Tripodal Compounds Research Articles

Tuning of the Anion Affinity and Selectivity of Tripyrromethane‐Based Receptors by Simple Structural Modification

AbstractTripyrromethane‐based tripodal compounds 1–3 were synthesized as anion receptors. It was revealed by 1H NMR spectroscopic analyses carried out in CDCl3 that tripyrromethane 1 with an ester group was capable of recognizing F−, Cl−, Br−, and H2PO4− with relatively high selectivity for F−. By contrast, receptor 2 having an additional hydrogen bond donor of an amide group binds F− and H2PO4− with much improved affinity relative to receptor 1. On the other hand, receptor 3 bearing formyl groups on its two pyrrole subunits showed markedly enhanced selectivity for F− presumably due to the increased acidity of the pyrrolic NHs and the resulting strengthened intermolecular hydrogen bonds. In addition, tripodal receptors 1–3 were found to bind H2PO4−, a tetrahedral oxyanion, more efficiently than 2‐dimensional macrocyclic calix[4]pyrrole 4.

Cationic Divalent Metal Sites (M = Mn, Fe, Co) Operating as Both Nitrene-Transfer Agents and Lewis Acids toward Mediating the Synthesis of Three- and Five-Membered N-Heterocycles.

The tripodal compounds [(TMG3trphen)MII-solv](PF6)2 (M = Mn, Fe, Co; solv = MeCN, DMF) and bipodal analogues [(TMG2biphen)MII(NCMe)x](PF6)2 (x = 3 for Mn, Fe; x = 2 for Co) and [(TMG2biphen)MIICl2] have been synthesized with ligands that feature a triaryl- or diarylmethyl-amine framework and superbasic tetramethylguanidinyl residues (TMG). The dicationic M(II) sites mediate catalytic nitrene-transfer reactions between the imidoiodinane PhI═NTs (Ts = tosyl) and a panel of styrenes in MeCN to afford aziridines and low yields of imidazolines (upon MeCN insertion) with an order of productivity that favors the bipodal over the tripodal reagents and a metal preference of Fe > Co ≥ Mn. In CH2Cl2, the more acidic Fe(II) sites favor formation of 2,4-diaryl-N-tosylpyrrolidines by means of an in situ (3 + 2) cycloaddition of the initially generated 2-aryl-N-tosylaziridine with residual styrene. In the presence of ketone, 1,3-oxazolidines can be formed in practicable yields, involving a single-pot cycloaddition reaction of alkene, nitrene, and ketone (2 + 1 + 2). Mechanistic studies indicate that the most productive bipodal Fe(II) site mediates stepwise addition of nitrene to olefins to generate aziridines with good retention of stereochemistry and further enables aziridine ring opening to unmask a 1,3-zwitterion that can undergo cycloaddition with dipolarophiles (MeCN, alkene, ketone) to afford five-membered N-heterocycles.

Tripodal Schiff Base Compounds Containing Triazole and Mn3+ and Fe3+ Complexes: Synthesis, Characterization, and Investigation of Their Spectral Properties

In this study, it was aimed to synthesize and elucidate the structure of tripodal Schiff bases, which are used in the fields of materials science, chemistry, and pharmacology, and especially for the synthesis of chemical sensor materials due to their very good tendency to form complexes with metals. For the synthesis of new Schiff base tripodal compounds and their complexation with metals; Tripodal compound was synthesized as a result of the reaction of 2-hydroxy-4-(prop-2-yn-1-yloxy) benzaldehyde and N1, N1-bis(2-aminoethyl) ethane-1,2-diamine. The obtained compounds were complexed with Fe3+ and Mn3+ metals. The structures of synthesized tripodal ligands and metal complexes were tried to be elucidated using IR, UV-vis, Photoluminescence, 1H-NMR, 13C-NMR spectroscopic methods.

Structure-antitumor activity relationships of tripodal imidazolium-amino acid based salts. Effect of the nature of the amino acid, amide substitution and anion.

