- The herringbone helix: A noncanonical folding in aromatic-aliphatic peptides
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Hybrid oligomeric sequences derived from both aliphatic and aromatic units are shown to adopt a folded conformation with an unprecedented architecture. Specifically, a δ-amino acid bearing an aliphatic amine-6-aminomethyl-2-pyridinecarboxylic (P)-was designed and synthesized as a flexible analogue of 6-amino-2-quinolinecarboxylic acid (Q). Oligomers Pn (n = 2, 4, 8) were first synthesized but show no sign of folding in solution in organic solvents, unlike the Qn oligomers from which they are derived, which adopt particularly stable helical conformations. Hybrid oligomers (PQ)n (n = 1, 2, 4) were also prepared and were shown to adopt a novel folded conformation in the solid state where PQ units arrange into two stacks at a 90° angle from each other. Comprehensive NMR studies demonstrate that in solution this peculiar organization coexists with a helical conformation resembling that of Qn oligomers. Copyright
- Delsuc, Nicolas,Godde, Frederic,Kauffmann, Brice,Leger, Jean-Michel,Huc, Ivan
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- Poly(ethylene glycol)-supported chiral pyridine-2,6-bis(oxazoline): synthesis and application as a recyclable ligand in CuI-catalyzed enantioselective direct addition of terminal alkynes to imines
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Pyridine-2,6-bis(oxazoline) immobilized on a soluble support, viz., poly(ethylene glycol) methyl ether with Mn = 5000 Da, has been synthesized for the first time. The efficiency of its application as a chiral ligand in CuI-catalyzed
- Tarasenko, Elena A.,Beletskaya, Irina P.
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- Catenane-based mechanically-linked block copolymers
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An original strategy for the synthesis of diblock copolymers where the blocks are linked by a catenane junction is described. Starting from a functionalized catenane precursor, our strategy enables the preparation of a variety of copolymers by different techniques such as ROP, ATRP and CuAAC click reaction.
- Ahamed, B. Nisar,Duchêne, Roland,Robeyns, Koen,Fustin, Charles-André
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- Synthesis of 2,6-di(1,8-naphthyridin-2-yl)pyridines functionalized at the 4-position: Building blocks for suitable metal complex-based dyes
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This study reports the synthesis of a methoxy-substituted 2,6-di(1,8-naphthyridin-2-yl)pyridine using Friedl?nder methodology. The functionalization at the 4-carbon of the methoxy-substituted derivative was confirmed by X-ray structural analysis. Finally, the methyl ether protecting group was cleaved to obtain 2,6-di(1,8-naphthyridin-2-yl)pyridine-4-ol. Using the compounds, coordination behavior to ruthenium(II) center was also examined.
- Nakamura, Shunsuke,Takase, Tsugiko,Oyama, Dai
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- Pyridine-based lanthanide complexes: Towards bimodal agents operating as near infrared luminescent and MRI reporters
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We report two prototype Ln3+ complexes that address requirements for both MRI and luminescence imaging and we demonstrate that the presence of two H2O molecules bound to the Ln3+, beneficial for MRI applications of the Gd3+ analogue, is not a major limitation for the development of NIR luminescent agents. The Royal Society of Chemistry 2008.
- Pellegatti, Laurent,Zhang, Jian,Drahos, Bohuslav,Villette, Sandrine,Suzenet, Franck,Guillaumet, Gerald,Petoud, Stephane,Toth, Eva
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- New Proton-ionizable Macrocyclic Ligands. Synthesis, Basicity, Reactions, and Structures of Two Aza Crown Ethers containing the 4-Hydroxypyridine Unit
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Two new reactive aza crown ethers, (1) and (2), containing the 4-hydroxypyridine unit have been prepared and found to be different with respect to pK(H2O) values for H2L(+), structures of the hydrates of HL, and complex formation with benzylamine and the benzylammonium ion.
- Nakatsuji, Yohji,Bradshaw, Jerald S.,Tse, Pui-Kwan,Arena, Giuseppi,Wilson, Bruce E.,et al.
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- Poly(ethylene glycol) modified Mn2+ complexes as contrast agents with a prolonged observation window in rat MRA
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A novel rigid Mn2+ complex (MnL) with pyridine and pyrrolidine rings was designed and synthesized. The complex was further modified with alkyne, and conjugated to azide-terminated PEG by click chemistry. PEGylated MnL shows considerably higher relaxivity (MnL-PEG2k-MnL: r1 = 6.38 mmol-1 s-1; MnL-PEG4.6k-MnL: r1 = 5.63 mmol-1 s-1) and much longer blood circulation time than free Mn2+ complexes (MnL: r1 = 3.73 mmol-1 s-1), providing a prolonged time window to acquire longitudinal images for rat contrast enhanced magnetic resonance angiography.
