Carboxylic Derivatives Research Articles

Chemoselective Oxyfunctionalization of Functionalized Benzylic Compounds with a Manganese Catalyst

AbstractWhilst allowing for easy access to synthetically versatile motifs and for modification of bioactive molecules, the chemoselective benzylic oxidation reactions of functionalized alkyl arenes remain challenging. Reported in this study is a new non‐heme Mn catalyst stabilized by a bipiperidine‐based tetradentate ligand, which enables methylene oxidation of benzylic compounds by H2O2, showing high activity and excellent chemoselectivity under mild conditions. The protocol tolerates an unprecedentedly wide range of functional groups, including carboxylic acid and derivatives, ketone, cyano, azide, acetate, sulfonate, alkyne, amino acid, and amine units, thus providing a low‐cost, more sustainable and robust pathway for the facile synthesis of ketones, increase of complexity of organic molecules, and late‐stage modification of drugs.

Twofold and Threefold Sinusoidal Patterns in Coupled Molecular Motions of 184,025 Structures of Phenylethane, Nitroethane, and Carboxylate Derivatives.

Scatter plot analyses for 14,169 phenylethanes of the substructure Cβ-CαH2-Ph with three open coordination positions at Cβ and 150,568 phenylethanes of Cβ-CαHX-Ph with an additional open coordination position X at Cα have been performed, based on searches in the Cambridge Structural Database. The correlation of rotation angle ψ = Cβ-Cα-Ci-Co with a pyramidalization angle θ = Co-Co'-Ci-Cα in a 360° rotation about the bond Cα-Ci reveals a sinusoidal pattern with three maxima and minima, whereas the correlation of rotation angle ψ with bond angle ω = Cβ-Cα-Ci and bond length d = Cβ-Cα results in sinusoidal patterns with two maxima and minima. A total of 3993 nitro derivatives of the substructure Cβ-CαHX-NO2 confirm the results and show that atoms Ci/Co/Co' in the phenyl compounds can be replaced by atoms N/O/O' without any change in the two- and threefold patterns. In 15,295 methyl acetates of the substructure Cβ-CαHX-C'(═O)OMe, pyramidalization of the group CαC'(═O)OMe results in a chiral flat tetrahedron with four different corners. (Rθ)/(Sθ) selectivity in the configuration of the tetrahedron is induced by the bonds Cα-Cβ, Cα-H, and Cα-X, emanating from the tetrahedral center Cα. It is surprising that bonds as different as Cα-Cβ, Cα-H, and Cα-X (X = H, C, N, O, S, etc.) give almost the same induction intensities.

Deprotonation-Induced Phase Transitions in the Self-Assembled Structure of Prochiral Carboxyl Derivatives

Deprotonation-Induced Phase Transitions in the Self-Assembled Structure of Prochiral Carboxyl Derivatives

Carboxyl derivatives of phosphazenes as modifiers of polymeric dental materials

The aryloxyphosphazenes containing carboxylic groups in phosphorus-linked radicals and capable of copolymerization with acrylic binders were used as modifiers of dental polymer compositions. Filled modified dental compositions have been obtained and tested. It has been shown that the best mechanical and physicochemical parameters are exhibited by cured compositions with a modifier based on aryloxyphosphazene with 4-hydroxycinnamic and eugenol radicals in the phosphazene ring.

Salts or complexes? Factors affecting the type of binding of biogenic organic amines by carboxyl derivatives of 1,1′-dinaphthylmethanes and calix[4]resorcinarenes

Polycyclic carboxyl-containing compounds were synthesized by alkaline hydrolysis of 1,1′-dinaphthylmethane and rctt ortho-methyl-tetra-С-naphthyl-calix[4]resorcinarene esters. Reactions of the obtained products with biologically active amines (ethanolamine, benzylamine, phenethylamine, tyramine, tryptamine) resulted in series of derivatives. Dinaphthylmethane acids formed ammonium salts with all of the used amines; in the case of resorcinarene acids, the outcome of the reaction depended on the combination of reactants: either salts or supramolecular systems were obtained. Irrespective of the structure of molecular platform, all ethanolamine salts and some dinaphthylmethane and resorcinarene salts of benzylamine, phenethylamine, and tyramine were readily soluble in water.

