Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 2.665
Filter
1.
Proc Natl Acad Sci U S A ; 121(25): e2316615121, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38861602

ABSTRACT

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.


Subject(s)
Antineoplastic Agents , Iridium , Methane , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Iridium/chemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Methane/analogs & derivatives , Methane/chemistry , Methane/pharmacology , Microfilament Proteins/metabolism , Neoplasm Metastasis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Xenograft Model Antitumor Assays , Male
2.
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
3.
Dalton Trans ; 53(23): 9700-9714, 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38775704

ABSTRACT

Silver compounds are mainly studied as antimicrobial agents, but they also have anticancer properties, with the latter, in some cases, being better than their gold counterparts. Herein, we analyse the first example of a new Ag(I)-biscarbene that can bind non-canonical structures of DNA, more precisely G-quadruplexes (G4), with different binding signatures depending on the type of G4. Moreover, we show that this Ag-based carbene binds the i-motif DNA structure. Alternatively, its Au(I) counterpart, which was investigated for comparison, stabilises mitochondrial G4. Theoretical in silico studies elucidated the details of different binding modes depending on the geometry of G4. The two complexes showed increased cytotoxic activity compared to cisplatin, overcoming its resistance in ovarian cancer. The binding of these new drug candidates with other relevant biosubstrates was studied to afford a more complete picture of their possible targets. In particular, the Ag(I) complex preferentially binds DNA structures over RNA structures, with higher binding constants for the non-canonical nucleic acids with respect to natural calf thymus DNA. Regarding possible protein targets, its interaction with the albumin model protein BSA was also tested.


Subject(s)
DNA , G-Quadruplexes , Silver , DNA/chemistry , Silver/chemistry , Humans , Methane/chemistry , Methane/analogs & derivatives , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cattle , Animals , Serum Albumin, Bovine/chemistry , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Fluorescent Dyes/chemistry
4.
Biochem Biophys Res Commun ; 722: 150160, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-38795453

ABSTRACT

Carbene transfer reactions have emerged as pivotal methodologies for the synthesis of complex molecular architectures. Heme protein-catalyzed carbene transfer reactions have shown promising results on model compounds. However, their limited substrate scope has hindered their application in natural product functionalization. Building upon the foundation of previously published work on a carbene transferase-myoglobin variant, this study employs computer-aided protein engineering to design myoglobin variants, using either docking or the deep learning-based LigandMPNN method. These variants were utilized as catalysts in carbene transfer reactions with a selection of monoterpene substrates featuring C-C double bonds, leading to seven target products. This cost-effective methodology broadens the substrate scope for heme protein-catalyzed reactions, thereby opening novel pathways for research in heme protein functionalities and offering fresh perspectives in the synthesis of bioactive molecules.


Subject(s)
Methane , Monoterpenes , Myoglobin , Myoglobin/chemistry , Methane/chemistry , Methane/analogs & derivatives , Monoterpenes/chemistry , Monoterpenes/metabolism , Protein Engineering/methods , Transferases/chemistry , Transferases/metabolism , Molecular Docking Simulation
5.
ACS Chem Neurosci ; 15(11): 2233-2242, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38753435

ABSTRACT

Detection of amyloid ß (Aß) oligomers, regarded as the most toxic aggregated forms of Aß, can contribute to the diagnosis and treatment of Alzheimer's disease (AD). Thus, the development of imaging probes for in vivo visualization of Aß oligomers is crucial. However, the structural uncertainty regarding Aß oligomers makes it difficult to design imaging probes with high sensitivity to Aß oligomers against highly aggregated Aß fibrils. In this study, we developed Aß oligomer-selective fluorescent probes based on triphenylmethane dyes through screening of commercially available compounds followed by structure-activity relationship (SAR) studies on cyclic or acyclic 4-dialkylamino groups. We synthesized 11 triarylmethane-based Aß oligomer probe (TAMAOP) derivatives. In vitro evaluation of fluorescence properties, TAMAOP-9, which had bulky 4-diisobutylamino groups introduced into three benzenes of a twisted triphenylmethane backbone, showed marked fluorescence enhancement in the presence of Aß oligomers and demonstrated high selectivity for Aß oligomers against Aß fibrils. In docking studies using the Aß trimer model, TAMAOP-9 bound to the hydrophobic surface and interacted with the side chain of Phe20. In vitro section staining revealed that TAMAOP-9 could visualize Aß oligomers in the brains of AD model mice. An in vivo fluorescence imaging study using TAMAOP-9 showed significantly higher fluorescence signals from the brains of AD model mice than those of age-matched wild-type mice, confirmed by ex vivo section observation. These results suggest that TAMAOP-9 is a promising Aß oligomer-targeting fluorescent probe applicable to in vivo imaging.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Fluorescent Dyes , Optical Imaging , Trityl Compounds , Amyloid beta-Peptides/metabolism , Animals , Fluorescent Dyes/chemistry , Mice , Trityl Compounds/chemistry , Trityl Compounds/pharmacology , Optical Imaging/methods , Alzheimer Disease/metabolism , Alzheimer Disease/diagnostic imaging , Methane/analogs & derivatives , Methane/chemistry , Humans , Structure-Activity Relationship , Brain/metabolism , Brain/diagnostic imaging , Mice, Transgenic
6.
Chemistry ; 30(28): e202401199, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38695718

