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.

Reversing the stereoselectivity of intramolecular [2+2] photocycloaddition utilizing cucurbit[8]uril as a molecular flask.

Macrocyclic hosts, such as cucurbit[8]uril (CB8), can significantly influence the outcomes of chemical reactions involving encapsulated reactive guests. In this study, we demonstrate that CB8 completely reverses the stereoselectivity of intramolecular [2+2] photo-cycloaddition reactions. Notably, it was also found that CB8 can trigger the unreactive diene to be reactive.

Synthesis of Mono-, Di-, Tri-, and Tetra-cationic Pyridinium and Vinylpyridinium Modified [2.2]Paracyclophanes: Modular Receptors for Supramolecular Systems.

In this report, a new series of mono-, di-, tri-, and tetra-cationic pyridinium and vinyl pyridinium-modified [2.2]paracyclophanes as useful molecular tectons for supramolecular systems are described. Regioselective functionalization at specific positions, followed by resolution step and successive transformations through Pd-catalyzed Suzuki-Miyaura and Mizoroki-Heck cross-coupling chemistry furnish a series of modular PCP scaffolds. In our proof-of-concept study, on N-methylation, the PCPs bearing (cationic) pyridyl functionalities were demonstrated as useful molecular receptors in host-guest supramolecular assays. The PCPs on grafting with light-responsive azobenzene (-N=N-) functional core as side-groups impart photosensitivity that can be remotely transformed on irradiation, offering photo-controlled smart molecular functions. Furthermore, the symmetrical PCPs bearing bi-, and tetra-pyridyl functionalities at the peripheries have enormous potential to serve as ditopic and tetratopic 3D molecular tectons for engineering non-covalent supramolecular assemblies with new structural and functional attributes.

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.

Thio-2 inhibits key signaling pathways required for the development and progression of castration resistant prostate cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BAG-1 mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited 'on-target' toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment resistant prostate cancer cell lines and patient derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation since the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2 mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.

Stereoselective synthesis and X-ray structure determination of novel 1,2-dihydroquinolinehydrazonopropanoate derivatives.

A novel series of 1,2-dihydroquinolinhydrazonopropanoate have been synthesized via a convenient aza-Michael addition reaction between hydrazinylquinolinones and ethyl propiolate in ethanol under refluxing temperature. The structures for all obtained products were confirmed with FTIR, NMR spectrums, as well as mass spectrometry. In addition, the monoclinic structure for compounds 8a, 8c, and 8d was also confirmed via X-ray crystallography analyses. The E-configuration for the obtained products was confirmed form the X-ray analysis. On the other hand, the crystal packing shows that the intermolecular and hydrogen bonds between atoms are parallel to the bc plan.

Optimized Detection of Volatile Organic Compounds Utilizing Durable and Selective Arrays of Tailored UiO-66-X SURMOF Sensors.

Metal-organic frameworks (MOFs), with their well-defined and highly flexible nanoporous architectures, provide a material platform ideal for fabricating sensors. We demonstrate that the efficacy and specificity of detecting and differentiating volatile organic compounds (VOCs) can be significantly enhanced using a range of slightly varied MOFs. These variations are obtained via postsynthetic modification (PSM) of a primary framework. We alter the original MOF's guest adsorption affinities by incorporating functional groups into the MOF linkers, which yields subtle changes in responses. These responses are subsequently evaluated by using machine learning (ML) techniques. Under severe conditions, such as high humidity and acidic environments, sensor stability and lifespan are of utmost importance. The UiO-66-X MOFs demonstrate the necessary durability in acidic, neutral, and basic environments with pH values ranging from 2 to 11, thus surpassing most other similar materials. The UiO-66-NH2 thin films were deposited on quartz-crystal microbalance (QCM) sensors in a high-temperature QCM liquid cell using a layer-by-layer pump method. Three different, highly stable surface-anchored MOFs (SURMOFs) of UiO-66-X obtained via the PSM approach (X: NH2, Cl, and N3) were employed to fabricate arrays suitable for electronic nose applications. These fabricated sensors were tested for their capability to distinguish between eight VOCs. Data from the sensor array were processed using three distinct ML techniques: linear discriminant (LDA), nearest neighbor (k-NN), and neural network analysis methods. The discrimination accuracies achieved were nearly 100% at high concentrations and over 95% at lower concentrations (50-100 ppm).

