Modulation of neuroinflammation and oxidative stress by targeting GPR55 - new approaches in the treatment of psychiatric disorders.

Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.

Modulating Aryl Azide Photolysis: Synthesis of a Room-Temperature Phosphorescent Carboline in Cucurbit[7]uril Host.

Cucurbit[7]uril (CB7), a supramolecular host, is employed to control the pathway of photolysis of an aryl azide in an aqueous medium. Normally, photolysis of aryl azides in bulk water culminates predominantly in the formation of azepine derivatives via intramolecular rearrangement. Remarkably, however, when this process unfolds within the protective confinement of the CB7 cavity, it results in a carboline derivative, as a consequence of a C─H amination reaction. The resulting carboline caged by CB7 reveals long-lived room temperature phosphorescence (RTP) in the solid state, with lifetimes extending up to 2.1 s. These findings underscore the potential of supramolecular hosts to modulate the photolysis of aryl azides and to facilitate novel phosphorescent materials.

Tetrazole and oxadiazole derivatives as thermally activated delayed fluorescence emitters.

Organic light-emitting diodes (OLEDs) are promising lighting solutions for sustainability and energy efficiency. Incorporating thermally activated delayed fluorescence (TADF) molecules enables OLEDs to achieve internal quantum efficiency (IQE), in principle, up to 100%; therefore, new classes of promising TADF emitters and modifications of existing ones are sought after. This study explores the TADF emission properties of six designed TADF emitters, examining their photophysical responses using experimental and theoretical methods. The design strategy involves creating six distinct types of a donor-acceptor (D-A) system, where tert-butylcarbazoles are used as donors, while the acceptor component incorporates three different functional groups: nitrile, tetrazole and oxadiazole, with varying electron-withdrawing character. Additionally, the donor-acceptor distance is adjusted using a phenylene spacer, and its influence on TADF functionality is examined. The clear dependency of an additional spacer, inhibiting TADF, could be revealed. Emitters with a direct donor-acceptor connection are demonstrated to exhibit TADF moderate emissive behavior. The analysis emphasizes the impact of charge transfer, singlet-triplet energy gaps (ΔEST), and other microscopic parameters on photophysical rates, permitting TADF. Among the emitters, TCz-CN shows optimal performance as a blue-green emitter with an 88% photoluminescence quantum yield (PLQY) and fast rate of reversible intersystem crossing of 2x106 s-1.

Key role of cycloalkyne nature in alkyne-dye reagents for enhanced specificity of intracellular imaging by bioorthogonal bioconjugation.

Conjugates of benzothiophene-fused azacyclononyne BT9N-NH2 with fluorescent dyes were developed to visualise azidoglycans intracellularly. The significance of the cycloalkyne core was demonstrated by comparing new reagents with DBCO- and BCN-dye conjugates. To reduce non-specificity during intracellular bioconjugation using SPAAC, less reactive BT9N-dye reagents are preferred over highly reactive DBCO- and BCN-dye conjugates.

Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.

Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells.

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Synthesis of substituted triazole-pyrazole hybrids using triazenylpyrazole precursors.

A synthesis route to access triazole-pyrazole hybrids via triazenylpyrazoles was developed. Contrary to existing methods, this route allows the facile N-functionalization of the pyrazole before the attachment of the triazole unit via a copper-catalyzed azide-alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole-triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In addition, the compatibility of the method with solid-phase synthesis is shown exemplarily.

Development of Fluorescent Isocoumarin-Fused Oxacyclononyne - 1,2,3-Triazole Pairs.

Fluorescent isocoumarin-fused cycloalkynes, which are reactive in SPAAC and give fluorescent triazoles regardless of the azide nature, have been developed. The key structural feature that converts the non-fluorescent cycloalkyne/triazole pair to its fluorescent counterpart is the pi-acceptor group (COOMe, CN) at the C6 position of the isocoumarin ring. The design of the fluorescent cycloalkyne/triazole pairs is based on the theoretical study of the S1 state deactivation mechanism of the non-fluorescent isocoumarin-fused cycloalkyne IC9O using multi-configurational ab initio and DFT methodologies. The calculations revealed that deactivation proceeds through the electrocyclic ring opening of the α-pyrone cycle and is accompanied by a redistribution of electron density in the fused benzene ring. We proposed that the S1 excited state deactivation barrier could be increased by introducing a pi-acceptor group into a position that is in direct conjugation with the formed C=O group and has a reduced electron density in the transition state. As a proof of concept, we designed and synthesized two fluorescent isocoumarin-fused cycloalkynes IC9O-COOMe and IC9O-CN bearing pi-acceptors at the C6 position. The importance of the nature of a pi-acceptor group was shown by the example of much less fluorescent CF3 -substituted cycloalkyne IC9O-CF3 .