- Wu, Changqiang,Yang, Li,Chen, Zhuzhong,Zhang, Houbing,Li, Danyang,Lin, Bingbing,Zhu, Jiang,Ai, Hua,Zhang, Xiaoming
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- Synthesis and evaluation of a rationally designed click-based library for G-Quadruplex selective DNA photocleavage
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DNA containing repeating G-rich sequences can adopt higher-order structures known as G-quadruplexes (G4). These structures are believed to form within telomeres and the promoter regions of some genes, particularly in a number of proto-oncogenes, where they may play a role in regulating transcription. Alternatively, G4 DNA may act as a barrier to replication. To investigate these potential biological roles, probes that combine highly selective G4 DNA targeting with photocleavage activity can allow temporal detection of G4 DNA, providing opportunities to obtain novel insights about the biological roles of G4 DNA. We have designed, synthesized, and screened a small library of potential selective G-quadruplex DNA photocleavage agents incorporating the G-quadruplex targeting moiety of 360A with known photocleavage groups linked via "click" chemistry.
- McBrayer, Dominic,Kerwin, Sean M.
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- Surface engineering of silica nanoparticles with a gadolinium-PCTA complex for efficient: T1-weighted MRI contrast agents
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New pyridine containing triAza; 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA) ligands presenting pendant carboxylic acid or alcohol functions have been synthesized and used to form diaqua Gd(iii) complexes, which
- Mathieu, Paul,Chalet, Marie,Clain, Marie Myriam,Teulon, Lauryanne,Benoist, Eric,Leygue, Nadine,Picard, Claude,Boutry, Sébastien,Laurent, Sophie,Stanicki, Dimitri,Hénoumont, Céline,Novio, Fernando,Lorenzo, Julia,Montpeyó, David,Ciuculescu-Pradines, Diana,Amiens, Catherine
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- Spectroscopic and DFT Characterization of a Highly Reactive Nonheme FeV-Oxo Intermediate
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The reaction of [(PyNMe3)FeII(CF3SO3)2], 1, with excess peracetic acid at -40 °C generates a highly reactive intermediate, 2b(PAA), that has the fastest rate to date for oxidizing cyclohexane by a nonheme iron species. It exhibits an intense 490 nm chromophore associated with an S = 1/2 EPR signal having g-values at 2.07, 2.01, and 1.94. This species was shown to be in a fast equilibrium with a second S = 1/2 species, 2a(PAA), assigned to a low-spin acylperoxoiron(III) center. Unfortunately, contaminants accompanying the 2(PAA) samples prevented determination of the iron oxidation state by M?ssbauer spectroscopy. Use of MeO-PyNMe3 (an electron-enriched version of PyNMe3) and cyclohexyl peroxycarboxylic acid as oxidant affords intermediate 3b(CPCA) with a M?ssbauer isomer shift δ = -0.08 mm/s that indicates an iron(V) oxidation state. Analysis of the M?ssbauer and EPR spectra, combined with DFT studies, demonstrates that the electronic ground state of 3b(CPCA) is best described as a quantum mechanical mixture of [(MeO-PyNMe3)FeV(O)(OC(O)R)]2+ (~75%) with some FeIV(O)(?OC(O)R) and FeIII(OOC(O)R) character. DFT studies of 3b(CPCA) reveal that the unbound oxygen of the carboxylate ligand, O2, is only 2.04 ? away from the oxo group, O1, corresponding to a Wiberg bond order for the O1-O2 bond of 0.35. This unusual geometry facilitates reversible O1-O2 bond formation and cleavage and accounts for the high reactivity of the intermediate when compared to the rates of hydrogen atom transfer and oxygen atom transfer reactions of FeIII(OC(O)R) ferric acyl peroxides and FeIV(O) complexes. The interaction of O2 with O1 leads to a significant downshift of the Fe-O1 Raman frequency (815 cm-1) relative to the 903 cm-1 value predicted for the hypothetical [(MeO-PyNMe3)FeV(O)(NCMe)]3+ complex.
- Fan, Ruixi,Serrano-Plana, Joan,Oloo, Williamson N.,Draksharapu, Apparao,Delgado-Pinar, Estefanía,Company, Anna,Martin-Diaconescu, Vlad,Borrell, Margarida,Lloret-Fillol, Julio,García-Espa?a, Enrique,Guo, Yisong,Bominaar, Emile L.,Que, Lawrence,Costas, Miquel,Münck, Eckard
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- Functionalized Triptycene-Derived Tripodal Ligands: Privileged Formation of Tetranuclear Cage Assemblies with Larger Ln(III)
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In this Article, we report the self-assembly of lanthanide complexes formed with two new tripodal ligands, L2 and L3, where binding strands are connected to a rigid triptycene anchor. The pyridine moieties are functionalized with methoxy and PEG groups to enhance ligand solubility and to evaluate the effect of these substituents on lanthanide coordination. These ligands were successfully synthesized and characterized, and their coordination properties were examined along the lanthanide series through speciation studies with NMR and ESI-MS. Well-defined tetranuclear complexes are formed with both ligands, but their stabilities with heavier lanthanides are considerably reduced, especially for complexes with L3. This is attributed to a destabilizing effect of pending PEG arms in combination with increased steric hindrance between binding strands upon complexation with smaller cations. The sensitization of lanthanide luminescence in tetranuclear complexes occurs despite one water molecule being coordinated to a metal ion.