The antitumor activity of imidazolium salts is highly dependent upon their lipophilicity that can be tuned by the introduction of different hydrophobic substituents on the nitrogen atoms of the imidazolium ring of the molecule. Taking this into consideration, we have synthesized and characterized a series of tripodal imidazolium salts derived from L-valine and L-phenylalanine containing different hydrophobic groups and tested them against four cancer cell lines at physiological and acidic pH. At acidic pH (6.2) the anticancer activity of some of the tripodal compounds changes dramatically, and this parameter is crucial to control their cytotoxicity and selectivity. Moreover, several of these compounds displayed selectivity against the control healthy cell line higher than four. The transmembrane anion transport studies revealed moderate transport abilities suggesting that the observed biological activity is likely not the result of just their transport activity. The observed trends in biological activity at acidic pH agree well with the results for the CF leakage assay. These results strongly suggest that this class of compounds can serve as potential chemotherapeutic agents.

Over-activation of a nonessential bacterial protease DegP as an antibiotic strategy

Rising antibiotic resistance urgently begs for novel targets and strategies for antibiotic discovery. Here, we report that over-activation of the periplasmic DegP protease, a member of the highly conserved HtrA family, can be a viable strategy for antibiotic development. We demonstrate that tripodal peptidyl compounds that mimic DegP-activating lipoprotein variants allosterically activate DegP and inhibit the growth of an Escherichia coli strain with a permeable outer membrane in a DegP-dependent fashion. Interestingly, these compounds inhibit bacterial growth at a temperature at which DegP is not essential for cell viability, mainly by over-proteolysis of newly synthesized proteins. Co-crystal structures show that the peptidyl arms of the compounds bind to the substrate-binding sites of DegP. Overall, our results represent an intriguing example of killing bacteria by activating a non-essential enzyme, and thus expand the scope of antibiotic targets beyond the traditional essential proteins or pathways.

Excitation/detection energy controlled anisotropy dynamics in asymmetrically cyano substituted tri-podal molecules.

In the present work, the photophysical properties of two series of asymmetrical tri-podal molecules are studied, in order to determine the dependence of energy localization/delocalization phenomena on excitation and detection wavelength, by means of steady state, femtosecond time-resolved fluorescence and anisotropy spectroscopy. The molecules bear triphenylamine as an electron donating core and an acetylenic or olefinic π-conjugated bridge. At the periphery, they are substituted by no, one, two or three -CN groups used as electron acceptors. Thus, the compounds with only one or two -CN groups are asymmetrically substituted. As a comparison, the photophysics of their dipolar and quadrupolar analogues is also presented. The steady state absorption spectra of the asymmetrical tri-podal compounds exhibit a broadening and a low energy shoulder due to the splitting of the excited states. The fluorescence spectra are more red-shifted in the tri-podal molecules with a single -CN group, providing the first evidence of its mostly dipolar nature. Time-resolved anisotropy measurements by using different excitation and detection wavelengths provide clear evidence that the asymmetrical tri-podal molecules with one or two -CN groups behave like octupolar molecules upon high-energy excitation (the initial anisotropy is found 0.1-0.15), while upon low-energy excitation they reveal a behavior expected for linear dipolar or V-shaped quadrupolar molecules (the initial anisotropy is very close to 0.4 and 0.17, respectively). The symmetrical tri-podal compounds with no or three cyano groups, exhibit an anisotropy depolarization time of 2.5 ps attributed to energy hopping. The amplitude of this energy hopping component is wavelength dependent and increases as the excitation is shifted towards the long wavelength edge.