Practical synthesis and biological screening of sulfonyl hydrazides.

A methodology for the synthesis of sulfonyl hydrazides mediated by hypervalent iodine is described. Taking advantage of the umpolung properties of hypervalent iodine reagents, the polarity of sodium sulfinate salts is reversed, and a key intermediate is generated and reacted with mono- and disubstituted hydrazines. To highlight the practical utility of this protocol, a diverse range of sulfonyl hydrazides were synthesized in yields up to 62%. Furthermore, a gram-scale reaction was performed, showing the robustness of the procedure. Mechanistic studies, including DFT calculations, were performed and the bioactivity of the generated compounds was evaluated.

Synthesis of bis-thiohydantoin derivatives as an antiproliferative agents targeting EGFR inhibitory pathway.

(R)/(S)-the two enantiomers of 3-substituted-1-[2-(5)-3-substituted-4-benzyl-5-oxo-4-phenyl-2-thioxoimid-azolidin-1-yl]ethyl/propyl-5-benzyl-5-phenyl-2-thioxoimidazolidin-4-ones were formed during the diastereoselective reaction between N,N″-1,ω-alkanediylbis[N'-organylthiourea] derivatives and 2,3-diphenylcyclopropenone in refluxing ethanol. The structures of the isolated compounds were confirmed by NMR, IR, mass spectra and elemental analyses. Moreover, single-crystal X-ray structure analysis was also used to elucidate the structure of the isolated compounds. The mechanism describes the reaction was also discussed. The tested compounds showed EGFR inhibitory activity with IC50 values ranging from 90 to 178 nM in comparison to the erlotinib as a reference with IC50 value of 70 nM. Compound 4c (R = allyl, n = 3) was found as the most potent antiproliferative, had the highest inhibitory effect on EGFR with an IC50 value of 90 nM, compared to erlotinib's IC50 value of 70 nM. The second and third-most active compounds were 4e (R = phenyl, n = 3) and 4d (R = ethyl, n = 3) and with IC50 values of 107 nM and 128 nM. These findings imply that the compounds tested had a significant antiproliferative effect as well as the ability to act as an EGFR inhibitor. Docking studies showed that compound 4c showed high affinity to EGFR based on its docking score (S; kcal/mol) within five test compounds.

Synthesis, Antioxidant and Antiproliferative Actions of 4-(1,2,3-Triazol-1-yl)quinolin-2(1H)-ones as Multi-Target Inhibitors.

The reaction of 4-azido-quinolin-2(1H)-ones 1a-e with the active methylene compounds pentane-2,4-dione (2a), 1,3-diphenylpropane-1,3-dione (2b), and K2CO3 was investigated in this study. This approach afforded 4-(1,2,3-triazol-1-yl)quinolin-2(1H)-ones 3a-j in high yields and purity. All newly synthesized products' structures were identified. Compounds 3a-j were tested for antiproliferative activity against a panel of four cancer cell lines. In comparison to the reference erlotinib (GI50 = 33), compounds 3f-j were the most potent derivatives, with GI50 values ranging from 22 nM to 31 nM. The most effective antiproliferative derivatives, 3f-j, were subsequently investigated as possible multi-target inhibitors of EGFR, BRAFV600E, and EGFRT790M. Compound 3h was the most potent inhibitor of the studied molecular targets, with IC50 values of 57 nM, 68 nM, and 9.70 nM, respectively. The apoptotic assay results demonstrated that compounds 3g and 3h function as caspase-3, 8, and Bax activators as well as down-regulators of the antiapoptotic Bcl2, and hence can be classified as apoptotic inducers. Finally, compounds 3g and 3h displayed promising antioxidant activity at 10 µM, with DPPH radical scavenging of 70.6% and 73.5%, respectively, compared to Trolox (77.6%).