ABSTRACT

Invited for the cover of this issue are Tatiyana Serebryanskaya, Mikhail Kinzhalov and co-workers at St. Petersburg State University, the Research Institute for Physical Chemical Problems, Belarusian State University, Togliatti State University and Blokhin National Medical Research Center of Oncology. The image depicts the shield of Pallas Athena with the structure of a palladium carbene complex that protects against triple-negative breast cancer. Read the full text of the article at 10.1002/chem.202400101.


Subject(s)
Antineoplastic Agents , Cell Proliferation , Coordination Complexes , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Humans , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Female , Cell Line, Tumor , Palladium/chemistry , Methane/analogs & derivatives , Methane/chemistry , Methane/pharmacology
7.
Anal Chem ; 96(19): 7566-7576, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38684118

ABSTRACT

Genetically encoding proximal-reactive unnatural amino acids (PrUaas), such as fluorosulfate-l-tyrosine (FSY), into natural proteins of interest (POI) confer the POI with the ability to covalently bind to its interacting proteins (IPs). The PrUaa-incorporated POIs hold promise for blocking undesirable POI-IP interactions. Selecting appropriate PrUaa anchor sites is crucial, but it remains challenging with the current methodology, which heavily relies on crystallography to identify the proximal residues between the POIs and the IPs for the PrUaa anchorage. To address the challenge, here, we propose a footprinting-directed genetically encoded covalent binder (footprinting-GECB) approach. This approach employs carbene footprinting, a structural mass spectrometry (MS) technique that quantifies the extent of labeling of the POI following the addition of its IP, and thus identifies the responsive residues. By genetically encoding PrUaa into these responsive sites, POI variants with covalent bonding ability to its IP can be produced without the need for crystallography. Using the POI-IP model, KRAS/RAF1, we showed that engineering FSY at the footprint-assigned KRAS residue resulted in a KRAS variant that can bind irreversibly to RAF1. Additionally, we inserted FSY at the responsive residue in RAF1 upon footprinting the oncogenic KRASG12D/RAF1, which lacks crystal structure, and generated a covalent binder to KRASG12D. Together, we demonstrated that by adopting carbene footprinting to direct PrUaa anchorage, we can greatly expand the opportunities for designing covalent protein binders for PPIs without relying on crystallography. This holds promise for creating effective PPI inhibitors and supports both fundamental research and biotherapeutics development.


Subject(s)
Methane , Methane/analogs & derivatives , Methane/chemistry , Humans , Protein Footprinting/methods , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/chemistry , Proto-Oncogene Proteins p21(ras)/metabolism , Protein Binding , Mass Spectrometry
8.
Anal Chem ; 96(18): 7311-7320, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38656817

ABSTRACT

Human herpesvirus type 6A (HHV-6A) can cause a series of immune and neurological diseases, and the establishment of a sensitive biosensor for the rapid detection of HHV-6A is of great significance for public health and safety. Herein, a bis-tridentate iridium complex (BisLT-Ir-NHC) comprising the N-heterocyclic carbene (NHC) ligand as a novel kind of efficient ECL luminophore has been unprecedently reported. Based on its excellent ECL properties, a new sensitive ECL-based sandwich immunosensor to detect the HHV-6A virus was successfully constructed by encapsulating BisLT-Ir-NHC into silica nanoparticles and embellishing ECL sensing interface with MXene@Au-CS. Notably, the immunosensor illustrated in this work not only had a wide linear range of 102 to 107 cps/µL but also showed outstanding recoveries (98.33-105.11%) in real human serum with an RSD of 0.85-3.56%. Undoubtedly, these results demonstrated the significant potential of the bis-tridentate iridium(III) complex containing an NHC ligand in developing ECL-based sensitive analytical methods for virus detection and exploring novel kinds of efficient iridium-based ECL luminophores in the future.