- Vuillamy, Alexandra,Zebret, Soumaila,Besnard, Céline,Placide, Virginie,Petoud, Stéphane,Hamacek, Josef
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- Molecular imaging of biothiols and: In vitro diagnostics based on an organic chromophore bearing a terbium hybrid probe
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In this research, a novel terbium-based luminescent hybrid inorganic/organic probe was designed and synthesized. Mesoporous silica nanospheres dispersed in water were used as the appropriate host for the covalently linked lanthanide-containing organic structures. The lanthanide structure was linked to a sulfonate ester unit, which, in the presence of biothiols, was cleaved to result in terbium emission. The hybrid probe exhibited the capabilities of quantitative determination and detection limits for biothiols were presented (36.8 nM for Cys, 32.5 nM for GSH, and 34.7 nM for Hcy). Evaluation of luminescence changes in cell culture demonstrated that this smart probe is cell membrane permeable and selectively lights up in the presence of cysteine and glutathione in human embryonic kidney cells and human lung adenocarcinoma cells. This variation in the presence of biothiols can be controlled by the treatment with N-methylmaleimide. The narrow line-like bands and long-lived excited states of this terbium luminescent sensor allows the discrimination of scattering signals and interfering fluorescence derived from biological tissues.
- Zhou, Zhan,Wang, Qianming,Zhang, Cheng Cheng,Gao, Jinwei
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- Sol-gel emulsion synthesis of biphotonic core-shell nanoparticles based on lanthanide doped organic-inorganic hybrid materials
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Eu3+ and Tb3+ complexes based on an organo-alkoxysilane derived from 4-azido dipicolinic acid by "click chemistry" were coated onto silica nanoparticles previously prepared by the water in oil emulsion method. Structural and optical properties of the resulting luminescent core-shell monodisperse (30 nm) nanohybrids were fully characterized by infrared and Raman spectroscopies as well as by electron microscopy. Fluorescence spectroscopy evidenced that an efficient ligand-to-Ln3+ energy transfer - both in the mono- and biphotonic modes - occurs. Furthermore, surface modification by amino groups was realized, paving the way for nanotags of biological interest. The Royal Society of Chemistry 2012.
- Guo, Xianmin,Canet, Jean-Louis,Boyer, Damien,Gautier, Arnaud,Mahiou, Rachid
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- Pseudopolymorphs of chelidamic acid and its dimethyl ester
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Different tautomeric and zwitterionic forms of chelidamic acid (4-hy-droxy-pyridine-2,6-dicarb-oxy-lic acid) are present in the crystal structures of chelidamic acid methanol monosolvate, C7H 5NO5·CH4O, (Ia), dimethyl-ammonium chelidamate (di-methyl-ammonium 6-carb-oxy-4-hy-droxy-pyridine-2-carboxyl-ate), C2H8N+·C7H4NO 5 -, (Ib), and chelidamic acid dimethyl sulfoxide monosolvate, C7H5NO7·C7H 6OS, (Ic). While the zwitterionic pyridinium carboxyl-ate in (Ia) can be explained from the pK a values, a (partially) deprotonated hy-droxy group in the presence of a neutral carb-oxy group, as observed in (Ib) and (Ic), is unexpected. In (Ib), there are two formula units in the asymmetric unit with the chelidamic acid entities connected by a symmetric O - H?O hydrogen bond. Also, crystals of chelidamic acid dimethyl ester (dimethyl 4-hy - droxy-pyridine-2,6-dicarboxyl-ate) were obtained as a monohydrate, C 9H9NO5·H2O, (IIa), and as a solvent-free mod-ifi - cation, in which both ester mol-ecules adopt the hy-droxy-pyridine form. In (IIa), the solvent water mol-ecule stabilizes the synperiplanar conformation of both carbonyl O atoms with respect to the pyridine N atom by two O - H?O hydrogen bonds, whereas an anti-periplanar arrangement is observed in the water-free structure. A database study and ab initio energy calculations help to compare the stabilities of the various ester conformations.
