Triazole Bridge Research Articles

Syntheses and structures of two new coordination polymers generated from a 4-aminotriazole-bridged organic ligand and CoII salts

Organic ligands and counter-anions influence the coordination spheres of metal cations and hence the construction of coordination polymers (CPs). The specific bent geometries of five-membered heterocyclic triazole bridging organic ligands are capable of generating CPs with novel patterns not easily obtained using rigid linear ligands. A multidentate 4-aminotriazole-bridged organic ligand, namely 4-amino-3,5-bis(4,3'-bipyridyl-5'-yl)-4H-1,2,4-triazole (L) has been prepared and used to synthesize two CoII coordination polymers, namely poly[[[μ2-4-amino-3,5-bis(4,3'-bipyridyl-5'-yl)-4H-1,2,4-triazole-κ2N:N']bis(methanol-κO)cobalt(II)] bis(perchlorate)], {[Co(C22H16N8)2(CH3OH)2](ClO4)2}n, (I), and poly[[μ3-4-amino-3,5-bis(4,3'-bipyridyl-5'-yl)-4H-1,2,4-triazole-κ3N:N':N'']dichloridocobalt(II)], [CoCl2(C22H16N8)]n, (II), using CoX2 salts [X = ClO4 for (I) and Cl for (II)] under solvothermal conditions. Single-crystal X-ray structure analysis revealed that they both feature two-dimensional networks. Cobalt is located on an inversion centre in (I) and in a general position in (II). In (I), L functions as a bidentate cis-conformation ligand linking CoII ions, while it functions as a tridentate trans-conformation linker binding CoII ions in (II). In addition, O-H...N and N-H...O hydrogen bonds and C-H...π interactions exist in (I), while N-H...Cl and π-π interactions exist in (II), and these weak interactions play an important role in aligning the two-dimensional nets of (I) and (II) in the solid state. As the compounds were synthesized under the same conditions, the significant structural variations between (I) and (II) are believed to be determined by the different sizes and coordination abilities of the counter-anions. IR spectroscopy and diffuse reflectance UV-Vis spectra were also used to investigate the title compounds.

Click synthesis of a triphenylamine-based fluorescent methanol probe with a unique D-π-A structure

Facile probing organic solvents is attracting intense attention due to the growing environmental issues. Herein, for the first time, we report a novel D-π-A structured methanol responsive fluorescence molecule (TTO), synthesized by coupling triphenylamine (electron-donor) and p-toluenesulfonyl (electron-acceptor) via Cu (I) catalytic 1,3-dipolar cycloaddition (click chemistry) forming a triazole bridge. Density functional theory (DFT) calculations and X-ray single crystal structure reveal that TTO has a highly twisted conformation and unique D-π-A structure which render it exceptional optical properties. TTO exhibits strong fluorescence in methanol (QE>0.67) but weak fluorescence in other organic solvents (QE<0.1) including various alcohols and can be used as a highly selective fluorescence probe for methanol identification. Notably, TTO is able to excellently probe methanol from its homologue ethanol in water with a detection limit of below 0.7% (volume concentration), which demonstrates the promise potential of TTO for practical applications.

Design of novel antimicrobial peptide dimer analogues with enhanced antimicrobial activity in vitro and in vivo by intermolecular triazole bridge strategy

Currently, antimicrobial peptides have attracted considerable attention because of their broad-sprectum activity and low prognostic to induce antibiotic resistance. In our study, for the first time, a series of side-chain hybrid dimer peptides J-AA (Anoplin-Anoplin), J-RR (RW-RW), and J-AR (Anoplin-RW) based on the wasp peptide Anoplin and the arginine- and tryptophan-rich hexapeptide RW were designed and synthesized by click chemistry, with the intent to improve the antimicrobial efficacy of peptides against bacterial pathogens. The results showed that all dimer analogues exhibited up to a 4–16 fold increase in antimicrobial activity compared to the parental peptides against bacterial strains. Furthermore, the antimicrobial activity was confirmed by time-killing kinetics assay with two strains which showed that these dimer analogues at 1, 2×MIC were rapidly bactericidal and reduced the initial inoculum significantly during the first 2–6h. Notably, dimer peptides showed synergy and additivity effects when used in combination with conventional antibiotics rifampin or penicillin respectively against the multidrug-resistant strains. In the Escherichia coli-infected mouse model, all of hybrid dimer analogues had significantly lower degree of bacterial load than the untreated control group when injected once i.p. at 5mg/kg. In addition, the infected mice by methicillin-resistant (MRSA) strain could be effectively treated with J-RR. All of dimer analogues had membrane-active action mode. And the membrane-dependent mode of action signifies that peptides functions freely and without regard to conventional resistant mechanisms. Circular dichroism analyses of all dimer analogues showed a general predominance of α-helix conformation in 50% trifluoroethanol (TFE). Additionally, the acute toxicities study indicated that J-RR or J-AR did not show the signs of toxicity when adult mice exposed to concentration up to 120mg/kg. The 50% lethal dose (LD50) of J-AA was 53.6mg/kg. In conclusion, to design and synthesize side chain-hybrid dimer analogues via click chemistry may offer a new strategy for antibacterial therapeutic option.

