Charge Transfer-Promoted Excited State of a Heavy-Atom-Free Photosensitizer for Efficient Application of Mitochondria-Targeted Fluorescence Imaging and Hypoxia Photodynamic Therapy.

Conventional photosensitizers (PSs) used in photodynamic therapy (PDT) have shown preliminary success; however, they are often associated with several limitations including potential dark toxicity in healthy tissues, limited efficacy under acidic and hypoxic conditions, suboptimal fluorescence imaging capabilities, and nonspecific targeting during treatment. In response to these challenges, we developed a heavy-atom-free PS, denoted as Cz-SB, by incorporating ethyl carbazole into a thiophene-fused BODIPY core. A comprehensive investigation into the photophysical properties of Cz-SB was conducted through a synergistic approach involving experimental and computational investigations. The enhancement of intersystem crossing (kISC) and fluorescence emission (kfl) rate constants was achieved through a donor-acceptor pair-mediated charge transfer mechanism. Consequently, Cz-SB demonstrated remarkable efficiency in generating reactive oxygen species (ROS) under acidic and low-oxygen conditions, making it particularly effective for hypoxic cancer PDT. Furthermore, Cz-SB exhibited good biocompatibility, fluorescence imaging capabilities, and a high degree of localization within the mitochondria of living cells. We posit that Cz-SB holds substantial prospects as a versatile PS with innovative molecular design, representing a potential "one-for-all" solution in the realm of cancer phototheranostics.

Synthesis of a 3,7-Disubstituted Isothiazolo[4,3-b]pyridine as a Potential Inhibitor of Cyclin G-Associated Kinase.

Disubstituted isothiazolo[4,3-b]pyridines are known inhibitors of cyclin G-associated kinase. Since 3-substituted-7-aryl-isothiazolo[4,3-b]pyridines remain elusive, a strategy was established to prepare this chemotype, starting from 2,4-dichloro-3-nitropyridine. Selective C-4 arylation using ligand-free Suzuki-Miyaura coupling and palladium-catalyzed aminocarbonylation functioned as key steps in the synthesis. The 3-N-morpholinyl-7-(3,4-dimethoxyphenyl)-isothiazolo[4,3-b]pyridine was completely devoid of GAK affinity, in contrast to its 3,5- and 3,6-disubstituted congeners. Molecular modeling was applied to rationalize its inactivity as a GAK ligand.

Discovery of a novel androgen receptor antagonist, MEL-6, with stereoselective activity and optimization of its metabolic stability.

A new chemical scaffold with antagonistic activity towards the androgen receptor (AR) was identified. The parent compound, (3-Methoxy-N-[1-methyl-2-(4-phenyl-1-piperazinyl)-2-(2-thienyl)ethyl]benzamide) referred to as MEL-6, binds in the ligand binding pocket of AR and induces an antagonistic conformation of the ligand binding domain, even in presence of the antagonist-to-agonist switch mutations W741C, T877A and F876L-T877A. MEL-6 has antiproliferative effects on several AR positive prostate cancer cell lines. We further identified AR as the specific target of MEL-6 since it demonstrates little effect on other steroid receptors. In LNCaP cells it also inhibits the androgen-regulated transcriptome. These findings identify MEL-6 as a promising candidate for treatment of patients with prostate tumors that have become resistant to current clinically used AR antagonists. Analytical studies on the chemical composition of MEL-6 identified the presence of four isomers (two enantiomeric pairs), among which one isomer is responsible for the antiandrogenic activity. We therefore developed a synthetic route towards the selective preparation of the active enantiomeric pair. Various MEL-6-like analogues had improved metabolic stability while maintaining antiandrogenic activity. Metabolite identification of MEL-6 derivatives pinpointed N-dealkylation of the piperazine as the main mode for inactivation by liver enzymes. For further structural optimization, MEL-6 derivatives were purchased or synthesized having alterations on the N-phenyl group of the piperazine, the benzoyl group and additionally substituting the thiophen-2-yl ring of MEL-6 to a phenyl ring. This optimization process resulted in compound 12b with sustained AR inhibition and a 4-fold increased half-life due to the 1-(5-chloro-2-methylphenyl)-piperazine substitution, thienyl-to-phenyl substitution and chloro in para-position of the benzoyl group.

A Highly Efficient Strategy for One-Pot and Pseudo-Six-Component Synthesis of Hexahydroquinolines.