- Tutughamiarso, Maya,Pisternick, Thorsten,Egert, Ernst
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- Synthesis and characterization of lipophilic cationic Ga(III) complexes based on the H2: CHX dedpa and H2dedpa ligands and their 67/68Ga radiolabeling studies
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68Ga is an attractive isotope for incorporation into a positron-emission tomography (PET) imaging agent, and is finding use as an alternative generator-produced isotope to 99mTc particularly in imaging of myocardial perfusion. We have synthesized six new chelating ligands based on our previously reported H2dedpa and H2CHXdedpa scaffolds (CHX = cyclohexyl, H2dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). These ligands are designed to incorporate several lipophilic appendages at the secondary nitrogens, and upon coordination to 68Ga(iii) will form lipophilic, cationic complexes designed to mimic the properties of other clinically relevant myocardial perfusion imaging agents. The non-radioactive Ga(iii) complexes were prepared and characterized by NMR spectroscopy; each ligand retained its predicted hexadentate N4O2 binding to Ga(iii). The radiolabeling properties of the six ligands were assessed using the longer-lived 68Ga surrogate, 67Ga. The absence of 'free' uncomplexed 67Ga in the HPLC radio-chromatograms indicated >99% radiochemical yields (10 minutes at ambient temperature, ligand concentrations of 10-4 M). However, the N,N′-benzyl functionalized derivatives displayed multiple peaks corresponding to the presence of additional 67Ga-complexes which complicated further study. Selected 67Ga-CHXdedpa complexes were tested for in vitro stability against the metal-binding protein apo-transferrin, and were found to be sufficiently stable (>80%) in a 2 h challenge assay, suggesting that alternative N,N′-alkylated derivatives which introduce more lipophilic character will be of interest in future studies.
- Ramogida,Schindler,Schneider,Tan,Huh,Ferreira,Adam,Orvig
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p. 103763 - 103773
(2016)
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- Sensitised lanthanide luminescence using a RuIIpolypyridyl functionalised dipicolinic acid chelate
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A visible light absorbing [RuII(tpy)2]2+-type chromophore appended with a dipicolinic acid LnIIIchelator has been prepared and complexed with several differing lanthanide cations to form the corresponding heterobimetallic d-f assemblies. The subseqent solution speciation analysed by1H NMR spectroscopy revealed an unexpected decrease in the LnIIIchelate complex stability, in particular for the 1?:?3 complex, when compared to the parent dipicolinic acid. As a result, the desired Ln(ML)3complexes could not be isolated, and the 1?:?1 LnIII-ML complexes were instead characterised and investigated using steady state absorption and emission spectroscopy. Sensitised NIR emission from the YbIII, NdIIIand ErIIIcomplexes was observed upon1MLCT excitation of the RuIIbased metalloligand in the visible region atca.485 nm. Investigations using transient absorption spectroscopy revealed essentially quantitative intersystem crossing to form the3MLCT excited state, as expected, which then acts as the energy donor for the metalloligand based antennae effect, facilitating sensitisation efficiencies of 4.8, 17.0 and 37.4% respectively for the YbIII, ErIIIand NdIIIcations.
- Chong, Bowie S. K.,Etchells, Isaac M.,Ireland, Alexander R.,Moore, Evan G.,Pfrunder, Michael C.,Rajah, Divya
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supporting information
p. 7400 - 7408
(2021/06/12)
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- Unusual Magnetic Field Responsive Circularly Polarized Luminescence Probes with Highly Emissive Chiral Europium(III) Complexes
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Chirality is ubiquitous within biological systems where many of the roles and functions are still undetermined. Given this, there is a clear need to design and develop sensitive chiral optical probes that can function within a biological setting. Here we report the design and synthesis of magnetically responsive Circularly Polarized Luminescence (CPL) complexes displaying exceptional photophysical properties (quantum yield up to 31 % and |glum| up to 0.240) by introducing chiral substituents onto the macrocyclic scaffolds. Magnetic CPL responses are observed in these chiral EuIII complexes, promoting an exciting development to the field of magneto-optics. The |glum| of the 5D0 → 7F1 transition increases by 20 % from 0.222 (0 T) to 0.266 (1.4 T) displaying a linear relationship between the Δglum and the magnetic field strength. These EuIII complexes with magnetic CPL responses, provides potential development to be used in CPL imaging applications due to improved sensitivity and resolution.
- Zhang, Junhui,Dai, Lixiong,Webster, Alexandra M.,Chan, Wesley Ting Kwok,Mackenzie, Lewis E.,Pal, Robert,Cobb, Steven L.,Law, Ga-Lai
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supporting information
p. 1004 - 1010
(2020/11/30)
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- Study on the structure-activity relationship of dihydroartemisinin derivatives: Discovery, synthesis, and biological evaluation of dihydroartemisinin-bile acid conjugates as potential anticancer agents
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A series of dihydroartemisinin derivatives was synthesized, and their anti-proliferation activity against cancer cells was evaluated. Structure-activity relationship studies led to the discovery of dihydroartemisinin-bile acid conjugates that exhibit broa
- Zou, Xiaosu,Liu, Chang,Li, Congcong,Fu, Rong,Xu, Wei,Bian, Hongzhu,Dong, Xun,Zhao, Xiaozhen,Xu, Zhenye,Zhang, Jinghua,Shen, Zhengwu
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supporting information
(2021/08/17)
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- Electron transfer pathways in photoexcited lanthanide(iii) complexes of picolinate ligands
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A series of luminescent lanthanide(iii) complexes consisting of 1,4,7-triazacyclononane frameworks and three secondary amide-linked carbostyril antennae were synthesised. The metal binding sites were augmented with two pyridylcarboxylate donors yielding octadentate ligands. The antennae carried methyl, methoxymethyl or trifluoromethyl substituents in their 4-positions, allowing for a range of excited state energies and antenna electronic properties. The1H NMR spectra of the Eu(iii) complexes were found to be analogous to each other. Similar results were obtained in the solid-state by single-crystal X-ray crystallography, which showed the structures to have nine-coordinate metal ions with heavily distorted tricapped trigonal prismatic geometries. Steady-state and time-resolved luminescence spectroscopy showed that the antennae could sensitize both Tb(iii) and Eu(iii), however, quantum yields were lower than in other octadentate complexes lacking pyridylcarboxylate. Complexes with more electron-poor pyridines were less emissive even when equipped with the same antenna. The oxidation and reduction potentials of the antennae and the pyridinecarboxylates, respectively, were determined by cyclic voltammetry. The obtained values were consistent with electron transfer from the excited antenna to the pyridine providing a previously unexplored quenching pathway that could efficiently compete with energy transfer to the lanthanide. These results show the crucial impact that photophysically innocent ligand binding sites can have on lanthanide luminescence.