Structural Insight into Electrogenerated Chemiluminescence of Para-Substituted Aryl–Triazole–Thienyl Compounds

There has been a strong push to develop new thiophene-based monomers to tailor the electrical and optical properties of the resulting polymers. However, the synthesis of these elaborated thienyl compounds is difficult to realize. Here, we report the successful click coupling of thienyl azides and para-substituted aryl alkynes to synthesize eight thiophene-based luminophores intended for electrochemical and electrochemiluminescence (ECL) study. These thiophenes could be separated into two series: monothienyl and bithienyl analogues and further categorized based on the nature of the ligand attachment to their phenyl rings (electron-donating or -withdrawing characteristics: NMe2, OMe, H, or F) on the other side of the triazole bridge. The electrochemical experiments indicated these compounds lacked stability when they were oxidized or reduced, with the exception of those with a dimethylamine ligand attached (quasireversible oxidations). Cyclic and differential pulse voltammetries revealed the redox potential...

Cyclization of a cell-penetrating peptide via click-chemistry increases proteolytic resistance and improves drug delivery.

In this work we report synthesis and biological evaluation of a cell-penetrating peptide (CPP), that is partly cyclized via a triazole bridge. Recently, beneficious properties have been reported for cyclized peptides concerning their metabolic stability and intracellular uptake. A CPP based on human calcitonin was used in this study, and side chain cyclization was achieved via copper catalyzed alkyne-azide click reaction. Cell viability studies in several cell-lines revealed no cytotoxic effects. Furthermore, efficient uptake in breast cancer MCF-7 cells could be determined. Moreover, preliminary studies using this novel peptide as drug transporter for daunorubicin were performed. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Excitonic Coupling and Femtosecond Relaxation of Zinc Porphyrin Oligomers Linked with Triazole Bridge: Dynamics and Modeling.

The synthesis of new zinc porphyrin oligomers linked by a triazole bridge was carried out via "click" reaction. A split in the porphyrin oligomer B-band was observed. It was considered as evidence of exciton-excitonic coupling. The relaxation of excited states in Q-band porphyrin oligomers was studied by the femtosecond laser spectroscopy technique with a 20 fs pump pulse. The transient oscillations of two B-band excitonic peaks have a π-radian shift. For explanation of the coherent oscillation, a theoretical model was developed. The model considered the combination of the exciton-excitonic coupling between porphyrin rings in dimer and weak exciton-vibronic coupling in one porphyrin ring. By varying the values of the structural parameters of porphyrins (the strength values of this couplings and measure of symmetry breaking), we obtained correspondence between the experimental data (phase shift and amplitudes of the spectrum oscillations) and the predictions of the model developed here.

1,2,3-Triazole Bridge as Conformational Constrain in β-Hairpin Peptides: Analysis of Hydrogen-Bonded Positions.

Conformational constrained β-hairpin peptides are useful tool to modulate protein-protein interactions. A triazole bridge in hydrogen-bonded positions between two antiparallel strands induces a conformational stabilization of the β-hairpin peptide. The entity of the stability of the β-hairpin peptide depends on the length of the bridge.

Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors.

The metallo-β-lactamases (MβLs) cleave the β-lactam ring of β-lactam antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors of representatives of the three subclasses of MβLs. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC50 value range of 0.15-1.90 μM, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 μM. Compounds 4d and 6c are partially mixed inhibitors with K i values of 0.49 and 0.63 μM using cefazolin as the substrate. Structure-activity relationship studies reveal that replacement of hydrogen on the aromatic ring by chlorine, heteroatoms, or alkyl groups can affect bioactivity, while leaving the aromatic ring of the triazolylthiols unmodified maintains the inhibitory potency. Docking studies reveal that the typical potent inhibitors of NDM-1, 4d and 6c, form stable interactions in the active site of NDM-1, with the triazole bridging Zn1 and Zn2, and the amide interacting with Lys 211 (Lys224).

