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1.
Bioorg Med Chem ; 107: 117756, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38759255

ABSTRACT

Herein, four silver(I) complexes bearing acetylated d-galactopyranoside-based N-heterocyclic carbene ligands were synthesized and fully characterized by elemental analysis, NMR, and X-ray photoelectron spectroscopy. All complexes were obtained with an anomeric ß-configuration and as monocarbene species. In this study, we investigated the biological effects of the silver(I) complexes 2a-d on the human rhabdomyosarcoma cell line, RD. Our results show concentration-dependent effects on cell density, growth inhibition, and activation of key signaling pathways such as Akt 1/2, ERK 1/2, and p38-MAPK, indicating their potential as anticancer agents. Notably, at 35.5 µM, the complexes induced mitochondrial network disruption, as observed with 2b and 2c, whereas with 2a, this disruption was accompanied by nuclear content release. These results provide insight into the utility of carbohydrate incorporated NHC complexes of silver(I) as new agents in cancer therapy.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Screening Assays, Antitumor , Rhabdomyosarcoma , Silver , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Silver/chemistry , Silver/pharmacology , Cell Proliferation/drug effects , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/pathology , Structure-Activity Relationship , Molecular Structure , Methane/chemistry , Methane/analogs & derivatives , Methane/pharmacology , Methane/chemical synthesis , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Dose-Response Relationship, Drug , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Cell Line, Tumor , Acetylation , Galactose/chemistry , Galactose/pharmacology
2.
J Enzyme Inhib Med Chem ; 36(1): 1938-1951, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34459690

ABSTRACT

In this paper, bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated for their inhibitory activity against α-glucosidase and α-amylase. All synthesised compounds showed potential α-glucosidase and α-amylase inhibitory activities. Compounds 5 g (IC50: 7.54 ± 1.10 µM), 5e (IC50: 9.00 ± 0.97 µM), and 5 h (IC50: 9.57 ± 0.62 µM) presented strongest inhibitory activities against α-glucosidase, that were ∼ 30 times stronger than acarbose. Compounds 5 g (IC50: 32.18 ± 1.66 µM), 5 h (IC50: 31.47 ± 1.42 µM), and 5 s (IC50: 30.91 ± 0.86 µM) showed strongest inhibitory activities towards α-amylase, ∼ 2.5 times stronger than acarbose. The mechanisms and docking simulation of the compounds were also studied. Compounds 5 g and 5 h exhibited bifunctional inhibitory activity against these two enzymes. Furthermore, compounds showed no toxicity against 3T3-L1 cells and HepG2 cells.HighlightsA series of bis (indol-3-yl) methanes (BIMs) were synthesised and evaluated inhibitory activities against α-glucosidase and α-amylase.Compound 5g exhibited promising activity (IC50 = 7.54 ± 1.10 µM) against α-glucosidase.Compound 5s exhibited promising activity (IC50 = 30.91 ± 0.86 µM) against α-amylase.In silico studies were performed to confirm the binding interactions of synthetic compounds with the enzyme active site.


Subject(s)
Glycoside Hydrolase Inhibitors/chemical synthesis , Indoles/chemical synthesis , Methane/chemical synthesis , alpha-Amylases/metabolism , alpha-Glucosidases/metabolism , 3T3 Cells , Acarbose/chemistry , Animals , Catalytic Domain , Glycoside Hydrolase Inhibitors/metabolism , Hep G2 Cells , Humans , Kinetics , Methane/metabolism , Mice , Molecular Docking Simulation , Protein Binding , Protein Conformation , Structure-Activity Relationship
3.
Arch Pharm (Weinheim) ; 354(9): e2100111, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34128256