- Kovacs, Daniel,Kocsi, Daniel,Wells, Jordann A. L.,Kiraev, Salauat R.,Borbas, K. Eszter
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supporting information
p. 4244 - 4254
(2021/04/06)
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- Coordination chemistry of [Y(pypa)]-and comparison immuno-PET imaging of [44Sc]Sc- And [86Y]Y-pypa-phenyl-TRC105
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Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein, a new bifunctional H4pypa ligand, H4pypa-phenyl-NCS, is synthesized, conjugate
- Li, Lily,de Guadalupe Jaraquemada-Peláez, María,Aluicio-Sarduy, Eduardo,Wang, Xiaozhu,Barnhart, Todd E.,Cai, Weibo,Radchenko, Valery,Schaffer, Paul,Engle, Jonathan W.,Orvig, Chris
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p. 5547 - 5562
(2020/05/13)
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- CHELATORS AND METHODS OF MAKING AND USING SAME
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A chelating agent having the general formula (I) is provided (I) Metal chelates and constructs for carrying out targeted radionuclide therapy incorporating such chelating agents are provided. Methods of making and using the chelating agent, metal chelates and constructs for carrying out targeted radionuclide therapy, as well as diagnostic and therapeutic methods using such constructs, are provided.
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Paragraph 0087; 0109
(2020/10/09)
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- The Photocatalyzed Thiol-ene reaction: A New Tag to Yield Fast, Selective and reversible Paramagnetic Tagging of Proteins
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Paramagnetic restraints have been used in biomolecular NMR for the last three decades to elucidate and refine biomolecular structures, but also to characterize protein-ligand interactions. A common technique to generate such restraints in proteins, which do not naturally contain a (paramagnetic) metal, consists in the attachment to the protein of a lanthanide-binding-tag (LBT). In order to design such LBTs, it is important to consider the efficiency and stability of the conjugation, the geometry of the complex (conformational exchanges and coordination) and the chemical inertness of the ligand. Here we describe a photo-catalyzed thiol-ene reaction for the cysteine-selective paramagnetic tagging of proteins. As a model, we designed an LBT with a vinyl-pyridine moiety which was used to attach our tag to the protein GB1 in fast and irreversible fashion. Our tag T1 yields magnetic susceptibility tensors of significant size with different lanthanides and has been characterized using NMR and relaxometry measurements.
- Cerofolini, Linda,Denis, Maxime,Fragai, Marco,Gentili, Matteo,Giuntini, Stefano,Luchinat, Claudio,Nativi, Cristina,Parigi, Giacomo,Popowicz, Grzegorz,Ravera, Enrico,Sattler, Michael,Softley, Charlotte
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- WATER-SOLUBLE TRIMETHOXYPHENYLPYRIDINE-TYPE COMPLEXING AGENTS, AND CORRESPONDING LANTHANIDE COMPLEXES
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The invention relates to complexing agents of formula (I): in which Ra, Chrom1, Chrom2 and Chrom3 are as defined in the description. The invention also relates to lanthanide complexes obtained from these complexing agents.
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Paragraph 0075
(2020/05/29)
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- Functionally Versatile and Highly Stable Chelator for 111In and 177Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting
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Here, we present the synthesis and characterization of a new potentially nonadentate chelator H4pypa and its bifunctional analogue tBu4pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H4pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H4pypa has outstanding affinities for both 111In (EC, t1/2 ≈ 2.8 days) and 177Lu (β-,?, t1/2 ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10-6 M, with excellent stability in human serum over at least 5-7 days (- complexes (M3+ = In3+, Lu3+, La3+) were dependent on the ionic radii, where the smaller In3+ has the highest pM value (30.5), followed by Lu3+ (22.6) and La3+ (19.9). All pM values are remarkably higher than those with DOTA, DTPA, H4octapa, H4octox, and H4neunpa. Moreover, the facile and versatile bifunctionalization enabled by the p-OH group in the central pyridyl bridge of the pypa scaffold (compound 14) allows incorporation of a variety of linkers for bioconjugation through easy nucleophilic substitution. In this work, an alkyl linker was selected to couple H4pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of 111In- and 177Lu-labeled tracers are different, but promising, with the 177Lu analogue particularly outstanding.