In this study, a homogeneous acid-catalyzed reaction of a series of benzaldehydes, benzylamines, and Meldrum's acid was presented, allowing the novel one-pot and multicomponent synthesis of hexahydroquinolines with high stereoselectivity. The current strategy has advantages including high regioselectivity, good efficiency, reasonable diversity, utilization of an inexpensive and safe catalyst, and easy purification of products by simple recrystallization. The current reaction utilizes 2 equiv of Meldrum's acid, 3 equiv of benzaldehyde derivatives, and one equiv of amine derivatives to yield (4'S,5'S,7'S)-1'-benzyl-2,2-dimethyl-4',5',7'-triphenyl-3',4',7',8'-tetrahydro-1'H-spiro[[1,3]dioxane-5,6'-quinoline]-2',4,6(5'H)-trione derivatives.

Identification of novel human CC chemokine receptor 8 (CCR8) antagonists via the synthesis of naphthalene amide and sulfonamide isosteres.

The human CC chemokine receptor 8 (CCR8) has been extensively pursued as target for the treatment of various inflammatory disorders. More recently, the importance of CCR8 in the tumor microenvironment has been demonstrated, spurring the interest in CCR8 antagonism as therapeutic strategy in immuno-oncology. On a previously described naphthalene sulfonamide with CCR8 antagonistic properties, the concept of isosterism was applied, leading to the discovery of novel CCR8 antagonists with IC50 values in the nM range in both the CCL1 competition binding and CCR8 calcium mobilization assay. The excellent CCR8 antagonistic activity of the most potent congeners was rationalized by homology molecular modeling.

Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to C,N-diheteroarylcarbamidines.

A novel and efficient base-catalyzed, transition-metal-free method for the synthesis of diheterocyclic compounds connected by an amidine linker, including apart from the common 1,2,3-triazole ring, either an additional pyrimidinedione, 4-nitroimidazole, isoxazole, 1,3,4-triazole, 2-oxochromone or thiazole ring, has been developed. The process was facilitated by a strong base and includes the cycloaddition reaction of 3,3-diaminoacrylonitriles (2-cyanoacetamidines) to heterocyclic azides followed by a Cornforth-type rearrangement to the final products. The reaction is tolerant to various N-monosubstituted 3,3-diaminoacrylonitriles and to different heterocyclic azides. The developed method has a broad scope and can be applied to obtain a variety of N-heteroaryl-1,2,3-triazole-4-carbimidamides with alkyl, allyl, propargyl, benzyl, cycloalkyl, and indolyl substituents at the N1 position .

Covalent immobilization of N-heterocyclic carbenes on pristine carbon substrates: from nanoscale characterization to bulk catalysis.

To control the synthesis of designer catalysts on graphitic materials up to the nanometer scale, methods should be provided that combine both nanoscale characterization and bulk scale experiments. This work reports the grafting of N-heterocyclic carbene (NHC)-type catalysts on graphite, both at nanometer and bulk scale, as it allows increased insights into the nature of the immobilized catalysts.

Exploration of 1,2,3-triazolo fused triterpenoids as inhibitors of human coronavirus 229E targeting the viral nsp15 protein.

The coronavirus disease-19 (COVID-19) pandemic has raised major interest in innovative drug concepts to suppress human coronavirus (HCoV) infections. We previously reported on a class of 1,2,3-triazolo fused betulonic acid derivatives causing strong inhibition of HCoV-229E replication via the viral nsp15 protein, which is proposedly related to compound binding at an intermonomer interface in hexameric nsp15. In the present study, we further explored the structure-activity relationship (SAR), by varying the substituent at the 1,2,3-triazolo ring as well as the triterpenoid skeleton. The 1,2,3-triazolo fused triterpenoids were synthesized by a multicomponent triazolization reaction, which has been developed in-house. Several analogs possessing a betulin, oleanolic acid, or ursolic acid core displayed favorable activity and selectivity (EC50 values for HCoV-229E: 1.6-3.5 µM), but neither of them proved as effective as the lead compound containing betulonic acid. The 18ß-glycyrrhetinic acid-containing analogs had low selectivity. The antiviral findings were rationalized by in silico docking in the available structure of the HCoV-229E nsp15 protein. The new SAR insights will aid the further development of these 1,2,3-triazolo fused triterpenoid compounds as a unique type of coronavirus inhibitors.