Extraction of scandium and other rare earth elements with a tricarboxylic acid derivative of tripodal pseudcalix[3]arene prepared from a new phenolic tripodal framework

We prepared a phenolic tripodal type extraction reagent to investigate the extraction of a series of rare earth metal ions. The extraction reaction and equilibrium extraction constants for rare earth ions with the tripodal extractant were evaluated using slope analysis and Job’s method. The tripodal reagent exhibited remarkably high extraction ability compared with a corresponding monopodal compound, and exhibited different extraction selectivities for rare earth metal ions than a calix[4]arene derivative because of the different size of the coordination site. The developed phenolic tripodal extraction reagent provides a new framework with a different size coordination site to those in calix[4]arene and alkyltrimethylol type tripodal compounds.

Exploring Rigid and Flexible Core Trivalent Sialosides for Influenza Virus Inhibition.

Herein, the chemical synthesis and binding analysis of functionalizable rigid and flexible core trivalent sialosides bearing oligoethylene glycol (OEG) spacers interacting with spike proteins of influenza A virus (IAV) X31 is described. Although the flexible Tris‐based trivalent sialosides achieved micromolar binding constants, a trivalent binder based on a rigid adamantane core dominated flexible tripodal compounds with micromolar binding and hemagglutination inhibition constants. Simulation studies indicated increased conformational penalties for long OEG spacers. Using a systematic approach with molecular modeling and simulations as well as biophysical analysis, these findings emphasize on the importance of the scaffold rigidity and the challenges associated with the spacer length optimization.

Crystalline Ammonium Complexes of Trimethyl‐ and Triethylbenzene‐Based Tripodal Compounds Bearing Pyrazole and Indazole Groups

Crystalline complexes of NH4+PF6– with trimethyl‐ and triethylbenzene‐based tripodal compounds, bearing either pyrazole or indazole groups, were prepared and characterized by X‐ray diffraction studies. The supramolecular motifs observed in the crystal structures and the conformations of the tripodal molecules have been the subject of a detailed analysis and are described in this paper. The pyrazole‐bearing side arms of the hosts with a trimethylbenzene scaffold are arranged in an aaa fashion and form a cavity including the ammonium ion. In the case of the triethylbenzene derivatives, the fully alternating arrangement of the pyrazole/indazole and ethyl groups is observed and by taking the ethyl groups into account, the conformation can be defined as ab′ab′ab′. The conformations observed in the crystals of the free host molecules can be defined as ab′ab′ba′ with the indazole‐bearing arms arranged in an aab fashion. The crystal packings of the complexes are, among other things, characterized by the presence of NH···F and CH···F hydrogen bonds as well as by CBr···N and CBr···π halogen bonds in the case of the bromo‐substituted derivatives.

Fluorinated tripodal receptors for potentiometric chloride detection in biological fluids

Fluorinated tripodal compounds were recently reported to be efficient transmembrane transporters for a series of inorganic anions. In particular, this class of receptors has been shown to be suitable for the effective complexation of chloride, nitrate, bicarbonate and sulfate anions via hydrogen bonding. The potentiometric properties of urea and thiourea-based fluorinated tripodal receptors are explored here for the first time, in light of the need for reliable sensors for chloride monitoring in undiluted biological fluids. The ion selective electrode (ISE) membranes with tren-based tris-urea bis(CF3) tripodal compound (ionophore I) were found to exhibit the best selectivity for chloride over major lipophilic anions such as salicylate (logKCl−/Sal−pot=+1.0) and thiocyanate (logKCl−/SCN−pot=+0.1). Ionophore I-based ISEs were successfully applied for chloride determination in undiluted human serum as well as artificial serum sample, the slope of the linear calibration at the relevant background of interfering ions being close to Nernstian (49.8±1.7mV). The results of potentiometric measurements were confirmed by argentometric titration. Moreover, the ionophore I-based ISE membrane was shown to exhibit a very good long-term stability of potentiometric performance over the period of 10 weeks. Nuclear magnetic resonance (NMR) titrations, potentiometric sandwich membrane experiments and density functional theory (DFT) computational studies were performed to determine the binding constants and suggest 1:1 complexation stoichiometry for the ionophore I with chloride as well as salicylate.