- Li, Lily,Jaraquemada-Peláez, María De Guadalupe,Kuo, Hsiou-Ting,Merkens, Helen,Choudhary, Neha,Gitschtaler, Katrin,Jermilova, Una,Colpo, Nadine,Uribe-Munoz, Carlos,Radchenko, Valery,Schaffer, Paul,Lin, Kuo-Shyan,Bénard, Fran?ois,Orvig, Chris
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p. 1539 - 1553
(2019/05/22)
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- Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo-β-Lactamases
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New Delhi metallo-β-lactamase-1 (NDM-1) poses an immediate threat to our most effective and widely prescribed drugs, the β-lactam-containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM-1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnII ions in the active site of NDM-1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM-1 (and related metallo-β-lactamases, IMP-1 and VIM-2). It was determined that the choice of carboxylate isostere influences both the potency of NDM-1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal-stripping mechanism can be re-engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM-1 inhibitor design and development.
- Chen, Allie Y.,Thomas, Pei W.,Cheng, Zishuo,Xu, Nasa Y.,Tierney, David L.,Crowder, Michael W.,Fast, Walter,Cohen, Seth M.
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p. 1271 - 1282
(2019/06/13)
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- Facile Access to the 12-Membered Macrocyclic Ligand PCTA and Its Derivatives with Carboxylate, Amide, and Phosphinate Ligating Functionalities
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We describe a convenient synthetic pathway to access the 12-membered PCTA macrocycle, a polyaminocarboxylate ligand for which its M2+ and M3+ complexes are commonly associated with applications in biomedical diagnostics and radiother
- Enel, Morgane,Leygue, Nadine,Saffon, Nathalie,Galaup, Chantal,Picard, Claude
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supporting information
p. 1765 - 1773
(2018/04/27)
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- A formal anti-Markovnikov hydroalkoxylation of allylic alcohols with a ruthenium catalyst
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Hydroalkoxylation of C-C double bonds was achieved through the use of a ruthenium catalyst. The reaction of allylic alcohols with nucleophilic alcohols was carried out in the presence of a ruthenium catalyst prepared by RuClH(CO)(PPh3)3 and 2,6-bis(n-butyliminomethyl)-4-(piperidin-1-yl)pyridine under mild reaction conditions to afford the corresponding γ-alkoxypropanols in good yield.
- Nakamura, Yushi,Ohta, Tetsuo,Oe, Yohei
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supporting information
p. 288 - 291
(2018/02/14)
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- The Influence of para Substituents in Bis(N-Heterocyclic Carbene) Palladium Pincer Complexes for Electrocatalytic CO2 Reduction
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The effect of modifying the pyridyl para position of lutidine-linked bis(N-heterocyclic carbene) Pd pincer complexes is studied both experimentally (R = OMe, H, Br, and COOR) and computationally, showing a strong effect on the first reduction potential of the complex and allowing the reduction potential to be tuned over a wide range in relation to the Hammett σp constant of the para substituent. The effect of the pyridyl para substituent on electron density of the metal center, frontier orbital energies, and dissociation energy of the trans ligand are also investigated in the context of reactivity with CO2 through electrochemical characterization of the complexes under N2 and CO2 and controlled potential electrolysis experiments where CO2 is reduced to CO.
- Therrien, Jeffrey A.,Wolf, Michael O.
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supporting information
p. 1161 - 1172
(2017/02/15)
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- Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1
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The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.
- Chen, Allie Y.,Thomas, Pei W.,Stewart, Alesha C.,Bergstrom, Alexander,Cheng, Zishuo,Miller, Callie,Bethel, Christopher R.,Marshall, Steven H.,Credille, Cy V.,Riley, Christopher L.,Page, Richard C.,Bonomo, Robert A.,Crowder, Michael W.,Tierney, David L.,Fast, Walter,Cohen, Seth M.
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p. 7267 - 7283
(2017/09/22)
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- ZnS Nanoparticles Sensitize Luminescence of Capping-Ligand-Bound Lanthanide Ions
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2,6-Bis(diethylamide)-4-oxo(3-thiopropane)pyridine (BDP) and 2,6-bis(methyl ester)-4-oxo(3-thiopropane)pyridine (BMP) were synthesized. These compounds chelated LnIII ions and sensitized their emission. The 3:1 complexes of BDP displayed effici
- Tigaa, Rodney A.,Lucas, Gary J.,De Bettencourt-Dias, Ana
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supporting information
p. 3260 - 3268
(2017/03/24)
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- An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy
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The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.