Subject(s)
Coordination Complexes , Electrochemical Techniques , Herpesvirus 6, Human , Iridium , Luminescent Measurements , Methane/analogs & derivatives , Iridium/chemistry , Humans , Immunoassay/methods , Ligands , Coordination Complexes/chemistry , Luminescent Measurements/methods , Electrochemical Techniques/methods , Methane/chemistry , Heterocyclic Compounds/chemistry
9.
Adv Healthc Mater ; 13(15): e2303666, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38431774

ABSTRACT

Carbene-based bioadhesives have favourable attributes for tissue adhesion, including non-specific bonding to wet and dry tissues, but suffer from relatively weak fracture strength after photocuring. Light irradiation of carbene-precursor (diazirine) also creates inert side products that are absent under thermal activation. Herein, a dual activation method combines light irradiation at elevated temperatures for the evaluation of diazirine depletion and effects on cohesive properties. A customized photo/thermal-rheometer evaluates viscoelastic properties, correlated to the kinetics of carbene:diazoalkane ratios via 19F NMR). The latter exploits the sensitive -CF3 functional group to determine joule-based light/temperature kinetics on trifluoroaryl diazirine consumption. The combination of heat and photoactivation produced bioadhesives that are 3× tougher compared to control. Dual thermal/light irradiation may be a strategy to improve viscoelastic dissipation and toughness of photo-activated adhesive resins.


Subject(s)
Methane , Methane/chemistry , Methane/analogs & derivatives , Diazomethane/chemistry , Viscosity , Tissue Adhesives/chemistry , Light , Materials Testing
10.
Int J Mol Sci ; 25(5)2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38473851

ABSTRACT

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.


Subject(s)
Coordination Complexes , Heterocyclic Compounds , Methane/analogs & derivatives , Neoplasms , Humans , Silver/chemistry , Gold/chemistry , Caffeine , Anti-Bacterial Agents/pharmacology , Methane/chemistry , Heterocyclic Compounds/chemistry , Coordination Complexes/chemistry
11.
Int J Mol Sci ; 25(5)2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38473872

ABSTRACT

The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Methane/analogs & derivatives , Humans , Selenocysteine , Thioredoxin-Disulfide Reductase/metabolism , Antineoplastic Agents/pharmacology , Gold/chemistry , Coordination Complexes/chemistry
12.
Chem Pharm Bull (Tokyo) ; 72(3): 313-318, 2024.
Article in English | MEDLINE | ID: mdl-38494725

ABSTRACT

Generating reliable data on functional group compatibility and chemoselectivity is essential for evaluating the practicality of chemical reactions and predicting retrosynthetic routes. In this context, we performed systematic studies using a functional group evaluation kit including 26 kinds of additives to assess the functional group tolerance of carbene-mediated reactions. Our findings revealed that some intermolecular heteroatom-hydrogen insertion reactions proceed faster than intramolecular cyclopropanation reactions. Lewis basic functionalities inhibited rhodium-catalyzed C-H functionalization of indoles. While performing these studies, we observed an unexpected C-H functionalization of a 1-naphthol variant used as an additive.


Subject(s)
Methane/analogs & derivatives , Rhodium , Catalysis , Rhodium/chemistry , Methane/chemistry , Hydrogen/chemistry
13.
Molecules ; 29(5)2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38474631

ABSTRACT

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Coordination Complexes , Methane/analogs & derivatives , Ovarian Neoplasms , Phosphines , Female , Humans , Cisplatin/chemistry , Platinum/chemistry , Cell Line, Tumor , Cyanides , Spectroscopy, Fourier Transform Infrared , Coordination Complexes/chemistry , Antineoplastic Agents/chemistry , Ligands
14.
Angew Chem Int Ed Engl ; 63(21): e202401189, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38506220

ABSTRACT

This study introduces a novel approach for synthesizing Benzoxazine-centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.