ABSTRACT

Nowadays, silver-N-heterocyclic carbene (silver-NHCs) complexes are widely used in medicinal chemistry due to their low toxic nature toward humans. Due to the success of silver-NHCs in medicinal applications, interest in these compounds is rapidly increasing. Therefore, the interaction of N,N-disubstituted benzimidazolium salts with Ag2 O in dichloromethane to prepare novel Ag(I)-NHCs complexes was carried out at room temperature for 120 h in the absence of light. The obtained complexes were identified and characterized by 1 H and 13 C nuclear magnetic resonance, Fourier-transform infrared, UV-Vis, and elemental analysis techniques. Then, the silver complexes were applied for three-component coupling reactions of aldehydes, amines, and alkynes. The effect of changing the alkyl substituent on the NHCs ligand on the catalytic performance was investigated. In addition, it has been found that the complexes are antimicrobially active and show higher activity than the free ligand. The silver-carbene complexes showed antimicrobial activity against specified microorganisms with MIC values between 0.24 and 62.5 µg/ml. These results showed that the silver-NHC complexes exhibit an effective antimicrobial activity against bacterial and fungal strains. A density functional theory calculation study was performed to identify the stability of the obtained complexes. All geometries were optimized employing an effective core potential basis, such as LANL2DZ for the Ag atom and 6-311+G(d,p) for all the other atoms in the gas phase. Electrostatic potential surfaces and LUMO-HOMO energy were computed. Transition energies and excited-state structures were obtained from the time-dependent density functional theory calculations.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Methane/analogs & derivatives , Silver Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Bacteria/drug effects , Density Functional Theory , Drug Stability , Fungi/drug effects , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Methane/chemical synthesis , Methane/chemistry , Methane/pharmacology , Microbial Sensitivity Tests , Silver Compounds/chemical synthesis , Silver Compounds/chemistry , Static Electricity , Structure-Activity Relationship , Time Factors
4.
Acc Chem Res ; 54(11): 2552-2564, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33930267

ABSTRACT

Carbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science and biotechnology. Access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is believed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of this glycosyl cation is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theoretical and experimental approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity.We also highlight that, from a chemical perspective, the glycosylation reaction can be described as a continuum, from unimolecular SN1 with naked oxocarbenium cations as intermediates to bimolecular SN2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-separated ion pairs, solvent-equilibrated ion pairs) with bimolecular features in most reactions is also highlighted.The role of theoretical calculations to predict the conformation, dynamics, and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under SN1-like conditions.Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterization of the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid solution by NMR spectroscopy.We also pay special attention to the reactivity of these glycosyl ions, which depends on the conditions, including the counterions, the possible intra- or intermolecular participation of functional groups that may stabilize the cation and the chemical nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different experimental perspectives, which identified the involved ionic intermediates, estimating their lifetimes and reactivities and studying their interactions with other molecules. In this context, we also emphasize the relationship between the chemical methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of molecules that regulate the stability and reactivity of glycosyl cations.


Subject(s)
Methane/analogs & derivatives , Glycosylation , Ions/chemical synthesis , Ions/chemistry , Methane/chemical synthesis , Methane/chemistry , Models, Molecular , Molecular Conformation
5.
Metallomics ; 13(2)2021 02 17.
Article in English | MEDLINE | ID: mdl-33595656

ABSTRACT

N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC-silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process. Biological evaluation was conducted with in vitro toxicology assays showing these novel complexes had excellent inhibition against Gram-negative strains E. coli, P. aeruginosa, and K. pneumoniae; further studies also confirmed the ability to inhibit biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) and C. Parapsilosis. In vivo testing using a murine thigh infection model showed promising inhibition of MRSA for the lead compound SBC3, which is derived from 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*).


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Silver/chemistry , Silver/pharmacology , Anti-Bacterial Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Fatty Acids/chemical synthesis , Fatty Acids/chemistry , Fatty Acids/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Methane/analogs & derivatives , Methane/chemical synthesis , Methane/chemistry , Methane/pharmacology , Models, Molecular
6.
Nat Protoc ; 16(3): 1476-1493, 2021 03.
Article in English | MEDLINE | ID: mdl-33504989

ABSTRACT

N-heterocyclic carbene gold(I) chloride and hydroxide complexes are regularly used as synthons to access various oxygen-, nitrogen- or carbon-bound gold complexes. They are also widely employed as efficient catalysts in addition reactions of hydroelements to unsaturated bonds and in several rearrangement and decarboxylation protocols. Here we describe the multigram synthesis of the most common mononuclear N-heterocyclic carbene gold(I) chloride complexes bearing the N,N'-bis-(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and N,N'-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene (IPr*) ligands. Their synthesis is achieved through the straightforward and practical weak base approach in a total time of 4-5 h. This straightforward methodology is conducted under air and possesses considerable advantages over alternative routes, such as the use of a sustainable reaction solvent, minimal amounts of a mild base and commercially available or easily obtained starting materials. Additionally, we describe the synthesis of the mononuclear gold(I) hydroxide complex bearing the IPr ligand, using the state-of-the-art method requiring 24 h. Finally, the improved synthesis of the dinuclear gold(I) hydroxide complex [{Au(IPr)}2(µ-OH)][BF4] is described (~3 h). All procedures can be performed by researchers with standard training and lead to high yields (76-99%) of microanalytically pure bench-stable materials.


