectivity toward MAGL by dynamic PET imaging using MAGL knockout and wild-type mice. Pretreatment with a MAGL drug candidate revealed a dose-dependent reduction of (R)-[11C]YH132 accumulation in WT mouse brains. This result validates its utility as a PET probe to assist drug development. Moreover, its potential application in neurodegenerative diseases was explored by in vitro autoradiography using brain sections from animal models of Alzheimer's disease and Parkinson's disease.

Controllable Chemoselectivity Cascade Reactions for the Synthesis of Phenanthrenols via Palladium‐Catalyzed‐Suzuki/Heck Reaction and Michael Addition

Palladium serves as a multi-functional catalyst which is controllable by tuning reaction conditions. This work demonstrated the utilization of a palladium catalyst for the synthesis of phenanthrenols by cascade palladium-catalyzed Suzuki/Heck reaction between chalcone and 2-bromophenylboronic acid, followed by Michael addition. The sequential reaction could be controlled by reactivity of the palladium catalyst in different solvents and concentrations of reagents. This protocol could be applied to a broad range of substrates to give products in low to good yields.

Pd(II) and Pt(II) saccharinate complexes with two phosphine derivatives: Synthesis, anticancer and antiangiogenic activities

Pd(II) and Pt(II) saccharinate complexes with two phosphine derivatives: Synthesis, anticancer and antiangiogenic activities

A trans-configured Pt(II) saccharinate complex bearing benzyldiphenylphosphine inhibits both growth of human colorectal carcinoma cells (HCT116) and angiogenesis, acting as a multifunctional anticancer and antiangiogenic agent.


As clinically used anticancer Pt(II) drugs have severe side effects, there is a growing interest for new metal complexes with great potential for cancer therapy. The current work aimed to prepare and characterize new Pd(II) and Pt(II) saccharinate (sac) complexes bearing pyridyl- and benzyldiphenylphosphines (PPh2Py and PPh2Bz, respectively), cis-[Pd(sac)2(PPh2Py)2] (1), cis-[PtCl(sac)(PPh2Py)2]·0.5DMF (2), cis-[Pd(sac)2(PPh2Bz)2]·DMF (3) and trans-[PtCl(sac)(PPh2Bz)2] (4) as promising anticancer and antiangiogenic drugs. The anticancer activity of the complexes was screened against seven cancer cell lines including HCT116 (colon), HepG2 (liver), MDA-MB-231 (breast), PANC-1 (pancreatic), A549 (lung), C6 (glioma), DU145 (prostate) and normal human lung epithelial cells (BEAS-2B). 1 and 2 did not show biological activity below 20 μM at 48 h, whereas 3 and 4 displayed significant cytotoxic effect on the cancer cells. 4 was the most potent complex (IC50 = 2.2–12.1 μM) and displayed much greater cytotoxicity than cisplatin in all the cancer cell lines. 4 caused apoptosis in HCT116 cells as evidenced by annexin V positivity and caspase 3/7 activity assays. Furthermore, the inhibition of antiapoptotic Bcl-2 proteins by the complex suggested the intrinsic apoptosis. In addition, 4 greatly enhanced generation of intracellular reactive oxygen species (ROS) and consequently caused remarkable DNA double-strand breaks in HCT116 cells. Moreover, the chick chorioallantoic membrane (CAM) assay was used to evaluate antiangiogenic potential of 4. The complex effectively inhibited angiogenesis at a dose of 50 ng, suggesting it as a promising multi-targeted agent for antiangiogenic cancer treatment.