From Mono- to Polynuclear 2-(Diphenylphosphino)pyridine-Based Cu(I) and Ag(I) Complexes: Synthesis, Structural Characterization, and DFT Calculations.

A series of monometallic Ag(I) and Cu(I) halide complexes bearing 2-(diphenylphosphino)pyridine (PyrPhos, L) as a ligand were synthesized and spectroscopically characterized. The structure of most of the derivatives was unambiguously established by X-ray diffraction analysis, revealing the formation of mono-, di-, and tetranuclear complexes having general formulas MXL3 (M = Cu, X = Cl, Br; M = Ag, X = Cl, Br, I), Ag2X2L3 (X = Cl, Br), and Ag4X4L4 (X = Cl, Br, I). The Ag(I) species were compared to the corresponding Cu(I) analogues from a structural point of view. The formation of Cu(I)/Ag(I) heterobimetallic complexes MM'X2L3 (M/M' = Cu, Ag; X = Cl, Br, I) was also investigated. The X-ray structure of the bromo-derivatives revealed the formation of two possible MM'Br2L3 complexes with Cu/Ag ratios, respectively, of 7:1 and 1:7. The ratio between Cu and Ag was studied by scanning electron microscopy-energy-dispersive X-ray analysis (SEM-EDX) measurements. The structure of the binuclear homo- and heterometallic derivatives was investigated using density functional theory (DFT) calculations, revealing the tendency of the PyrPhos ligands not to maintain the bridging motif in the presence of Ag(I) as the metal center.

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.

Photochemically Activated 3D Printing Inks: Current Status, Challenges, and Opportunities.

3D printing with light is enabled by the photochemistry underpinning it. Without fine control over the ability to photochemically gate covalent bond formation by the light at a certain wavelength and intensity, advanced photoresists with functions spanning from on-demand degradability, adaptability, rapid printing speeds, and tailored functionality are impossible to design. Herein, recent advances in photoresist design for light-driven 3D printing applications are critically assessed, and an outlook of the outstanding challenges and opportunities is provided. This is achieved by classing the discussed photoresists in chemistries that function photoinitiator-free and those that require a photoinitiator to proceed. Such a taxonomy is based on the efficiency with which photons are able to generate covalent bonds, with each concept featuring distinct advantages and drawbacks.

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.

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.

Quinazolin-4-one/3-cyanopyridin-2-one Hybrids as Dual Inhibitors of EGFR and BRAFV600E: Design, Synthesis, and Antiproliferative Activity.

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects.

Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection.

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2,000 deaths annually. While the emergence of resistant bacteria has become concerningly common, identification of useful new drug classes has been limited over the past 40+ years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killing P. aeruginosa and displays sufficiently low toxicity for mammalian cells to allow for use in treatment of infections. Interestingly, TM5 kills P. aeruginosa more rapidly than traditional antibiotics, within 30-60 minutes in vitro , and is effective against a range of clinical isolates. In vivo , TM5 significantly reduced bacterial load in the lungs within 24 hours compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDR P. aeruginosa respiratory infections.

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.

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%).

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.

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor-positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor-positive (ER+) breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ERα and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein-protein interactions such as BAG1-mortalin (GRP75) interaction as well as wild-type p53-mortalin or mutant p53-BAG2 interactions. These activities together reactivated p53 and resulted in cell-cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers. Significance: An imidazopyridine that selectively degrades ERα and is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis.

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 .

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.