Design and synthesis of a BOAHY-derived tracker for fluorescent labeling of mitochondria.

Fluorescence microscopy has proven to be a crucial powerful tool to specifically visualize cellular organelles. In-depth visualization of the structure of mitochondria in living cells is of great value to better understand their function. Herein, based on our experience in construction of fluorescent difluoroboronate anchored acylhydrazones (BOAHY) chromophores, we rationally designed a novel monoboron complex with a connected triphenylphosphonium moiety, and evaluated its spectroscopic properties, cytotoxicity and intracellular localization. Owing to the positive charge on our fluorescent dye, the molecule had an excellent mitochondria-targeting ability (Pearson's correlation is 0.86).To the best of our knowledge, this is the first example of a BOAHY dye which has been applied as an efficient tracker to target mitochondria in living cells.

Synthesis and structure-activity relationship study of phenoxybenzylpiperazine analogues as CCR8 agonists.

CCR8 agonists hold promise for the treatment of various auto-immune diseases. Despite the fact that phenoxybenzylpiperazine derivatives are known to be endowed with CCR8 agonistic activity, systematic structure-activity relationship studies have not been reported. In this study, ZK756326, a previously disclosed CCR8 agonist, was divided in various fragments and each subunit was subjected to structural modifications. All newly synthesized analogues were evaluated in a CCR8 calcium mobilization assay, revealing that only limited structural variation was tolerated in both phenyl rings and at the benzylic position. In contrast, various linkers gave analogues with good CCR8 agonistic potency. In addition, the presence of small substituents on the piperazinyl moiety or the exchange of the piperazinyl for a piperidinyl group afforded compounds with promising CCR8 agonism, with the most potent congener being 10-fold more potent than ZK756326.

Synthesis and Modification of Morphine and Codeine, Leading to Diverse Libraries with Improved Pain Relief Properties.

Morphine and codeine, two of the most common opioids, are widely used in the clinic for different types of pain. Morphine is one of the most potent agonists for the µ-opioid receptor, leading to the strongest analgesic effect. However, due to their association with serious side effects such as respiratory depression, constriction, euphoria, and addiction, it is necessary for derivatives of morphine and codeine to be developed to overcome such drawbacks. The development of analgesics based on the opiate structure that can be safe, orally active, and non-addictive is one of the important fields in medicinal chemistry. Over the years, morphine and codeine have undergone many structural changes. The biological investigation of semi-synthetic derivatives of both morphine and codeine, especially morphine, shows that studies on these structures are still significant for the development of potent opioid antagonists and agonists. In this review, we summarize several decade-long attempts to synthesize new analogues of morphine and codeine. Our summary placed a focus on synthetic derivatives derived from ring A (positions 1, 2, and 3), ring C (position 6), and N-17 moiety.

Tandem Cycloaddition of Azides to 3,3-Diaminoacrylonitriles (2-Cyanoacetamidines) and Cornforth-Type Rearrangement as an Approach to 5-Amino-1,2,3-triazole-4-N-substituted Imidamides.

An efficient base-catalyzed, metal-free method for the synthesis of 5-amino-1,2,3-triazole-4-N-sulfonyl- and arylimidamides, directed by the structure of the amidine group, has been developed. It is based on a previously unknown tandem process involving cycloaddition reaction to 3,3-diaminoacrylonitriles (2-cyanoacetamidines) with aryl(alkyl)sulfonyl or aryl azides and Cornforth-type rearrangement. During the reaction optimization, different factors were found to facilitate the title reaction, which include the use of a strong base and N-mono- or N,N'-disubstituted 3,3-diaminoacrylonitriles. The reaction is tolerant to variously N-monosubstituted and N,N'-disubstituted 3,3-diaminoacrylonitriles and to various aryl- and aryl/alkyl sulfonyl azides. The developed method has a broad scope and can be applied to obtain a variety of 5-amino-1,2,3-triazole-4-carbimidamides bearing at the N1 position alkyl, allyl, propargyl, benzyl, cycloalkyl, and heteroaryl substituents and sulfonyl and aryl substituents at the amidine group. Post-cyclization reactions of prepared 5-amino-1,2,3-triazoles with DMF-DMA DMA-DMF leads to 1,2,3-triazolo[4,5-d]pyrimidines, 8-aza purine analogues demonstrating the applicability of the prepared compounds in organic synthesis.