Copper Oxide Anchored Carbon Nanofibers: A Versatile Platform for Multiplex Detection of Antibiotics, Heavy Metals and Pesticides

Electrochemical sensors offer promising prospects for real-time pollutant monitoring. In this study, copper oxide-dispersed graphitic carbon nanofibers (CuO-CNFs) grown via chemical vapour deposition were employed as a robust platform for detecting a variety of environmental pollutants. This array-based sensor adeptly identifies three different classes of analytes, i.e., antibiotics (chloramphenicol (CP) and tylosin tartrate (TT)), heavy metals (cadmium (Cd) and lead (Pb)), and pesticides (quinalphos (QP) and imidacloprid (IP)). The CuO-CNF-modified GCE array rapidly discerns (<15 sec) a broad linear range: 1-20 ppm for CP, 1-13.33 ppm for TT, 0.66-11.66 ppm for Cd, 20-33.33 ppm for Pb, 1.6-11.6 ppm for QP, and 5-25 ppm for IP, boasting quantification limits of 1.0, 1.0, 0.66, 20.0, 1.6, and 5.0 ppm for CP, TT, Cd, Pb, QP, and IP, respectively. Notably, this sensor achieves simultaneous identification of mixed analytes, including CP and TT, Cd and Pb, and QP and IP, within real tap water. The electrochemical sensor exhibits robustness; heightened sensitivity, selectivity, and stability;  swift response; and impressive reproducibility in detecting CP, TT, Cd, Pb, QP, and IP within aqueous samples. Consequently, this array-based electrochemical sensor has emerged as a rapid and simultaneous detection tool for diverse pollutant residues in surface and groundwater samples.

Cadmium (II) metal–organic architecture based on versatile multi‐N‐donor “3,5‐diaminotriazole” and dicarboxylate spacer: Synthesis, crystal structure, and its photocatalytic degradation of organic dye

Cadmium (II) metal–organic architecture based on versatile multi-N-donor “3,5-diaminotriazole” and dicarboxylate spacer: Synthesis, crystal structure, and its photocatalytic degradation of organic dye

The polyfunctional coordination polymer Cd-CP was synthesized using benzene-1,4-dicarboxylic acid and 3,5-diaminotriazole via solvothermal reaction. The Cd-CP has been fully characterized by using single X-ray, TGA, FT-IR, Raman spectroscopy, SEM, PXRD, and BET analysis. The Cd-CP demonstrated a significant level of photocatalytic efficacy at 99.19% under visible light irradiation against MG dye. The kinetic data exhibited pseudo-first order. The •OH is the principal ROS responsible for the degradation of MG.


Herein, we have designed polyfunctional materials of d10-configuration Cd (II) “Cd-CP.” The coordination polymer Cd-CP was synthesized using benzene-1,4-dicarboxylic acid and 3,5-diaminotriazole via solvothermal reaction. The Cd-CP has been fully characterized by using single X-ray crystallography, thermogravimetric analysis (TGA), Fourier transform–infrared (FT-IR) spectroscopy, Raman spectroscopy, scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Brunauer–Emmett–Teller (BET) analysis. Single crystal X-ray crystallography revealed that the CP-Cd crystallized in triclinic space group P – 1 with the chemical composition [(BDC)(DAT)2Cd2Cl] (CH3)2 NH2 + · H2O. The present study investigated the impact of different reaction parameters, including the concentration of MG, the dosage of catalyst, and the duration of irradiation, on the outcome demonstrating a high level of photocatalytic efficacy at 99.19% under visible light irradiation. The obtained kinetic data exhibited conformity with a pseudo-first-order model, indicating that the rate-determining step is likely to be photo-absorption. The value of the apparent rate constant was found to be 0.019 min−1 for 50 mg L−1, 0.016 min−1 for 100 mg L−1, and 0.015 min−1 for 150 mg L−1 MG concentration. The corresponding half-life time was found to be 36.44, 43.31, and 46.20 min with values of correlation coefficient (R 2) as 0.99, 0.93, and 0.98, respectively. Moreover, a trapping experiment was conducted to demonstrate that hydroxy radicals (•OH) are the principal reactive oxygen species (ROS) responsible for the degradation of MG. The results of the total organic carbon (TOC) study indicated a mineralization value of around 89%, suggesting that the dye has been completely degraded into non-toxic by-products such as carbon dioxide (CO2) and water (H2O).