Trimethyl-, triethyl- and trimethoxybenzene-based tripodal compounds bearing pyrazole groups: conformations and halogen-/hydrogen-bond patterns in the crystalline state

X-ray analyses of a series of benzene-based tripodal molecules1–9provide interesting insights into the molecular recognition phenomena and give information about the different conformations which adopt the molecules in the solvent-free crystals and in solvates.

Linear and branched alkyl-esters and amides of gallic acid and other (mono-, di- and tri-) hydroxy benzoyl derivatives as promising anti-HCV inhibitors

Linear and branched compounds that contain two, three or five units of galloyl (3,4,5-trihydroxybenzoyl) or its isomer 2,3,4-trihydroxybenzoyl, as well as other mono- or dihydroxybenzoyl moieties have been synthesized. These molecules have been evaluated for their in vitro inhibitory effects against a wide panel of viruses showing preferential activity against HIV and HCV.Our structure-activity relationship studies demonstrated that the 2,3,4-trihydroxybenzoyl moiety provides better antiviral activities than the galloyl (3,4,5-trihydroxybenzoyl) moiety that is present in natural green tea catechins. This observation can be of interest for the further rational exploration of compounds with anti-HCV/HIV properties.The most notable finding with respect to HIV is that the tripodal compounds 43 and 45, with three 2,3,4-trihydroxybenzoyl moieties, showed higher activities than linear compounds with only one or two. With respect to HCV, the linear compounds, 52 and 41, containing a 12 polymethylene chain and two 2,3 di- or 2,3,4 tri-hydroxybenzoyl groups respectively at the ends of the molecule showed good antiviral efficiency. Furthermore, the anti-HCV activity of both compounds was observed at concentrations well below the cytotoxicity threshold. A representative member of these compounds, 41, showed that the anti-HCV activity was largely independent of the genetic make-up of the HCV subgenomic replicon and cell lines used.

Synthesis of Tripodal and Hexapodal Pyrazole- and Benzimidazole-Bearing Compounds

The syntheses of eight new tripodal and hexapodal benzimidazole- and pyrazole-bearing compounds, which are all potentially applicable for use as artificial receptors, are described. The prepared compounds contain either bromo-substituted heteroaromatic rings, able to participate in halogen-bonding interactions, or their analogues lacking the bromo substituents. Furthermore, the preparation of a new trisbenzimidazolium cage is included in this work. All used practical synthetic procedures are facilely accomplishable and provide the products in good to excellent yields. In addition, slightly modified, simplified synthetic procedures for five known tripodal compounds, which lead to better yields than those previously reported, are also detailed.

Improving the Binding Characteristics of Tripodal Compounds on Single Layer Graphene

Graphene is an atomically thin, transparent, and conductive electrode material of interest for sensors and energy conversion and storage devices, among others. Fully realizing its potential will require robust and general methods to anchor active functionality onto its pristine basal plane. Such strategies should not utilize covalent bond formation, which disrupts the graphene's π-electron system, from which most of its desirable properties arise. We recently introduced a tripodal binding motif, which forms robust monolayers on graphene capable of immobilizing active proteins and preventing their denaturation. Here we describe structure-property relationships for a series of tripod binding groups with "feet" of different sizes. Each derivative adsorbs strongly (ΔGads ≈ -39 kJ mol(-1)) to graphene's basal plane, yet the resulting monolayers exhibit kinetic stabilities that vary over 2 orders of magnitude and molecular densities that vary by a factor of 2. This study identifies phenanthrene as a superior anchor relative to pyrene on the basis of its increased monolayer density and similar kinetic stability. We also demonstrate that varying the length of the methylene linkers between the feet and tripodal core does not affect binding substantially. These results represent the first demonstration of structure-property relationships in the assembly of molecular adsorbates on graphene and provide a paradigm for designing effective graphene binding motifs.