Rational steering of insulin binding specificity by intra-chain chemical crosslinking.

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22–B30 segment, using the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26–B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone’s B-chain C-terminus for its IR-B specificity.

Tuning the properties of a novel short cell-penetrating peptide by intramolecular cyclization with a triazole bridge

Cell-penetrating peptides (CPPs) present a versatile alternative to viral gene delivery vectors, addressing the still challenging task to suitably transport the desired gene to the target cell. In this work, the rational design of triazole-bridged CPPs and their detailed investigation concerning peptide/lipid interactions, using also NMR-based structure calculations, are reported.

New complexation behaviour of the potentially bis-terdentate triazole based ligands PMAT and PMPT: FeIII4 oxo-bridged metallomacrocycles

The reaction of the potentially bis-terdentate ligand PMPT with [FeII(py)4(NCS)2] in methanol under an inert atmosphere gives [FeIIn(PMPT)n(NCS)2n] (1), where PMPT=4-pyrrolyl-3,5-bis{[(2-pyridylmethyl)-amino]methyl}-4H-1,2,4-triazole. In contrast, conducting this reaction in dimethylformamide (DMF), or recrystallizing 1 from DMF, leads to the formation of the tetranuclear FeIII metallomacrocycle [FeIII4(PMPT)2(O)2(NCS)8(DMF)2] (2). This is the first structurally characterised complex of a ligand of this type that does not bind in a bis-terdentate manner with a 1:1 metal:ligand stoichiometry and N1N2 bridging of the bound metal ions. Instead, each ligand strand binds in an asymmetric fashion, providing two well separated (no triazole bridge) bidentate and terdentate binding pockets, with the additional binding sites on the iron(III) centres occupied by N-bound thiocyanate anions (NB. previous complexations have involved non-coordinating anions), oxide bridges, and/or DMF. Analogous reactions of [FeII(py)4(NCS)2] and the closely-related ligand PMAT appear to result in ligand decomposition, although a few crystals of the complex [FeIII4(PMAT)2(O)2(NCS)8(DMF)2]·solvents, (3·solvents) were obtained (PMAT=4-amino-3,5-bis{[(2-pyridylmethyl)-amino]methyl}-4H-1,2,4-triazole).

Femtopicosecond relaxation of zinc porphyrinate trimer linked by the triazole bridge

The femtosecond dynamics of excitation relaxation of the zinc porphyrinate trimer was studied by the pumping—scanning method. The obtained results were examined using semi-empirical quantum chemical calculations. The dynamics of excitation relaxation shows that the application of similar systems as models for studying photosystems and development of artificial analogs of natural photosynthetic centers is promising. An explanation for the observed coherent dynamics of exciton bands was proposed.

Total Chemical Synthesis of a Heterodimeric Interchain Bis-Lactam-Linked Peptide: Application to an Analogue of Human Insulin-Like Peptide 3

Nonreducible cystine isosteres represent important peptide design elements in that they can maintain a near-native tertiary conformation of the peptide while simultaneously extending the in vitro and in vivo half-life of the biomolecule. Examples of these cystine mimics include dicarba, diselenide, thioether, triazole, and lactam bridges. Each has unique physicochemical properties that impact upon the resulting peptide conformation. Each also requires specific conditions for its formation via chemical peptide synthesis protocols. While the preparation of peptides containing two lactam bonds within a peptide is technically possible and reported by others, to date there has been no report of the chemical synthesis of a heterodimeric peptide linked by two lactam bonds. To examine the feasibility of such an assembly, judicious use of a complementary combination of amine and acid protecting groups together with nonfragment-based, total stepwise solid phase peptide synthesis led to the successful preparation of an analogue of the model peptide, insulin-like peptide 3 (INSL3), in which both of the interchain disulfide bonds were replaced with a lactam bond. An analogue containing a single disulfide-substituted interchain lactam bond was also prepared. Both INSL3 analogues retained significant cognate RXFP2 receptor binding affinity.