Subject(s)
Gold/chemistry , Heterocyclic Compounds/chemical synthesis , Methane/analogs & derivatives , Catalysis , Heterocyclic Compounds/chemistry , Imidazoles , Imidazolidines , Ligands , Methane/chemical synthesis , Models, Molecular
7.
J Antibiot (Tokyo) ; 74(3): 219-224, 2021 03.
Article in English | MEDLINE | ID: mdl-33318623

ABSTRACT

A series of new compounds-arylbis(indol-3-yl)methylium derivatives-were synthesized and their antimicrobial activity was evaluated. All the compounds turned out to be highly active, with MIC depending on their structure and the length of N-alkyl residues. The parent triarylmethane compounds possess weaker activity.


Subject(s)
Anti-Bacterial Agents/pharmacology , Methane/analogs & derivatives , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Methane/chemical synthesis , Methane/chemistry , Methane/pharmacology , Microbial Sensitivity Tests , Structure-Activity Relationship
8.
Eur J Med Chem ; 207: 112777, 2020 Dec 01.
Article in English | MEDLINE | ID: mdl-32971427

ABSTRACT

The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.


Subject(s)
Methane/chemistry , Methane/pharmacology , Receptors, Aryl Hydrocarbon/metabolism , Hep G2 Cells , Humans , Methane/chemical synthesis , Methane/metabolism , Molecular Docking Simulation , Molecular Targeted Therapy , Protein Binding , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/chemistry , Transcriptional Activation/drug effects
9.
J Oleo Sci ; 69(8): 871-882, 2020 Aug 06.
Article in English | MEDLINE | ID: mdl-32641614

ABSTRACT

In this study, an N-heterocyclic carbene (NHC)-based metal coordinate surfactant (MCS), NHC-Au-MCS, in which the NHC framework afforded the bonding of the Au(I) at the linkage of the hydrophilic and hydrophobic moieties, was synthesized. The structure of NHC-Au-MCS was confirmed by 1H and 13C NMR spectroscopic measurements together with elemental analysis. Matrix-assisted laser desorption/ionization (MALDI), laser desorption/ionization (LDI), and electrospray ionization mass spectrometry (ESI-MS) indicated the distinct reactivity of NHC-Au-MCS, such as the exchange of Br to Cl and the formation of a cationic Au complex, where the two NHC ligands were coordinated to an Au(I) center upon laser activation. The surface tension and dynamic light scattering (DLS) measurements revealed that the coordination of Au(I) to NHC reduced the critical micelle concentration (CMC) of NHC-Au-MCS (1.3×10-5 M), which resulted in the formation of micelles at concentrations higher than the CMC in water. We also confirmed that the surface-active Au(I) complex of NHC-Au-MCS catalyzed the hydration of 1-dodecyne to 2-dodecanone in water in the absence of an organic solvent. On the basis of the detailed mechanistic investigations regarding the reactivity of NHC-Au-MCS, we revealed that NHC-Au-MCS partially translated into Au nanoparticles (AuNPs), which facilitated alkyne hydration. These mechanistic studies were supported by UV-vis measurements, transmission electron microscopy (TEM), and LDI-MS.


Subject(s)
Alkynes/chemistry , Gold/chemistry , Heterocyclic Compounds/chemical synthesis , Metal Nanoparticles/chemistry , Methane/analogs & derivatives , Surface-Active Agents/chemical synthesis , Catalysis , Heterocyclic Compounds/chemistry , Hydrogenation , Hydrophobic and Hydrophilic Interactions , Methane/chemical synthesis , Methane/chemistry , Micelles , Surface-Active Agents/chemistry , Water
10.
Bioconjug Chem ; 31(5): 1313-1319, 2020 05 20.
Article in English | MEDLINE | ID: mdl-32379426

ABSTRACT

Since the asialoglycoprotein receptor (also known as the "Ashwell-Morell receptor" or ASGPR) was discovered as the first cellular mammalian lectin, numerous drug delivery systems have been developed and several gene delivery systems associated with multivalent ligands for liver disease targeting are undergoing clinical trials. The success of these systems has facilitated the further study of new ligands with comparable or higher affinity and less synthetic complexity. Herein, we designed two novel trivalent ligands based on the esterification of tris(hydroxymethyl) aminomethane (TRIS) followed by the azide-alkyne Huisgen cycloaddition with azido N-acetyl-d-galactosamine. The presented triazolyl glycoconjugates exhibited good binding to ASGPR, which was predicted using in silico molecular docking and assessed by a surface plasmon resonance (SPR) technique. Moreover, we demonstrated the low level of in vitro cytotoxicity, as well as the optimal spatial geometry and the required amphiphilic balance, for new, easily accessible ligands. The conjugate of a new ligand with Cy5 dye exhibited selective penetration into HepG2 cells in contrast to the ASGPR-negative PC3 cell line.