Enhanced intersystem crossing in a thiohelicene

The photophysics of a helicene derivative in which two benzene units are replaced by thiophene units (thiohelicene, 6H) was studied by steady state and transient absorption and emission spectroscopies covering time ranges from femtoseconds to minutes. Efficient intersystem crossing (ISC) to the triplet state was observed, by far exceeding that of the parent helicene and the corresponding oxo-helicene. Quantum chemical calculations indicate that the helical distortion and the heavy atom effect of sulfur cooperate in promoting spin-orbit coupling, and that the most efficient decay channel involved the T2 or even the T3 state. These insights can help in the design of more efficient triplet sensitizes for may applications.

Tuning Sensing Efficacy: The Influence of Alkyl Substituents on Metal Ion Detection at Mesoscopic Interface

In this work, we conducted a comparative analysis of the metal ion sensing capabilities of two pyridine-end oligo p-phenylenevinylene compounds featuring different alkyl substituents (-C4H9 and -C16H33) within a micelle medium. Our findings revealed a correlation between the positioning of the probe molecules within the micelle and the length of the alkyl chains, impacting their self-assembly tendencies and optical characteristics. The compound with shorter alkyl chains demonstrated a superior affinity towards Hg2+ ions, whereas exposure to the compound with longer alkyl substituent resulted in a color-changing response with both Cu2+and Hg2+ ions. Intriguingly, the sensitivity towards Hg2+ ions heightened with increasing alkyl chain length. This trend persisted in non-polar solvents like THF. The capacity to modulate sensing efficacy solely by adjusting the length of the alkyl chains represents a relatively uncommon occurrence in the existing literature. This discovery suggests promising prospects for engineering sensory devices equipped with adaptable sensitivity.

Synthesis of phosphine‐tethered indenyl ruthenium complexes through c‐h bonds activation followed by C‐C bond coupling: High performance catalysts for the redox isomerization of allylic alcohols

Synthesis of phosphine-tethered indenyl ruthenium complexes through c-h bonds activation followed by C-C bond coupling: High performance catalysts for the redox isomerization of allylic alcohols

In this paper, we studied the reactions of Ru(PPh3)3Cl2 with 3-(2-pyridyl)indene and its derivatives, generating two phosphine-tethered indenyl ruthenium complexes {η 5,κ 1 P-(C5H4N-C9H4R-C6H4PPh2)}RuCl(PPh3) (R = H, 1; R = CH3, 2) and an η 5-coordination mode complex {η 5-(CH3C5H3N-C9H6)}RuCl(PPh3)2 (3). Complexes 1 and 2 are formed via C-C coupling of the 2-position of the indenyl ring with the ortho-position of a phenyl ring from triphenylphosphine, which is rare in organometallic chemistry.


Reactions of 3-(2-pyridyl)indene and 5-methyl-3-(2-pyridyl)indene with Ru(PPh3)3Cl2, generated two phosphine-tethered indenyl ruthenium complexes {η 5,κ 1 P-(C5H4N-C9H4R-C6H4PPh2)}RuCl(PPh3) (R = H, 1; R = CH3, 2), respectively. While treatment of 3-(6-methyl-2-pyridyl)indene with Ru(PPh3)3Cl2 gave a product {η 5-(CH3C5H3N-C9H6)}RuCl(PPh3)2 (3); 1 could further react with NaBArF 4 to produce a cationic complex [{η 5,κ 1 P-(C5H4N-C9H5-C6H4PPh2)}Ru(PPh3)][BArF 4] (15). When treated with NaOMe in methanol, 1 was converted into [{η 5,κ 1 P-(C5H4N-C9H5-C6H4PPh2)}RuH(PPh3)] (16). These five complexes were investigated as catalysts for redox isomerization of allylic alcohols, and 16 exhibited best catalytic activity in the presence of t BuOK, reaching quantitative yield in 5 min when α-vinylbenzyl alcohol was used as the substrate, requiring catalyst loading of 1 mol%.