A photo-induced colorimetric reaction of N,N'-bis[2-(trimethylammonium)ethyl]-1,8:4,5-naphthalenetetracarboxdiimide for detection of carboxylate anions

Here we show a novel colorimetric sensor system with a photo-induced colorimetric reaction of N,N'-bis[2-(trimethylammonium)ethyl]-1,8:4,5-naphthalenetetracarboxdiimide (TENDI) to detect and quantify carboxylate derivatives. In the presence of CH3COONa, TENDI aqueous solution under UV irradiation shows a photo-induced colorimetric reaction, which is due to the production of naphthalenediimide (NDI)-based radical anions whose absorbance peaks appear at around 400–600 nm. In contrast, no color changes are observed in the cases of diverse inorganic salts. In addition, TENDI shows another ability to discriminate the structural features of carboxylate derivatives by color tone. Moreover, interestingly, the Hill equation can approximate the relationship between carboxylate concentrations and absorbance values on the maximum absorbance wavelengths of the absorbance peaks due to the NDI-radical anions.

Gold Nanoparticles Supported on Poly(2,6‐dimethyl‐1,4‐phenylene oxide) as Robust, Selective and Cost‐Effective Catalyst for Aerobic Oxidation and Direct Oxidative Esterification of Alcohols

AbstractA new catalytic system based on gold nanoparticles (AuNPs) incarcerated in poly(2,6‐dimethyl‐1,4‐phenylene oxide) (PPO) matrix has been synthesized and successfully tested in aerobic oxidation of alkyl alcohols. PPO is a cheap and commercially available polymer, showing nanoporous morphology, high glass transition temperature (Tg =220 °C), semi‐crystallinity, excellent thermal stability, and interesting chemo‐physical properties. The synthesis of the AuNPs‐PPO catalyst is simple, cost‐effective and allows a fine control of the gold concentration, as well as an optimal dispersion of 7–8 nm sized AuNPs in the polymer matrix. AuNPs‐PPO is an efficient, robust and selective catalyst active in the aerobic oxidation and oxidative esterification of alcohols in water under mild reaction conditions (35 °C, atmospheric pressure of oxygen). The testing of AuNPs‐PPO in aerobic oxidation of 1‐phenylethanol to acetophenone, as a benchmark reaction, highlighted that this gold catalyst exhibits activity values among the highest so far reported for polymer‐supported AuNPs under mild reaction conditions. The oxidation of primary alcohols, such as benzyl and cinnamyl alcohols, could be addressed to the corresponding aldehyde or carboxylate derivatives. Alkyl cinnamates were obtained with efficiency in the one‐pot aerobic oxidation of cinnamyl alcohol in the presence of alkyl alcohols, such as n‐butanol or n‐hexanol. The role of the polymer matrix and the reaction conditions on both activity and selectivity of the AuNPs‐PPO catalyst were also investigated and discussed.

Ti-Catalyzed Diastereoselective Cyclopropanation of Carboxylic Derivatives with Terminal Olefins.

Cyclopropanols and cyclopropylamines not only serve as important structural motifs in medicinal chemistry but also show diverse reactivities in organic synthesis. Owing to the high ring strain energy, the development of a general protocol from stable and readily available starting materials to afford these cyclopropyl derivatives remains a compelling challenge. Herein, we describe that a Ti-based catalyst can effectively promote the diastereoselective syntheses of cyclopropanols and cyclopropylamines from widely accessible carboxylic derivatives (acids, esters, amides) with terminal olefins. To the best of our knowledge, this method represents the first example of direct converting alkyl carboxylic acids into cyclopropanols. Distinct from conventional studies in Ti-mediated cyclopropanations with reactive alkyl Grignard reagents as nucleophiles or reductants, this protocol utilizes Mg and Me2SiCl2 to turn over the Ti catalyst. Our method exhibits broad substrate scope with good functional group compatibility and is amenable to late-stage synthetic manipulations of natural products and biologically active molecules.

Theoretical Analysis of Anticancer Cellular Effects of Glycoside Amides.