Subject(s)
Alkynes , Benzoxazines , Methane , Methane/analogs & derivatives , Methane/chemistry , Methane/pharmacology , Alkynes/chemistry , Benzoxazines/chemistry , Benzoxazines/pharmacology , Benzoxazines/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemical synthesis , Humans , Stereoisomerism , Analgesics/chemistry , Analgesics/pharmacology , Analgesics/chemical synthesis , Molecular Structure , Catalysis , Drug Discovery , Animals
15.
Adv Sci (Weinh) ; 11(19): e2309343, 2024 May.
Article in English | MEDLINE | ID: mdl-38477505

ABSTRACT

The control of potato virus Y (PVY) induced crop failure is a challengeable issue in agricultural chemistry. Although many anti-PVY agents are designed to focus on the functionally important coat protein (CP) of virus, how these drugs act on CP to inactivate viral pathogenicity, remains largely unknown. Herein, a PVY CP inhibitor -3j (S) is disclosed, which is accessed by developing unusually efficient (up to 99% yield) and chemo-selective (> 99:1 er in most cases) carbene-catalyzed [3+4] cycloaddition reactions. Compound -3j bears a unique arylimidazole-fused diazepine skeleton and shows chirality-preferred performance against PVY. In addition, -3j (S) as a mediator allows ARG191 (R191) of CP to be identified as a key amino acid site responsible for intercellular movement of virions. R191 is further demonstrated to be critical for the interaction between PVY CP and the plant functional protein NtCPIP, enabling virions to cross plasmodesmata. This key step can be significantly inhibited through bonding with the -3j (S) to further impair pathogenic behaviors involving systemic infection and particle assembly. The study reveals the in-depth mechanism of action of antiviral agents targeting PVY CP, and contributes to new drug structures and synthetic strategies for PVY management.


Subject(s)
Antiviral Agents , Cycloaddition Reaction , Imidazoles , Antiviral Agents/pharmacology , Imidazoles/pharmacology , Imidazoles/chemistry , Potyvirus/drug effects , Catalysis , Capsid Proteins/metabolism , Capsid Proteins/genetics , Plant Diseases/virology , Methane/analogs & derivatives , Methane/pharmacology , Capsid/drug effects , Capsid/metabolism
16.
J Chem Inf Model ; 64(2): 412-424, 2024 Jan 22.
Article in English | MEDLINE | ID: mdl-38247361

ABSTRACT

Methods for computational de novo design of inorganic molecules have paved the way for automated design of homogeneous catalysts. Such studies have so far relied on correlation-based prediction models as fitness functions (figures of merit), but the soundness of these approaches has yet to be tested by experimental verification of de novo-designed catalysts. Here, a previously developed criterion for the optimization of dative ligands L in ruthenium-based olefin metathesis catalysts RuCl2(L)(L')(═CHAr), where Ar is an aryl group and L' is a phosphine ligand dissociating to activate the catalyst, was used in de novo design experiments. These experiments predicted catalysts bearing an N-heterocyclic carbene (L = 9) substituted by two N-bound mesityls and two tert-butyl groups at the imidazolidin-2-ylidene backbone to be promising. Whereas the phosphine-stabilized precursor assumed by the prediction model could not be made, a pyridine-stabilized ruthenium alkylidene complex (17) bearing carbene 9 was less active than a known leading pyridine-stabilized Grubbs-type catalyst (18, L = H2IMes). A density functional theory-based analysis showed that the unsubstituted metallacyclobutane (MCB) intermediate generated in the presence of ethylene is the likely resting state of both 17 and 18. Whereas the design criterion via its correlation between the stability of the MCB and the rate-determining barrier indeed seeks to stabilize the MCB, it relies on RuCl2(L)(L')(═CH2) adducts as resting states. The change in resting state explains the discrepancy between the prediction and the actual performance of catalyst 17. To avoid such discrepancies and better address the multifaceted challenges of predicting catalytic performance, future de novo catalyst design studies should explore and test design criteria incorporating information from more than a single relative energy or intermediate.


Subject(s)
Alkenes , Methane/analogs & derivatives , Phosphines , Ruthenium , Thermodynamics , Pyridines
17.
J Am Chem Soc ; 146(5): 2959-2966, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38270588

ABSTRACT

The mechanism of cyclopropanations with diazirines as air-stable and user-friendly alternatives to commonly employed diazo compounds within iron heme enzyme-catalyzed carbene transfer reactions has been studied by means of density functional theory (DFT) calculations of model systems, quantum mechanics/molecular mechanics (QM/MM) calculations, and molecular dynamics (MD) simulations of the iron carbene and the cyclopropanation transition state in the enzyme active site. The reaction is initiated by a direct diazirine-diazo isomerization occurring in the active site of the enzyme. In contrast, an isomerization mechanism proceeding via the formation of a free carbene intermediate in lieu of a direct, one-step isomerization process was observed for model systems. Subsequent reaction with benzyl acrylate takes place through stepwise C-C bond formation via a diradical intermediate, delivering the cyclopropane product. The origin of the observed diastereo- and enantioselectivity in the enzyme was investigated through MD simulations, which indicate a preferred formation of the cis-cyclopropane by steric control.