Subject(s)
Asialoglycoprotein Receptor/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Alkynes/chemistry , Asialoglycoprotein Receptor/chemistry , Azides , Chemistry Techniques, Synthetic , Drug Design , Esterification , Galactosamine/chemistry , Hep G2 Cells , Humans , Ligands , Methane/chemical synthesis , Methane/chemistry , Methane/metabolism , Methane/pharmacology , Molecular Docking Simulation , PC-3 Cells , Protein Conformation
11.
Molecules ; 25(4)2020 Feb 12.
Article in English | MEDLINE | ID: mdl-32059503

ABSTRACT

Cyclic amino(ylide)carbenes (CAYCs) are the ylide-substituted analogues of N-heterocyclic Carbenes (NHCs). Due to the stronger π donation of the ylide compared to an amino moiety they are stronger donors and thus are desirable ligands for catalysis. However, no stable CAYC has been reported until today. Here, we describe experimental and computational studies on the synthesis and stability of CAYCs based on pyrroles with trialkyl onium groups. Attempts to isolate two CAYCs with trialkyl phosphonium and sulfonium ylides resulted in the deprotonation of the alkyl groups instead of the formation of the desired CAYCs. In case of the PCy3-substituted system, the corresponding ylide was isolated, while deprotonation of the SMe2-functionalized compound led to the formation of ethene and the thioether. Detailed computational studies on various trialkyl onium groups showed that both the α- and ß-deprotonated compounds were energetically favored over the free carbene. The most stable candidates were revealed to be α-hydrogen-free adamantyl-substituted onium groups, for which ß-deprotonation is less favorable at the bridgehead position. Overall, the calculations showed that the isolation of CAYCs should be possible, but careful design is required to exclude decomposition pathways such as deprotonations at the onium group.


Subject(s)
Hydrogen/chemistry , Methane/analogs & derivatives , Molecular Structure , Catalysis , Methane/chemical synthesis , Methane/chemistry , Stereoisomerism , Sulfides/chemistry
12.
Bioorg Chem ; 96: 103591, 2020 03.
Article in English | MEDLINE | ID: mdl-32004896

ABSTRACT

We describe herein the synthesis, characterization and biological studies of novel PEGylated triarylmethanes. Non-symmetrical and symmetrical triarylmethanes series have been synthesized by Friedel-Crafts hydroxyalkylation or directly from bisacodyl respectively followed by a functionalization with PEG fragments in order to increase bioavailability and biological effectiveness. The antimicrobial activity was investigated against Gram-positive and Gram-negative foodborne pathogens and against Candida albicans, an opportunistic pathogenic yeast. The anti-biocidal activity was also studied using Staphylococcus aureus as a reference bacterium. Almost all PEGylated molecules displayed an antifungal activity comparable with fusidic acid with MIC values ranging from 6.25 to 50 µg/mL. Compounds also revealed a promising antibiofilm activity with biofilm eradication percentages values above 80% for the best molecules (compounds 4d and 7). Compounds 7 and 8b showed a modest antiproliferative activity against human colorectal cancer cell lines HT-29. Finally, in silico molecular docking studies revealed DHFR and DNA gyrase B as potential anti-bacterial targets and in silico predictions of ADME suggested adequate drug-likeness profiles for the synthetized triarylmethanes.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Methane/analogs & derivatives , Methane/pharmacology , Anti-Bacterial Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Bacteria/drug effects , Bacterial Infections/drug therapy , Biofilms/drug effects , Candida albicans/drug effects , Candida albicans/physiology , Candidiasis/drug therapy , Cell Proliferation/drug effects , HT29 Cells , Humans , Methane/chemical synthesis , Microbial Sensitivity Tests , Molecular Docking Simulation , Polycyclic Aromatic Hydrocarbons/chemical synthesis , Polycyclic Aromatic Hydrocarbons/chemistry , Polycyclic Aromatic Hydrocarbons/pharmacology , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology
13.
Molecules ; 25(3)2020 Jan 23.
Article in English | MEDLINE | ID: mdl-31979363