This article is a continuation of Theoretical Analysis for the Safe Form and Dosage of Amygdalin Product and Theoretical Study of the Process of Passage of Glycoside Amides through the Cell Membrane of Cancer Cell. They consider some possible natural modifications and hypothesize that it is not nitrile glycosides that have antitumor properties but their amide / carboxyl derivatives. The possibility of using this circumstance in conservative oncology is also considered. A mechanism for crossing the cell membrane and overcoming the immune functions of the cancer cell is presented. The physiologically active cancer cell itself is quite inert to external influences. It is far more stable than any physiologically active structural and/or functional organismal cell. Its defenses are discussed in detail in the article, and its main weakness was defined, namely: the cancer cell feeds mainly on carbohydrates and/ or carbohydrate complexes. In an effort to preserve its gene set, it has evolved to counteract biologically active substances by maximally preventing its passage through its cell membrane. It is this property that could be used to minimize its effect on the whole body. In the same article, based on theoretical calculations and literature references, a hypothesis is stated: cancers could turn from severe infectious to controlled chronic ones (similar to diabetes, chronic hepatitis, etc.) Objective: The pharmaceutical form allows deviation from the chemically pure substance. It is a convenient and at the same time accessible (from a financial and/or technological point of view) form for admission by patients. Due to the great variety of natural glycosamide nitriles (starting material for the production of amide/ carboxylic acid), modern pharmacology allows their combined intake by chemical nature and concentration of the active form crossing the cell membrane. Natural nitrile glycosides hydrolyzed to amide/carboxylic acid are still unexplored but with great theoretical potential. As biologically active substances, these compounds also have significant toxicity. One of the purposes of this article is to organize laboratory tests on animals. A comparative analysis is performed on the basis of stoichiometric calculations for the concentration of the active form and the prediction of the bioactivity. For this purpose, the following methodology is applied: Data analysis for active anticancer cell molecular form and Determination of the drug dose. The derived chemicals obtained immediately after the passage of glycosamide across the cancer cell membrane are: (R)-2-hydroxy-2-phenylacetamide, (R)-2- hydroxy-2-(4-hydroxyphenyl)acetamide, (R)-2-hydroxy-2-(3-hydroxyphenyl)acetamide, 2-hydroxy-2-methylpropanamide, (S)-2-hydroxy-2-methylbutanamide, 2-hydroxy-3-methylbut-2-enamide, (2Z,4E)-4-(2-amino-1-hydroxy-2-oxoethylide ne)hex-2-enedioic acid, (S)-1-hydroxycyclopent-2-ene-1-carboxamide, (1S,4S)-1,4-dihydroxycyclopent-2-ene-1-carbox amide, (1R,4R)-1,4,5-trihydroxycyclopent-2-ene-1-carboxamide, (Z)-2-((4S,6R)-4,6-dihydroxycyclohex-2-en-1-ylidene) acetamide, (R)-2-hydroxy-3-methylbutanamide, (E)-2-((4S,5R,6R)-4,5,6-trihydroxycyclohex-2-en-1-ylidene)acetamide, (Z)-2-((4R,5R,6S)-5,6-dihydroxy-4-methoxycyclohex-2-en-1-ylidene)acetamide, (E)-2-((4R,6S)-4,6-dihydroxycyclohex- 2-en-1-ylidene)acetamide и (E)-2-((4S,5R,6R)-4,5,6-trihydroxycyclohex-2-en-1-ylidene)acetamide. The use of two or more pharmaceutical forms would not prevent their penetration, subject to the mass ratios between the active antitumor amide and the active carboxyl transfer form. Amides resulting from the hydrolysis of nitrile glycosides would have the ability to cross the cell membrane of a cancer cell and thus cause its cellular response. The pharmaceutical form must represent the exact amide / carboxylic acid ratio for the corresponding active anticancer cell form.