Transition Metal Complexes of Thiosemicarbazides, Thiocarbohydrazides, and Their Corresponding Carbazones with Cu(I), Cu(II), Co(II), Ni(II), Pd(II), and Ag(I)-A Review.

This review focuses on some interesting and recent applications of transition metals towards the complexation of thiosemicarbazides, thiocarbohydrazides, and their corresponding carbazones. We started the review with a description of the chosen five metals, including Cu[Cu(I), Cu(II], Co(II), Ni(II), Pd(II), and Ag(I) and their electronic configurations. The stability of the assigned complexes was also discussed. We shed light on different routes describing the synthesis of these ligands. We also reported on different examples of the synthesis of Cu(I), Cu(II), Co(II), Ni(II), Ag(I), and Pd(II) of thiosemicarbazide and thiocarbohydrazide complexes (until 2022). This review also deals with a summary of the fruitful use of metal complexes of thiosemicarbazones and thiocarbazones ligands in the field of catalysis. Finally, this recent review focuses on the applications of these complexes related to their biological importance.

New 1,2,3-Triazole/1,2,4-triazole Hybrids as Aromatase Inhibitors: Design, Synthesis, and Apoptotic Antiproliferative Activity.

A novel series of 1,2,3-triazole/1,2,4-triazole hybrids 5a, 5b, and 6a-i was designed and synthesized as antiproliferative agents targeting aromatase enzymes. The antiproliferative activity of the new hybrids against four cancer cells was studied using Erlotinib as a control. Compounds 6a and 6b demonstrated the highest antiproliferative activity among these hybrids, with GI50 values of 40 nM and 35 nM, respectively. Compound 6b was the most potent derivative, with a GI50 of 35 nM, comparable to Erlotinib's GI50 of 33 nM. Compound 6b inhibited all cancer cell lines with comparable efficacy to Erlotinib. Compounds 5a, 5b, and 6a-i were tested for inhibitory action against aromatase as a potential target for their antiproliferative activity. Results revealed that compounds 6a and 6b were the most potent aromatase inhibitors, with IC50 values of 0.12 ± 0.01 µM and 0.09 ± 0.01 µM, respectively, being more potent than the reference Ketoconazole (IC50 = 2.6 ± 0.20 µM) but less potent than Letrozole (IC50 = 0.002 ± 0.0002). These findings indicated that compounds 6a and 6b had significant aromatase inhibitory action and are potential antiproliferative candidates. The findings were further linked to molecular docking investigations, which gave models of strong interactions with the aromatase domain for inhibitors with high binding scores.

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways.

A series of novel 3-cyanopyridone/pyrazoline hybrids (21-30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.

Synthesis and Antiproliferative Potential of Thiazole and 4-Thiazolidinone Containing Motifs as Dual Inhibitors of EGFR and BRAFV600E.

Thiazole and thiazolidinone recur in a wide range of biologically active compounds that reach different targets within the context of tumors and represent a promising starting point to access potential candidates for treating metastatic cancer. Therefore, searching for new lead compounds that show the highest anticancer potency with the fewest adverse effects is a major drug-discovery challenge. Because the thiazole ring is present in dasatinib, which is currently used in anticancer therapy, it is important to highlight the ring. In this study, cycloalkylidenehydrazinecarbothioamides (cyclopentyl, cyclohexyl, cyclooctyl, dihydronapthalenylidene, flurine-9-ylidene, and indolinonyl) reacted with 2-bromoacetophenone and diethylacetylenedicarboxylate to yield thiazole and 4-thiazolidinone derivatives. The structure of the products was confirmed by using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray analyses. The antiproliferative activity of the newly synthesized compounds was evaluated. The most effective inhibitory compounds were further tested in vitro against both epidermal growth factor receptor (EGFR) and B-Raf proto-oncogene, serine/threonine kinase (BRAFV600E) targets. Additionally, molecular docking analysis examined how these molecules bind to the active sites of EGFR and BRAFV600E.