ABSTRACT

The increasing population creates excess pressure on the plantation and production of fruits and vegetables across the world. Consumption demand during the whole year has made production compulsory in the covered production system (greenhouse). Production, harvesting, processing, transporting, and distribution chains of fruit and vegetables have resulted in a huge amount of wastes as an alternative source to produce biofuels. In this study, optimization of two pretreatment processes (NaOH and HCl assisted thermal) was investigated to enhance methane production from fruit and vegetable harvesting wastes (FVHW) that originate from greenhouses. NaOH concentration (0-6.5%), HCl concentration (0-5%), reaction temperature (60-100 °C), solid content (1-5%), time of reaction (1-5 h), and mixing speed (0-500 rpm) were chosen in a wide range of levels to optimize the process in a broad design boundary and to evaluate the positive and negative impacts of independent variables along with their ranges. Increasing NaOH and HCl concentrations resulted in higher COD solubilization but decreased the concentration of soluble sugars that can be converted directly into methane. Thus, the increasing concentrations of NaOH and HCl in the pretreatments have resulted in low methane production. The most important independent variables impacting COD and sugar solubilization were found to be chemical concentration (as NaOH and HCl), solid content and reaction temperature for the optimization of pretreatment processes. The high amount of methane productions in the range of 222-365 mL CH4 gVS-1 was obtained by the simple thermal application without using chemical agents as NaOH or HCl. Maximum enhancement of methane production was 47-68% compared to raw FVHW when 5% solid content, 1-hour reaction time and 60-100 °C reaction temperature were applied in pretreatments.


Subject(s)
Bioreactors , Carbohydrates/chemistry , Fruit/chemistry , Methane/chemical synthesis , Refuse Disposal/methods , Vegetables/chemistry , Anaerobiosis , Biofuels , Biological Oxygen Demand Analysis , Hydrochloric Acid/chemistry , Methane/chemistry , Microscopy, Electron, Scanning , Sodium Hydroxide/chemistry , Surface Properties , Temperature
14.
Chem Soc Rev ; 49(3): 908-950, 2020 Feb 10.
Article in English | MEDLINE | ID: mdl-31958107

ABSTRACT

Donor and donor-donor carbenes are two important kinds of carbenes, which have experienced tremendous growth in the past two decades. This review provides a comprehensive overview of the recent development of donor and donor-donor carbene chemistry. The development of this chemistry offers efficient protocols to construct a wide variety of C-C and C-X bonds in organic synthesis. This review is organized based on the different types of carbene precursors, including diazo compounds, hydrazones, enynones, cycloheptatrienes and cyclopropenes. The typical transformations, the reaction mechanisms, as well as their subsequent applications in the synthesis of complex natural products and bioactive molecules are discussed. Due to the rapidly increasing interest in this area, we believe that this review will provide a timely and comprehensive discussion of recent progress in donor and donor-donor carbene chemistry.


Subject(s)
Methane/analogs & derivatives , Azo Compounds/chemistry , Catalysis , Cyclopropanes/chemistry , Hydrazones/chemistry , Metals/chemistry , Methane/chemical synthesis , Molecular Structure , Stereoisomerism
15.
J Inorg Biochem ; 205: 110976, 2020 04.
Article in English | MEDLINE | ID: mdl-31926377

ABSTRACT

Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC complexes Ir1 and Ir2 have been explored as mitochondria-targeted anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, and display higher cytotoxicity in the presence of 450 nm and 630 nm LED light. Colocalization and quantitative studies indicated that these complexes could specially localize to mitochondria. Mechanism studies show that these complexes increase intracellular reactive oxygen species (ROS) level, reduce mitochondrial membrane potential (MMP) and induce some degree of early apoptosis. Further studies found that Ir1could induce mitophagy at dark and necrocytosis under the irradiation of 630 nm LED light. The in vitro and in vivo photoxicity studies revealed that Ir1 is a promising photodynamic therapy (PDT) agent and could significantly inhibit tumor growth.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Iridium , Neoplasms, Experimental/drug therapy , Photochemotherapy , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Humans , Iridium/chemistry , Iridium/pharmacology , Methane/analogs & derivatives , Methane/chemical synthesis , Methane/chemistry , Mice , Mice, Nude , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Xenograft Model Antitumor Assays
16.
Article in English | MEDLINE | ID: mdl-31838991