Three-Step Synthetic Pathway toward Fully Decorated [1,2,3]Triazolo[4,5-d]pyrimidine (8-Azapurine) Derivatives.

[1,2,3]Triazolo[4,5-d]pyrimidines (8-azapurines) are known bioisosteres of the purine nucleus. A step-efficient synthesis of 8-azapurines, in particular 6-alkyl derivatives, is currently unavailable. This work focuses on a three-step synthetic pathway for the synthesis of fully decorated 8-azapurines, with special attention on 6-alkyl-8-azapurines. A diverse library of 8-azapurines was obtained starting from various alkynes, azides, and amidines, involving interrupted CuAAC, oxidation, and cyclization reactions. Additionally, postfunctionalization reactions were demonstrated for a selected number of substrates.

Optimization of triazolo[4,5-d]pyrimidines towards human CC chemokine receptor 7 (CCR7) antagonists.

CCR7 signaling directs the migration of both immune cells and cancer cells to the lymph nodes, is involved in numerous chronic inflammatory disorders and lymph node metastases. Despite the therapeutic promise of CCR7 antagonists, no potent and selective small molecule CCR7 antagonists have been reported to date. Since most human chemokine G protein-coupled receptors (GPCRs) share a conserved intracellular allosteric binding site, new CCR7 antagonist chemotypes may be identified by screening small molecules that are known to target this site in other chemokine GPCRs. In this work, our previously prepared series of 14 scaffold-modified analogues of a known thiazolo[4,5-d]pyrimidine CXCR2 antagonist were screened as potential CCR7 antagonists. This resulted in the discovery of a triazolo[4,5-d]pyrimidine analogue with an IC50 of 2.43 µM against CCR7 and 0.66 µM against CXCR2. Exploration of the structure-activity relationship (SAR) for the 3-, 5- and 7-position substituents of this triazolo[4,5-d]pyrimidine resulted in improved potency and selectivity, with an IC50 of 0.43 µM and 11.02 µM against CCR7 and CXCR2, respectively, for the most selective derivative. Molecular docking showed that the binding mode of these triazolo[4,5-d]pyrimidines in CCR7 and CXCR2 corresponds with those of previously co-crystallized ligands.

Exploration of Pyrido[3,4-d]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2.

Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4-d]pyrimidine analogue as a promising CXCR2 antagonist with an IC50 value of 0.11 µM in a kinetic fluorescence-based calcium mobilization assay. This study aims at exploring the structure-activity relationship (SAR) and improving the CXCR2 antagonistic potency of this pyrido[3,4-d]pyrimidine via systematic structural modifications of the substitution pattern. Almost all new analogues completely lacked the CXCR2 antagonism, the exception being a 6-furanyl-pyrido[3,4-d]pyrimidine analogue (compound 17b) that is endowed with similar antagonistic potency as the original hit.

Synthesis and discovery of mitochondria-targeting oleanolic acid derivatives for potential PI3K inhibition.

Oleanolic acid and its derivatives have been widely reported for their antitumor activities. Recently, the introduction of a triphenylphosphonium cation moiety has been described to improve the selectivity and cytotoxicity of pentacyclic triterpenoids by targeting the mitochondria of human cancer cells. In this work, a series of novel mitochondria-targeting oleanolic acid derivatives were synthesized and their antitumor activities assessed. The majority of the compounds are more cytotoxicity to cancer cells than normal cells, especially for 6c with IC50 of 0.81 µM in A549 cells, which showed a slight increase compared to doxorubicin (0.97 µM). Mechanism studies demonstrated that 6c induced apoptosis of A549 cells in a dose-dependent manner, and reactive oxygen species production, mitochondrial membrane potential depolarization, and particularly pro-apoptotic proteins upregulated by western blotting experiment may be responsible for the results. Moreover, 6c arrested the cell cycle at G2/M phase and cell migration in A549 cells. Compound 6c had a comparable or somewhat improved activity to the positive control LY294002 in molecular docking studies and in vitro testing, demonstrating that the apoptosis mechanism may involve inhibition of the PI3K-Akt pathway. These results augur well for the use of 6c as a novel triphenylphosphonium-conjugated anticancer agent.

Adsorptive separation using self-assembly on graphite: from nanoscale to bulk processes.