Bilastine Based Drugs as SARS-CoV-2 Protease Inhibitors: Molecular Docking, Dynamics, and ADMET Related Studies

Bilastine drugs, structurally piperidine-1-carboxylate and sulfonyloxyethyl carboxylate derivatives, have significantly been employed as the medication of second-generation antihistamine drugs, and are used for the treatment of allergic rhinoconjunctivities and urticarial (hives). The bilastine drugs, composed of benzene carboxylate, propanoate, carboxylate, methyl-sulfonate, propanoic acid, butanoic acid, and pentanoic acid derivatives, were investigated through computational tools against SARS-CoV-2. The COVID-19 virus consists of five proteases where the curial function is performed by main proteases (Mpro) and Spike proteases (Spro). The Mpro and Spro were selected for calculation of molecular docking by these bilastine drugs which showed higher binding energy (<-6.5 kcal/mol) for both proteases. The main carboxylic acid group in bilastine drugs is found the primary key for a high binding score to show the large binding affinity with Mpro and Spro, and is highly responsible for forming the hydrogen bond although the various hydrophobic bonds were produced as a weak interaction. For justification, the stability of molecular docked ligand-protein complexes was investigated with molecular dynamics. It showed that the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of all these drugs were below the 0.9 Å after residue interaction. Moreover, the HOMO-LUMO gap, hardness, and softness provided full details for their chemical reactivity. In this view, the pharmacokinetics and Lipinski rule were calculated, and all of these molecules had satisfied the Lipinski rule. Finally, using the admetSAR online database, absorption, distribution, metabolism, excretion, and toxicity have been calculated which indicated that these bilastine drugs are non-carcinogenic and less harmful for both aquatic and non-aquatic species. DOI: http://dx.doi.org/10.17807/orbital.v14i1.1642

Design, synthesis, insecticidal activities, and molecular docking of novel pyridylpyrazolo carboxylate derivatives

AbstractBased on our previous work, using the strategies of “scaffold hopping” and “intermediate derivatization method” (IDM), a total of 44 novel pyridylpyrazolo carboxylate derivatives were designed and synthesized. The structures of these compounds were identified by 1H NMR and 13C NMR, and the insecticidal activities of the target compounds against Plutella xylostella and Spodoptera frugiperda were tested. Compound G35 showed the best insecticidal activities against P. xylostella (LC50 = 33.65 mg/L) and S. frugiperda (mortality rate = 61.21% at 100 mg/L). Preliminary structure–activity relationship analysis showed that the introduction of amino group and acetamide on the benzene ring helped to improve the insecticidal activity of the scaffold. Molecular docking model between compounds G34 or G35 and Ryanodine receptors (RyRs) of P. xylostella showed that RyRs may be a potential target of this series compounds and explained the difference in insecticidal activities. These findings provided guidance for further optimization of the pyridylpyrazolo carboxylate scaffold as potential insecticide.

Synthesis, Cyclization and Nucleophilic Substitution Reactions of Substituted Pyrazole Carboxylic Acid

Substituted pyrazole carboxylic acid 2a-b derivatives, obtained from 2,3-furandione 1 and benzaldehyde hydrazone 11a-b was converted via reactions of its acid chloride 3a-b. The corresponding ester 6a-b, urea 7a-b, and amide derivatives 4a-b, 8a-b were obtained from the reaction of the acyl chloride of the pyrazole carboxylic acid with various alcohols, urea, and amines. Additionally, the corresponding nitrile derivatives 5 were obtained by extracting water from the amide derivatives (SOCl2 / DMF). Furthermore, cyclization reactions of substituted pyrazole carboxylic acid derivatives using hydrazine were investigated 9 and reaction of 2b decarboxylation product 10.

Dinuclear Nickel and Cobalt Complexes Containing Biocompatible Carboxylate Derivatives as Effective Catalysts for Coupling of Carbon Dioxide with Epoxides: Synthesis, Characterization, and Catalysis

Dinuclear Nickel and Cobalt Complexes Containing Biocompatible Carboxylate Derivatives as Effective Catalysts for Coupling of Carbon Dioxide with Epoxides: Synthesis, Characterization, and Catalysis

Palladium-Catalyzed Intermolecular Carbonylation-Based Difunctionalization of Alkenes