ABSTRACT

AIMS AND OBJECTIVE: An efficient and practical procedure for the synthesis of heterocyclic compounds such as quinazolines, quinoxalines and bis(indolyl)methanes was developed using 3,5-bis(trifluoromethyl) phenyl ammonium hexafluorophosphate (BFPHP) as a novel organocatalyst. MATERIALS AND METHODS: All of the obtained products are known compounds and identified by IR, 1HNMR, 13CNMR and melting points. RESULT: Various products were obtained in good to excellent yields under reaction conditions. CONCLUSION: The BFPHP organocatalyst demonstrates a novel class of non-asymmetric organocatalysts, which has gained much attention in green chemistry.


Subject(s)
Combinatorial Chemistry Techniques , Indoles/chemical synthesis , Methane/chemical synthesis , Phosphoric Acids/chemistry , Quinazolines/chemical synthesis , Quinoxalines/chemical synthesis , Catalysis , Indoles/chemistry , Methane/chemistry , Molecular Structure , Quinazolines/chemistry , Quinoxalines/chemistry
18.
Org Biomol Chem ; 17(22): 5533-5537, 2019 06 05.
Article in English | MEDLINE | ID: mdl-31090781

ABSTRACT

Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.


Subject(s)
Biocompatible Materials/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Methane/analogs & derivatives , Palladium/chemistry , Solid-Phase Synthesis Techniques , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Catalysis , Cell Survival/drug effects , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Ligands , MCF-7 Cells , Methane/chemical synthesis , Methane/chemistry , Methane/pharmacology , Molecular Structure
19.
J Am Chem Soc ; 141(16): 6473-6478, 2019 04 24.
Article in English | MEDLINE | ID: mdl-30964670

ABSTRACT

Carbene polymerization provides polyolefins that cannot be readily prepared from olefin monomers; however, controlled and living carbene polymerization has been a long-standing challenge. Here we report a new class of initiators, (π-allyl)palladium carboxylate dimers, which polymerize ethyl diazoacetate, a carbene precursor in a controlled and quasi-living manner, with nearly quantitative yields, degrees of polymerization >100, molecular weight dispersities 1.2-1.4, and well-defined, diversifiable chain ends. This method also provides block copolycarbenes that undergo microphase segregation. Experimental and theoretical mechanistic analysis supports a new dinuclear mechanism for this process.


Subject(s)
Density Functional Theory , Methane/analogs & derivatives , Methane/chemical synthesis , Methane/chemistry , Molecular Structure , Polymerization
20.
ChemMedChem ; 14(11): 1086-1095, 2019 06 05.
Article in English | MEDLINE | ID: mdl-30924298

ABSTRACT

Heterometallic titanocene-based compounds containing gold(I)-phosphane fragments have been extremely successful against renal cancer in vitro and in vivo. The exchange of phosphane by N-heterocyclic carbene ligands to improve or modulate their pharmacological profile afforded bimetallic complexes effective against prostate cancer, but less effective against renal cancer in vitro. Herein we report the synthesis of new bimetallic Ti-Au compounds by the incorporation of two previously reported highly active gold(I)-N-heterocyclic carbene fragments derived from 4,5-diarylimidazoles. The two new compounds [(η5 -C5 H5 )2 TiMe(µ-mba)Au(NHC)] (where NHC=1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene, NHC-Bn 2 a; or 1,3-diethyl-4,5-diphenylimidazol-2-ylidene, NHC-Et 2 b) with the dual linker (-OC(O)-p-C6 H4 -S-) containing both a carboxylate and a thiolate group were evaluated in vitro against renal and prostate cancer cell lines. The compounds were found to be more cytotoxic than previously described Ti-Au compounds containing non-optimized gold(I)-N-heterocyclic fragments. We present studies to evaluate their effects on cell death pathways, migration, inhibition of thioredoxin reductase (TrxR) and vascular endothelial growth factor (VEGF) in the PC3 prostate cancer cell line. The results show that the incorporation of a second metallic fragment such as titanocene into biologically active gold(I) compounds improves their pharmacological profile.


Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Gold/pharmacology , Heterocyclic Compounds/pharmacology , Methane/analogs & derivatives , Organometallic Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Density Functional Theory , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Gold/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Methane/chemical synthesis , Methane/chemistry , Methane/pharmacology , Molecular Structure , Organometallic Compounds/chemistry , Structure-Activity Relationship
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