Stacking Cyclophanes into Chiral Microvessels.

Engineering novel micro-/nanoscale systems and devices based on supramolecular assembly has tremendous potential from diverse applications perspective. However, controlling the size, shape, spatial arrangements, and hierarchical transcription by a dimensional organizing principle (1D-3D arrangement) without the help of templates remains a challenging task. In this vein, a recent study by Oki and colleagues reporting the stacking of chiral cyclophanes via intermolecular non-covalent interactions for crafting synchronous microcrystalline 3D chiral vessels with controlled conformational arrangements represents a truly remarkable illustration of molecular engineering. The microvessels bear stereocontrolled skeletal morphology, recognize stereoisomers and serve as containers to accommodate microcrystals, polymer particles, and fluorescent dyes. The full application scope of this fascinating research is far beyond non-covalent interactions, supramolecular self-assembly, and crystal engineering.

Metal-Organic Framework Thin Films as Ideal Matrices for Azide Photolysis in Vacuum.

Studies on reactions in solutions are often hampered by solvent effects. In addition, detailed investigation on kinetics is limited to the small temperature regime where the solvent is liquid. Here, we report the in situ spectroscopic observation of UV-induced photochemical reactions of aryl azides within a crystalline matrix in vacuum. The matrices are formed by attaching the reactive moieties to ditopic linkers, which are then assembled to yield metal-organic frameworks (MOFs) and surface-mounted MOFs (SURMOFs). These porous, crystalline frameworks are then used as model systems to study azide-related chemical processes under ultrahigh vacuum (UHV) conditions, where solvent effects can be safely excluded and in a large temperature regime. Infrared reflection absorption spectroscopy (IRRAS) allowed us to monitor the photoreaction of azide in SURMOFs precisely. The in situ IRRAS data, in conjunction with XRD, MS, and XPS, reveal that illumination with UV light first leads to forming a nitrene intermediate. In the second step, an intramolecular rearrangement occurs, yielding an indoloindole derivative. These findings unveil a novel pathway for precisely studying azide-related chemical transformations. Reference experiments carried out for solvent-loaded SURMOFs reveal a huge diversity of other reaction schemes, thus highlighting the need for model systems studied under UHV conditions.

Substrate-Bound Diarylethene-Based Anisotropic Metal-Organic Framework Films as Photoactuators with a Directed Response.

Molecular machines and responsive materials open a plethora of new opportunities in nanotechnology. We present an oriented crystalline array of diarylethene (DAE)-based photoactuators, arranged in a way to yield an anisotropic response. The DAE units are assembled, together with a secondary linker, into a monolithic surface-mounted metal-organic framework (SURMOF) film. By Infrared (IR) and UV/Vis spectroscopy as well as by synchrotron X-ray diffraction, we show that the light-induced extension changes of the molecular DAE linkers multiply to yield mesoscopic and anisotropic length changes. Due to the special architecture and substrate-bonding of the SURMOF, these length changes are transferred to the macroscopic scale, leading to the bending of a cantilever and performing work. This research shows the potential of assembling light-powered molecules into SURMOFs to yield photoactuators with a directed response, presenting a path to advanced actuators.

Twisting of Porphyrin by Assembly in a Metal-Organic Framework yielding Chiral Photoconducting Films for Circularly-Polarized-Light Detection.

While materials based on organic molecules usually have either superior optoelectronic or superior chiral properties, the combination of both is scarce. Here, a crystalline chiroptical film based on porphyrin with homochiral side groups is presented. While the dissolved molecule has a planar, thus, achiral porphyrin core, upon assembly in a metal-organic framework (MOF) film, the porphyrin core is twisted and chiral. The close packing and the crystalline order of the porphyrin cores in the MOF film also results in excellent optoelectronic properties. By exciting the Soret band of porphyrin, efficient photoconduction with a high On-Off-ratio is realized. More important, handedness-dependent circularly-polarized-light photoconduction with a dissymmetry factor g of 4.3×10-4 is obtained. We foresee the combination of such assembly-induced chirality with the rich porphyrin chemistry will enable a plethora of organic materials with exceptional chiral and optoelectronic properties.