AbstractThe palladium(II)-catalyzed carbonylation of alkenes presents one of most efficient methods for the synthesis of alkyl-substituted carbonyls and has received much attention. In this Account, we summarize our recent studies on the palladium-catalyzed intermolecular carbonylation-based 1,2-difunctionalization of alkenes, in which two strategies were involved: (1) a cooperative strategy involves the sequential iodine(III)-mediated alkene activation and palladium-catalyzed carbonylation, leading to the intermolecular β-oxy-, fluoro-, and azidocarbonylation of alkenes; (2) the classic strategy initiated by intermolecular nucleopalladation and carbonylation, including the asymmetric oxycarbonylation of alkenes. These methods provide a series of efficient approaches to synthesize β-functionalized aliphatic carboxylic derivatives.1 Introduction2 A Cooperative Strategy Involving Iodine(III)-Mediated Alkene Activation and Palladium-Catalyzed Carbonylation2.1 Intermolecular Oxycarbonylation of Alkenes2.2 Intermolecular Fluorocarbonylation of Alkenes2.3 Intermolecular Azidocarbonylation of Alkenes3 Intermolecular Aminocarbonylation of Alkenes Initiated by Aminopalladation4 Intermolecular Arylcarbonylation of Alkenes Initiated by Arylpalladation5 Intermolecular Enantioselective Oxycarbonylation of Alkenes Initiated by Oxypalladation6 Conclusion

Untargeted Metabolomics Reveals Multiple Phytometabolites in the Agricultural Waste Materials and Medicinal Materials of Codonopsis pilosula

Codonopsis pilosula has been used in traditional Chinese medicine for hundreds of years, where it has been used to treat anaemia, fatigue, a weak spleen, and stomach problems, among other ailments. The roots of C. pilosula are considered medicinal, while the aerial parts are always directly discarded after harvest in autumn or winter. Some studies have shown that the stems and leaves of C. pilosula also contain a variety of active metabolites, including saponins, flavonoids, terpenoids, and polysaccharides. To efficiently utilise resources, waste products from C. pilosula leaves and stems were analysed by untargeted metabolomics and chemometrics. A total of 1508 metabolites were detected and annotated, of which 463 were identified as differentially expressed metabolites (DEMs). These DEMs were grouped into classes, such as carboxylic acids and derivatives, steroids, organic oxygen compounds, fatty acyls, prenol lipids, and flavonoids. Metabolic profiling of C. pilosula tissues showed that the contents of polyacetylenes, polyenes, flavonoids, some alkaloids, steroids, terpenoids, and organic acids were higher in stems and leaves, whereas the contents of the main lignans and some alkaloids were more enriched in roots. Moreover, C. pilosula stems and leaves also contained a lobetyolin, syringin and atractylenolide III, which were detected by LC-MS/MS and HPLC-UV. The extracts of C. pilosula aerial parts also showed stronger antioxidant properties than roots. C. pilosula stems and leaves were rich in active ingredients and might have great value for development and utilisation.

Influence of light supplement on duck sternal calcification from integrated analysis of metabolome and transcriptome

Calcification of bones is the critical process of bone development in birds, which is very important for sustaining the normal biological function of bones. Light is one of the vital factors affecting bone development, but whether light intensity affects bone calcification and the underlying mechanism is still unknown. In this study, we used duck sternum as a model to analyze the calcification process under different light regimes. In addition, the underlying mechanism was also illustrated by integrating metabolomics and transcriptome methods.The experiment lasted from 14 to 51 d of duck age. The control group (LP1) kept light intensity 2 lx during the whole experiment. The two light supplement groups (LP2, LP3) were given light with the intensity of 70 lx at different time (14–29 d for LP2, 14–43 d for LP3). Samples were collected at 52 d of duck age. Sternal calcification analysis showed no significant difference in proportion of area of cartilage matrix and trabecular bone in keel tissue among the 3 groups, but the degree of keel calcification in LP3 was higher than in the other 2 groups. Serum metabolomics showed 32 and 28 differentially accumulated metabolites (DAMs) in the 2 comparison groups, LP1 vs. LP3 and LP1 vs. LP2, respectively. Carboxylic acids and derivatives were the most abundant among the DAMs. Sternal transcriptome analysis showed 231 differentially expressed genes (DEGs), including 177 upregulated genes and 54 downregulated genes in group LP1 vs. LP3, and 22 DEGs in group LP1 vs. LP2. Protein-protein interaction (PPI) network analysis on DEGs between LP1 and LP3 showed that genes BTRC, GLI1, BMP4, and FOS were in the core position of the interaction network, and are also involved in bone development. KEGG pathway analysis of DAMs and DEGs showed that differences in Hedgehog signaling pathway, MAPK signaling pathway, apoptosis, energy metabolism, and amino acid metabolism following light treatment seem likely to have contributed to the observed difference in calcification of duck sternum.