- Thiele, Nikki A.,Brown, Victoria,Kelly, James M.,Amor-Coarasa, Alejandro,Jermilova, Una,MacMillan, Samantha N.,Nikolopoulou, Anastasia,Ponnala, Shashikanth,Ramogida, Caterina F.,Robertson, Andrew K. H.,Rodríguez-Rodríguez, Cristina,Schaffer, Paul,Williams, Clarence,Babich, John W.,Radchenko, Valery,Wilson, Justin J.
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supporting information
p. 14712 - 14717
(2017/10/23)
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- HETEROARYLAMINOISOQUINOLINES, METHODS FOR THEIR PREPARATION AND THERAPEUTIC USES THEREOF
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The application is directed to compounds of formula (IA) : and specifically compounds of formula (I) and their salts and solvates, wherein R1, R11, R12, R13, R4, R5, n, A1, A2, and A3 are as set forth in the specification, as well as to a method for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of conditions associated with the alteration of the activity of β-galactosidase, specially galactosidase beta-1 or GLB1, including GM1 gangliosidoses and Morquio syndrome, type B.
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Page/Page column 107; 108
(2016/08/23)
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- Reprogramming the mechanism of action of chlorambucil by coupling to a G-quadruplex ligand
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The nitrogen mustard Chlorambucil (Chl) generates covalent adducts with double-helical DNA and inhibits cell proliferation. Among these adducts, interstrand cross-links (ICLs) are the most toxic, as they stall replication by generating DNA double strand breaks (DSBs). Conversely, intrastrand cross-links generated by Chl are efficiently repaired by a dedicated Nucleotide Excision Repair (NER) enzyme. We synthesized a novel cross-linking agent that combines Chl with the G-quadruplex (G4) ligand PDS (PDS-Chl). We demonstrated that PDS-Chl alkylates G4 structures at low μM concentrations, without reactivity toward double- or single-stranded DNA. Since intramolecular G4s arise from a single DNA strand, we reasoned that preferential alkylation of such structures might prevent the generation of ICLs, while favoring intrastrand cross-links. We observed that PDS-Chl selectively impairs growth in cells genetically deficient in NER, but did not show any sensitivity to the repair gene BRCA2, involved in double-stranded break repair. Our findings suggest that G4 targeting of this clinically important alkylating agent alters the overall mechanism of action. These insights may inspire new opportunities for intervention in diseases specifically characterized by genetic impairment of NER, such as skin and testicular cancers.
- Di Antonio, Marco,McLuckie, Keith I. E.,Balasubramanian, Shankar
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supporting information
p. 5860 - 5863
(2014/05/20)
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- Development of a tailor-made bis(oxazolidine)pyridine-metal catalyst for the [3+2] cycloaddition of azomethine imines with propiolates
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A series of bis(oxazolidine)pyridine ligands (the PyBodines) were newly designed and synthesized for the development of a highly efficient, tailor-made catalyst for the [3+2] cycloaddition of azomethine imines with propiolates. The PyBodine(l-Ala)-Cu(OAc)2 catalyst was selected on the basis of solid-phase catalysis/CD-HTS and exhibited high efficiency, producing the (R)-adducts with excellent enantioselectivity.
- Arai, Takayoshi,Ogino, Yuta,Sato, Toru
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supporting information
p. 7776 - 7778
(2013/09/02)
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- Synthesis, structural investigation and computational modelling of water-binding aquafoldamers
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Detailed studies on water-binding aquafoldamers are presented that illustrate the potential use of the elongated larger aquafoldamers for recognizing larger water clusters of diverse topologies. A novel self-trapping dimerization mode involving two tetramer molecules is proposed, which is consistent with the obtained varying experimental evidences. The Royal Society of Chemistry 2012.
- Zhao, Huaiqing,Ong, Wei Qiang,Fang, Xiao,Zhou, Feng,Hii, Meng Ni,Li, Sam Fong Yau,Su, Haibin,Zeng, Huaqiang
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scheme or table
p. 1172 - 1180
(2012/03/07)
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- Selective RNA versus DNA G-quadruplex targeting by situ click chemistry
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It all clicks into place: A potent telomere-targeting small molecule has been identified by using the copper-free 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks catalyzed by a non-Watson-Crick DNA secondary structure (see picture). This method rapidly identifies, otherwise unanticipated, potent small-molecule probes to selectively target a given RNA or DNA. Copyright
- Di Antonio, Marco,Biffi, Giulia,Mariani, Angelica,Raiber, Eun-Ang,Rodriguez, Rapha?l,Balasubramanian, Shankar
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supporting information
p. 11073 - 11078
(2013/01/15)
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- Encapsulation of conventional and unconventional water dimers by water-binding foldamers
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Water-binding foldamers have been rarely studied. By orienting both H-bond donors and acceptors toward their interior, two pyridine-derived crescent-shaped folding oligoamides were found to be capable of trapping both conventional and unconventional water dimer clusters in their cavity (~2.5 A radius). In the unconventional water dimer cluster, the two water molecules stay in contact via an unusual H-H interaction (2.25 A) rather than the typical H-bond.