Long-Range Charge Separation in a Ferrocene–(Zinc Porphyrin)–Naphthalenediimide Triad. Asymmetric Role of 1,2,3-Triazole Linkers

New dyad and triad systems based on a zinc porphyrin (ZnP), a naphthalenediimide (NDI), and a ferrocene (Fc) as molecular components, linked by 1,2,3-triazole bridges, ZnP-NDI (3) and Fc-ZnP-NDI (4), have been synthesized. Their photophysical behavior has been investigated by both visible excitation of the ZnP chromophore and UV excitation of the NDI unit. Dyad 3 exhibits relatively inefficient quenching of the ZnP singlet excited state, slow charge separation, and fast charge recombination processes. Excitation of the NDI chromophore, on the other hand, leads to charge separation by both singlet and triplet quenching pathways, with the singlet charge-separated (CS) state recombining in a subnanosecond time scale and the triplet CS state decaying in ca. 90 ns. In the triad system 4, primary formation of the Fc-ZnP+-NDI– charge-separated state is followed by a secondary hole shift process from ZnP to Fc. The product of the stepwise charge separation, Fc+-ZnP-NDI–, undergoes recombination to the ground state in 1.9 μs. The charge-separated states are always formed more efficiently upon NDI excitation than upon ZnP excitation. DFT calculations on a bridge–acceptor fragment show that the bridge is expected to mediate a fast donor-to-bridge-to-acceptor electron cascade following excitation of the acceptor. More generally, triazole bridges may behave asymmetrically with respect to photoinduced electron transfer in dyads, kinetically favoring hole-transfer pathways triggered by excitation of the acceptor over electron-transfer pathways promoted by excitation of the donor.

Synthesis and properties of porphyrin-expanded porphyrin click dyads

Six covalently linked 1,2,3-triazole bridged porphyrin-expanded porphyrin dyads containing Zn(II) porphyrin as energy donor and thiarubyrin, oxasmaragdyrin and BF2–oxasmaragdyrin as energy acceptors were synthesized under click reaction conditions. The click dyads were synthesized by coupling of azido Zn(II) porphyrin with ethynyl functionalized expanded porphyrins under Cu(I) catalyzed mild reaction conditions. Both rigid and flexible triazole bridges were used to understand the interaction between the Zn(II) porphyrin and expanded porphyrin units in dyads. The dyads were characterized by mass, NMR, absorption, fluorescence and electrochemical studies. The NMR, absorption and electrochemical studies indicated that the Zn(II) porphyrin and expanded porphyrin units in dyads interact weakly and maintain their independent characteristic features. The fluorescence studies indicated a possibility of energy transfer from donor Zn(II) porphyrin unit to expanded porphyrin unit such as oxasmaragdyrin and BF2–oxasmaragdyrin units in both flexible and rigid porphyrin-expanded porphyrin dyads.

Self-Assembly of Pentanuclear Mesocate versus Octanuclear Helicate: Size Effect of the [MII3(μ3-O/X)]n+ Triangle Core

The first cluster mesocate (H(3)O)[{Fe(2)(μ-L)(3)}{Fe(3)(μ(3)-O)(μ-Cl)(3)}]·3EtOH (1) and a new series of cluster helicates, [{Mn(μ-L)(3)}(2){Mn(3)(μ(3)-Cl)}(2)](ClO(4))(2)·2MeOH·6H(2)O (2), [{Cd(μ-L)(3)}(2){Cd(3)(μ(3)-Br)}(2)]Br(2)·2DMF·14H(2)O (3), and [{Cd(μ-L)(3)}(2){Cd(3)(μ(3)-I)}(2)](CdI(4))·3H(2)O (4), have been synthesized by the self-assembly of a C(2)-symmetric tritopic ligand, 2,6-bis[5-(2-pyridinyl)-1H-triazol-3-yl]pyridine (H(2)L) with different metal halogen salts. Single-crystal X-ray diffraction and electrospray ionization mass spectrometry measurements were carried out on these complexes. 1 was crystallized as a triple-stranded pentanuclear mesocate in which a [Fe(II)(3)(μ(3)-O)](4+) triangle core was wrapped by a [Fe(II)(2)(μ-L)(3)](2-) shell. 2-4 have similar octanuclear helicate structures in which two propeller-shaped [M(II)(μ-L)(3)](4-) units embrace two [M(II)(3)(μ(3)-X)](5+) triangles inside. The [M(II)(3)(μ(3)-O/X)](n+) triangle core were found to play an important role in the selective synthesis of the two architectures: the smaller [Fe(II)(3)(μ(3)-O)](4+) triangle core prefers a mesocate structure because it matches the small cavity imposed by the [Fe(II)(2)(μ-L)(3)](2-) shell, while the bigger [M(II)(3)(μ(3)-X)](5+) induces a screwed arrangement of the ligands, thus stabilizing the helicate structure. Variable-temperature magnetic susceptibility measurements indicate that both 1 and 2 display an overall antiferromagnetic coupling. Density functional theory calculations for 1 confirm the strong antiferromagnetic interaction in the central [Fe(II)(3)(μ(3)-O)](4+), while interaction through the triazole bridging ligands is slightly ferromagnetic. For 2, three interaction pathways were considered and all sets of J values reveal the presence of weak antiferromagnetic interaction.