Subject(s)
Diazomethane , Heme , Methane/analogs & derivatives , Heme/chemistry , Models, Molecular , Iron , Cyclopropanes/chemistry , Catalysis
18.
Anal Chem ; 96(2): 934-942, 2024 01 16.
Article in English | MEDLINE | ID: mdl-38165813

ABSTRACT

The establishment of rapid target identification and analysis methods for antibiotic resistance genes (ARGs) is urgently needed. In this study, we unprecedently designed a target-catalyzed hairpin assembly (CHA) electrochemiluminescent (ECL) biosensor for the ultrasensitive detection of ampicillin resistance genes (ARGAMP) based on a novel, efficient near-infrared ruthenium carbene complex/TPrA/PEI ternary ECL system with low oxidation potential. The ternary NIR-ECL system illustrated in this work displayed double ECL intensity in comparison with their corresponding traditional binary ECL system. The as-prepared ECL biosensor illustrated in this work demonstrates highly selective and sensitive determination of ARGAMP from 1 fM to 1 nM and a low detection limit of 0.23 fM. Importantly, it also exhibits good accuracy and stabilities to identify ARGAMP in plasmid and bacterial genome DNA, which demonstrates its excellent reliability and great potential in detecting ARGAMP in real environmental samples.


Subject(s)
Biosensing Techniques , Methane/analogs & derivatives , Ruthenium , Electrochemical Techniques/methods , Reproducibility of Results , Ampicillin Resistance , Luminescent Measurements/methods , DNA , Biosensing Techniques/methods , Limit of Detection
19.
Macromol Rapid Commun ; 45(3): e2300458, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37955104

ABSTRACT

A straightforward approach is employed to synthesize methylene-bridged poly(hetero aromatic)s based on furan, pyrrole, thiophene, and thiophene derivatives. The process involves an electrophilic aromatic substitution reaction facilitated by a visible light-initiated system consisting of manganese decacarbonyl and an iodonium salt. The approach mainly relies on the formation of halomethylium cation, the attack of this cation to heteroaromatic, regeneration of methylium cation on the heteroaromatic, and reactivity differences between halomethylium and heteroaromatic methylium cations for successful polymerizations. This innovative synthetic strategy lead to the formation of polymers with relatively high molecular weights as the stoichiometric imbalance between the comonomers increased. Accordingly, these newly obtained polymers exhibit remarkable fluorescence properties, even at excitation wavelengths as low as 330 nm. Moreover, by harnessing the halogens at chain ends of homopolymers, block copolymers are successfully synthesized, offering opportunities for tailored applications in diverse fields.


Subject(s)
Light , Methane/analogs & derivatives , Polymers , Polymerization , Cations , Thiophenes
20.
J Biochem Mol Toxicol ; 38(1): e23554, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37855258

ABSTRACT

This work includes the synthesis of a new series of palladium-based complexes containing both morpholine and N-heterocyclic carbene (NHC) ligands. The new complexes were characterized using NMR (1 H and 13 C), FTIR spectroscopic, and elemental analysis techniques. The crystal structure of complex 1b was obtained by utilizing the single-crystal X-ray diffraction method. X-ray studies show that the coordination environment of palladium atom is completed by the carbene carbon atom of the NHC ligand, the nitrogen atom of the morpholine ring, and a pair of bromide ligand, resulting in the formation of slightly distorted square planar geometry. All complexes were determined for some metabolic enzyme activities. Results indicated that all the synthetic complexes exhibited powerful inhibitory actions against all aims as compared to the control molecules. Ki values of new morpholine-liganded complexes bearing 4-hydroxyphenylethyl group 1a-e for hCA I, hCA II, AChE, BChE, and α-glycosidase enzymes were obtained in the ranges 0.93-2.14, 1.01-2.03, 4.58-10.27, 7.02-13.75, and 73.86-102.65 µM, respectively. Designing of reported complexes is impacted by molecular docking study, and interaction with the current enzymes also proclaimed that compounds 1e (-12.25 kcal/mol for AChE and -11.63 kcal/mol for BChE), 1c (-10.77 kcal/mol and -9.26 kcal/mol for α-Gly and hCA II, respectively), and 1a (-8.31 kcal/mol for hCA I) are showing binding affinity and interaction from the synthesized five novel complexes.


Subject(s)
Methane/analogs & derivatives , Morpholines , Palladium , Molecular Structure , Molecular Docking Simulation , Palladium/chemistry , Ligands , Morpholines/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...