- Ong, Wei Qiang,Zhao, Huaiqing,Fang, Xiao,Woen, Susanto,Zhou, Feng,Yap, Weiliang,Su, Haibin,Li, Sam F. Y.,Zeng, Huaqiang
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supporting information; scheme or table
p. 3194 - 3197
(2011/08/06)
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- Fe3O4 nanoparticle-supported copper(I) pybox catalyst: Magnetically recoverable catalyst for enantioselective direct-addition of terminal alkynes to imines
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An Fe3O4 nanoparticle-supported copper(I) pybox catalyst, which exhibits excellent reactivity and yields products with good enantioselectivity, was developed. As a proof of concept, six optically active propargyl amines were obtained
- Zeng, Tieqiang,Yang, Luo,Hudson, Reuben,Song, Gonghua,Moores, Audrey R.,Li, Chao-Jun
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supporting information; experimental part
p. 442 - 445
(2011/04/15)
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- Synthesis of new enantiopure dimethyl- and diisobutyl -substituted pyridino-18-crown-6 ethers containing a halogen atom or a methoxy group at position 4 of the pyridine ring for enantiomeric recognition studies
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New enantiomerically pure dimethyl- and diisobutyl-substituted pyridino-18-crown-6 ethers containing a halogen atom or a methoxy group at position 4 of the pyridine ring [(S,S)-1, (S,S)-2, (S,S)-3, (S,S)-4] have been synthesized. A new synthetic route and
- Kupai, Jozsef,Huszthy, Peter,Szekely, Kata,Toth, Tuende,Parkanyic, Laszlo
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scheme or table
p. 77 - 93
(2011/06/10)
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- Light Emitting Polymer Devices Using Self-Assembled Monolayer Structures
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A light emitting device comprising a transparent substrate; a layer of conducting material in contact with the transparent substrate; a self-assembled monolayer bonded to the layer of conducting material; one or more light emitting polymer layers in electron contact to the self-assembled monolayer; and a reflective metal layer in electron contact with the light emitting polymer layer is provided. The light emitting device provided gives enhanced performance as compared to currently available devices. Also provided is a self-assembled monolayer having the formula: R2-R3—Y where Y is a group capable of electron contact with a light emitting polymer, R3 contains a conjugated group, and R2 is a group capable of bonding to a conducting material.
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- Cyclometallated platinum(II) complexes containing pyridyl-acetylide ligands: The selective influence of lead binding on luminescence
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The design, synthesis, photophysical properties, and the ion-binding properties of cyclometallated platinum(ii) complexes containing pyridyl-appended alkynyl ligands are described. When the pyridyl group is incorporated into an azamacrocycle, a specific response towards lead(ii) cations involves a change in the nature of the excited charge transfer state, resulting in the appearance of a low-energy absorption band and a partial quenching of luminescence.
- Lanoe, Pierre-Henri,Bozec, Hubert Le,Gareth Williams,Fillaut, Jean-Luc,Guerchais, Veronique
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supporting information; scheme or table
p. 707 - 710
(2010/04/25)
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- Improved synthesis of functionalized mesogenic 2,6-bisbenzimidazolylpyridine ligands
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A versatile one-pot synthetic platform for the preparation of a range of functionalized 2,6-bisbenzimidazolylpyridine (Bip) derivatives is presented. This protocol significantly reduces the cost and time of previous synthetic routes, while facilitating sc
- McKenzie, Blayne M.,Miller, Adriane K.,Wojtecki, Rudy J.,Johnson, J. Casey,Burke, Kelly A.,Tzeng, Karis A.,Mather, Patrick T.,Rowan, Stuart J.
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p. 8488 - 8495
(2008/12/20)
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- Copper dipicolinates as peptidomimetic ligands for the Src SH2 domain
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The introduction of copper chelates into peptide mimetics creates the Src SH2 binding ligands and paramagnetic complexes suitable for EPR studies of peptide protein interactions. The dipicolinic acid was attached to SH2 domain targeting fragments by two different linkers.
- Schmidt, Boris,Jiricek, Jan,Titz, Alexander,Ye, Guofeng,Parang, Keykavous
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p. 4203 - 4206
(2007/10/03)
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- Synthesis of binuclear ligands possessing two discrete multidentate N-heterocyclic podand coordination sites and their bimetallic nickel(II) complexes
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Binuclear ligands possessing two discrete multidentate N-heterocyclic podand coordination sites connected by a flexible propylene spacer and a rigid m-xylene spacer were synthesized. Treatment of the binuclear ligands with Ni(OAc)2 afforded the
- Moriuchi, Toshiyuki,Nakayama, Isao,Nishimura, Kouichirou,Nishiyama, Masahito,Mochizuki, Eiko,Kai, Yasushi,Hirao, Toshikazu
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p. 1328 - 1329
(2007/10/03)
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