Exploring Förster electronic energy transfer in a decoupled anthracenyl-based borondipyrromethene (bodipy) dyad

An anthracenyl-Bodipy dyad containing a triazole bridge, that acts to decouple the two units in the ground state, has been synthesised and structurally characterised. Efficient electronic energy transfer occurs from the anthracenyl-based unit to the Bodipy system in toluene in around 12 ps, and becomes faster in solvents of lower refractive index. The rate of electronic energy transfer is discussed in terms of Förster theory.

1,2,4-Triazole functionalized adamantanes: a new library of polydentate tectons for designing structures of coordination polymers

A series of functionalized adamantanes: 1,3-bis(1,2,4-triazol-4-yl)(tr(2)ad); 1,3,5-tris(1,2,4-triazol-4-yl)-(tr(3)ad); 1,3,5,7-tetrakis(1,2,4-triazol-4-yl)adamantanes (tr(4)ad) and 3,5,7-tris(1,2,4-triazol-4-yl)-1-azaadamantane (tr(3)ada) were developed as a new family of geometrically rigid polydentate tectons for supramolecular synthesis of framework solids. The coordination compounds were prepared under hydrothermal conditions; their structures reveal a special potential of the triazolyl adamantanes for the generation of highly-connected and open frameworks as well as structures based upon polynuclear metal clusters assembled with short-distance N(1),N(2)-triazole bridges. Complexes [Cd{L}(2)]A·nH(2)O [L = tr(3)ad, A = 2NO(3)(-) (4), CdCl(4)(2-) (5); L = tr(3)ada, A = CdI(4)(2-) (7)] are isomorphous and adopt a layered 3,6-connected structure of CdI(2) type. [{Cu(3)(OH)}(2)(SO(4))(5)(H(2)O)(2){tr(3)ad}(3)]·26H(2)O (6) is a layered polymer based upon Cu(3)(μ(3)-OH) nodes and trigonal tr(3)ad links. In [Cu(3)(OH)(2){tr(3)ada}(2)(H(2)O)(4)](ClO(4))(4) (8), [Cu(2){tr(3)ada}(2)(H(2)O)(3)](SO(4))(2)·7H(2)O (9) and [Cd(2){tr(3)ada}(3)]Cl(4)·28H(2)O (10) (UCl(3)-type net) the organic tripodal ligands bridge polynuclear metal clusters. Complexes [Ag{tr(4)ad}]NO(3)·3.5H(2)O (11) and [Cu{tr(4)ad}(H(2)O)](ClO(4))(2)·3H(2)O (12) have 3D SrAl(2)-type frameworks with the metal ions and adamantane tectons as topologically equivalent tetrahedral nodes, while in [Cd(3)Cl(6){tr(4)ad}(2)]·9H(2)O (13) the ligands bridge trinuclear six-connected Cd(3)Cl(6)(μ-tr)(4)(tr)(2) clusters. In the compounds [Cd(2){tr(2)ad}(4)(H(2)O)(4)](CdBr(4))(2)·2H(2)O (2) and [Cd{tr(2)ad}(4){CdI(3)}(2)]·4H(2)O (3) the bitopic ligands provide simple links between the metal ions, while in [Ag(2){tr(2)ad}(2)](NO(3))(2)·2H(2)O (1) the ligand is tetradentate and generates a 3D framework.

β-Hairpin stabilization through an interstrand triazole bridge

β-Hairpin peptides were conformationally stabilized through a 1,4 disubstituted 1,2,3-triazole interstrand linkage. A NMR conformational analysis revealed that the β-hairpin content depends on the number and position of substituent methylene units of the 1,2,3-triazole ring. These results will allow the design of metabolically stable peptidomimetic analogs of bioactive β-hairpin peptides.

ChemInform Abstract: Peptides and Proteins as a Continuing Exciting Source of Inspiration for Peptidomimetics

AbstractReview: ca. 200 refs.