Adsorptive separation is a promising lower-energy alternative for traditional industrial separation processes. While carbon-based materials have a long history in adsorptive removal of organic contaminants from solution or gas mixtures, separation using an adsorption/desorption protocol is rarely considered. The main drawbacks are the limited control in bulk adsorption experiments, as often all organic molecules are adsorbed, and lack of desorption methods to retrieve the adsorbed molecules. Using high-resolution on-surface characterization with scanning tunneling microscopy (STM), an increased understanding of the on-surface adsorption behavior under different conditions was obtained. The insight obtained from the nanoscale experiments was used to develop a highly selective separation method using adsorption and desorption on graphite, which was tested for the separation of quinonoid zwitterions. These experiments on adsorptive separation using self-assembly on graphite show its potential and demonstrate the advantage of combining surface characterization techniques with bulk experiments to exploit different possible applications of carbon-based materials.

Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones.

Substituted 4-acetyl-3-hydroxy-3-pyrroline-2-ones have been prepared via three-component reactions and the tautomerism of these 3-pyrroline-2-ones is due to the slight difference of energy, and the significantly large rate constant of transformation between two tautomers. 1,4,5-Trisubstituted pyrrolidine-2,3-dione derivatives were prepared from the above mentioned 2-pyrrolidinone derivatives and aliphatic amines, which exist in enamine form and are stabilized by an intramolecular hydrogen bond. A possible reaction mechanism between 3-pyrroline-2-one and aliphatic amine (CH3NH2) was proposed based on computational results and the main product is formed favorably following the PES via the lowest ΔG # pathway in both the gas-phase and an ethanol solvent model. DFT calculations showed that kinetic selectivity is more significant than thermodynamic selectivity for forming main products.

Rhodium-Catalyzed Transannulation of 4,5-Fused 1-Sulfonyl-1,2,3-triazoles with Nitriles. The Selective Formation of 1-Sulfonyl-4,5-fused Imidazoles versus Secondary C-H Bond Migration.

The reactivity of readily available 4,5-fused-1-sulfonyl-1,2,3-triazoles was examined in the Rh(II)-catalyzed transannulation reaction with nitriles. We have come across the interesting observation that 1-sulfonyl cycloalkeno[d][1,2,3]triazoles that possess ß-hydrogens resist intramolecular ß-hydride migration and could serve as a new source of Rh-iminocarbenoids for intermolecular Rh(II)-catalyzed transannulation reactions. As a result, 1-sulfonyl cyclohexeno-, cyclohepteno-, dihydropyrano-, 5-phenyltetrahydrobenzo-, and 4,5-dihydronaphtho[d]imidazoles were synthesized from various nitriles in good yields. A one-pot methodology has also been executed for the synthesis of NH-imidazoles.

Isolation and In Silico Inhibitory Potential against SARS-CoV-2 RNA Polymerase of the Rare Kaempferol 3-O-(6″-O-acetyl)-Glucoside from Calligonum tetrapterum.

The phytochemical constituents of Calligonum tetrapterum Jaub. & Spach (Family Polygonaceae) were studied for the first time. The study resulted in the isolation of the rare flavonol glycoside, kaempferol 3-O-(6″-O-acetyl)-glucoside,(K3G-A). The potential inhibitive activity of K3G-A toward SARS-CoV-2 was investigated utilizing several in silico approaches. First, molecular fingerprints and structural similarity experiments were carried out for K3G-A against nine co-crystallized ligands of nine proteins of SARS-CoV-2 to reveal if there is a structural similarity with any of them. The conducted studies showed the high similarity of K3G-A and remdesivir, the co-crystallized ligand of SARS-CoV-2 RNA-dependent RNA polymerase (PDB ID: 7BV2), RdRp. To validate these findings, a DFT study was conducted and confirmed the proposed similarity on the electronic and orbital levels. The binding of K3G-A against RdRp was confirmed through molecular docking studies exhibiting a binding energy of -27.43 kcal/mol, which was higher than that of remdesivir. Moreover, the RdRp-K3G-A complex was subjected to several MD studies at 100 ns that authenticated the accurate mode of binding and the correct dynamic behavior. Finally, in silico ADMET and toxicity evaluation of K3G-A was conducted and denoted the safety and the drug-likeness of K3G-A. In addition to K3G-A, two other metabolites were isolated and identified to be kaempferol (K) and ß-sitosterol (ß-S).