Enantioselective construction of new chiral cyclic scaffolds using [2 + 2 + 2] cycloaddition

Two types of enantioselective [2 + 2 + 2] cycloadditions of triynes using chiral rhodium catalysts are disclosed. The intramolecular reaction of ortho-aminophenol-tethered triynes provides chiral tripodal compounds. Consecutive inter- and intramolecular reactions of ortho-phenylene-tethered triynes provide chiral tetraphenylenes.

Modular synthesis of ruthenium tripodal system with variable anchoring groups positions for semiconductor sensitization

We describe an improved synthetic approach to access tripodal compounds with variable footprints and anchor groups. Two ruthenium(II) bipyridine tripodal complexes with three carboxylic acid groups in meta ( Ru- m - COOH, 1) and para ( Ru- p - COOH, 2) positions, and with large (180–250 Å 2) footprints were synthesized and bound to the surface of nanostructured TiO 2. Selected properties of 1 and 2 in solution and bound are reported.

Synthesis and photoluminescent properties of two novel tripodal compounds containing coumarin moieties

Two novel tripodal compounds, tris[2-(7-diethylamino-coumarin-3-carboxamide)ethyl]amine (Tren-C1) and tris[2-(benzo[5,6]coumarin-3-carboxamide)ethyl]amine (Tren-C2), were synthesized and characterized. The UV–vis and fluorescence properties of Tren-C1 and Tren-C2 in solutions were investigated. These two compounds exhibited strong blue emission under ultraviolet light excitation. The maximal fluorescence emission occurred at about the level of 10 −5 mol/L. The chromophore units in the tripodal compounds shown a little interaction in the ground state, while the interactions in the excited state was notable and which leads to a broad and bathochromic shift of the emission bands.

New synthesis of two tridentate bipyrazolic compounds and their cytotoxic activity tumor cell lines

Two new tripodal compounds—4-{bis[(3,5-dimethyl-1H-pyrazole-1-yl)methyl]amino}butane-1-ol (1); ethyl 1-[((2-hydroxyethyl){[3-(ethoxycarbonyl)-5-methyl-1H-pyrazole-1-yl]methyl} amino)methyl]-5-methyl-1H-pyrazole-3-carboxylate (2) were reported. The evaluation of the cytotoxic properties in vitro of these ligands, was examined on two tumor cell lines—P815 (mastocytome murine) and Hep (carcinoma of human larynx). The concentration required to induce 50% of lysis (IC50) was more pronounced against P815 cell line (IC50: 39.42 µg mL−1 for the compound 1 and 97.74 µg mL−1 for the compound 2) than the Hep cell line (IC50: 83.49 µg mL−1 for compound 1 and 185.30 µg mL−1 for compound 2). Statistical analysis shows that the compound 1 is two to three folds more cytotoxic than the compound 2 (p < 0.05). Interestingly, the cytotoxic activity depends strongly on both the substituents linked to the aminic nitrogen and pyrazolic rings.

Tailoring tripodal ligands for zinc sensing

Zinc plays an important role in biological processes. It is implicated in many diseases, including those affecting the brain. Imaging zinc is becoming crucial to the elucidation of zinc concentration, distribution, kinetics and functions in cells and tissues. This review highlights recent advances in the development of picolylamine-based tripodal compounds as zinc sensors, especially our work in the field of sensing “invisible” Zn(II) using steady-state fluorescence, fluorescence lifetimes and chiroptical spectroscopy. Our approach has emphasized creative ligand design and detection schemes. Utilizing tris(2-pyridylmethyl)amine-based N4 tripodal ligands has provided a flexible system for engineering zinc sensors with improved sensitivity, selectivity and contrast. Also included are results with tripodal ligands that have focused more on applications.

The synthesis and characterization of phenylacetylene tripodal compounds containing boroxine cores

A convergent synthesis of phenylacetylene tripodal compounds containing boroxine cores has been accomplished. The boroxine cores are assembled in high yield either by chemical dehydration or ligand-facilitated trimerization of the corresponding monomeric boronic acids.