Synthesis of Novel Diastereomer Pyrimido[1,2-a]Benzimidazoles by Using Silica Sulfuric Acid/Ethylene Glycol

The scope of the reaction of 2-aminobenzimidazole, aldehydes and diethyl malonate in the presence of silica sulfuric acid/ethylene glycol was investigated. The reaction gave two unexpected products, 2-hydroxyethyl 3-hydroxy-4-aryl-2-oxo-tetrahydropyrimidobenzimidazole-3-carboxylates 2 and 4-aryl-hydropyrimido[1,2-a]- benzimidazol-2(1H)-ones 3 without isolation of the expected ethyl 4-aryl-2-oxo-1,2,3,4-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-3-carboxylates 1. NMR spectroscopic data and X-Ray analysis were used for assignment and confirmation the structures of the unexpected products. 2-Hydroxyethyl carboxylate derivatives 2 may be obtained via formation of 1 as intermediates, which were subjected to trans-esterification by ethylene glycol and oxidation of the proton on pyrimidine ring at position-3 to afford products 2. The unexpected products 3 may be obtained via formation of compounds 1 that was subjected to deesterification followed by decarboxylation to afford compounds 3.

Freshness monitoring of raw fish by detecting biogenic amines using a gold nanoparticle-based colorimetric sensor array.

We herein report the quantitative detection of biogenic amines using a gold nanoparticle-based colorimetric chemosensor array for food analysis. The gold nanoparticles are functionalized with carboxylate derivatives, which capture target amines through hydrogen bonds and electrostatic interactions. The simultaneous discrimination of 10 amine derivatives was achieved by a linear discriminant analysis with a 100% correct classification based on the multi-colorimetric response pattern of structural differences. Furthermore, a real sample analysis for raw fish (i.e., tuna) demonstrated highly accurate determination of histamine concentrations by a support vector machine, the result of which was matched with high-performance liquid chromatography. Most importantly, the chemosensor array succeeded in detecting the time-dependent concentration change of histamine in the raw fish, meaning that the decomposition of the fish could be monitored by the colorimetric changes. Hence, the proposed chemosensor array combined with pattern recognition techniques can be a user-friendly analytical method for food freshness monitoring.

Sonochemistry in an organocatalytic domino reaction: an expedient multicomponent access to structurally functionalized dihydropyrano[3,2-b]pyrans, spiro-pyrano[3,2-b]pyrans, and spiro-indenoquinoxaline-pyranopyrans under ambient conditions.

A highly convenient and sustainable one-pot approach for the diversely-oriented synthesis of a variety of medicinally privileged amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives on the basis of a domino three-component reaction of readily available carbonyl compounds including aryl aldehydes or isatins, active methylene compounds, and kojic acid as a Michael donor using secondary amine catalyst l-proline under ultrasound irradiation in aqueous ethanolic solution at ambient temperature has been developed. This methodology can involve the assembly of C–C, C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C, C–O, C–N bonds via a one-pot operation, and following this protocol, a series of novel amino-substituted spiro[indeno[1,2-b]quinoxaline-11,4-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylates have been synthesized. The practical utility of this method was found to be very efficient for scale-up reaction and other useful transformations. The methodology provides significant advantages including mild reaction conditions, energy-efficiency, short reaction time, fast reaction, simple work-up procedure, broad functional group tolerances, utilization of reusable catalyst, green solvent system, being metal-free, ligand-free, waste-free, inexpensive, etc. Excellent chemical yields have been achieved without using column chromatography. To address the issues of green and more sustainable chemistry, several metrics including Atom Economy (AE), Reaction Mass Efficiency (RME), Atom efficiency, E-factor, Process Mass Intensity (PMI), and Carbon Efficiency (CE) have been quantified for the present methodology that indicates the greenness of the present protocol.

6-Heterocyclic Carboxylic Ester Derivatives of Gliotoxin Lead to LSD1 Inhibitors in Gastric Cancer Cells

6-Heterocyclic Carboxylic Ester Derivatives of Gliotoxin Lead to LSD1 Inhibitors in Gastric Cancer Cells