- Synthesis, Resolution, and Absolute Configuration of Chiral Tris(2-pyridylmethyl)amine-Based Hemicryptophane Molecular Cages
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The synthesis, characterization, and chiroptical properties of a new class of hemicryptophane cages combining a cyclotriveratrylene unit and a tris(2-pyridylmethyl)amine (TPA) moiety are reported. Changing the linkers between these two units allows for the modification of the size and shape of the cavity. The synthesis is straightforward and efficient, providing gram-scale of cage compounds. The racemic mixture of each hemicryptophane host can be readily resolved by chiral HPLC, giving an easy access to the enantiopure molecular cages of which absolute configurations have been assigned by ECD spectroscopy. These new hemicryptophanes are available chemical platforms ready to use for various purposes due to the versatile metal complexation properties of the TPA unit. A Zn(II)@hemicryptophane complex has been obtained and used as a heteroditopic host for the selective recognition of zwitterionic guests.
- Zhang, Dawei,Bousquet, Benjamin,Mulatier, Jean-Christophe,Pitrat, Delphine,Jean, Marion,Vanthuyne, Nicolas,Guy, Laure,Dutasta, Jean-Pierre,Martinez, Alexandre
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- Azide-Coordination in Homometallic Dinuclear Lanthanide(III) Complexes Containing Nonequivalent Lanthanide Metal Ions: Zero-Field SMM Behavior in the Dysprosium Analogue
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A series of homometallic dinuclear lanthanide complexes containing nonequivalent lanthanide metal centers [Ln2(LH2)(LH)(CH3OH)(N3)]·xMeOH·yH2O [1, Ln = DyIII, x = 0, y = 2; 2, Ln = TbIII, x = 1, y = 1] have been synthesized [LH4 = 6-((bis(2-hydroxyethyl)amino)-N′-(2-hydroxybenzylidene)picolinohydrazide] and characterized. The dinuclear assembly contains two different types of nine-coordinated lanthanide centers, because the nonequivalent binding of the azide co-ligand as well as the varying coordination of the deprotonated Schiff base ligand. Detailed magnetic studies have been performed on the complexes 1 and 2. Complex 1 and its diluted analogue (15%) are zero-field SMMs with effective energy barriers (Ueff) of magnetization reversal equal to 59(3) K and 66(3) K and relaxation times of τ0 = 10(4) × 10-6 s and 10(4) × 10-8 s, respectively. On the other hand, complex 2 shows a field-induced SMM behavior. Combined ab initio and density functional theory calculations were performed to explain the experimental findings and to unravel the nature of the magnetic anisotropy, exchange-coupled spectra, and magnetic exchange interactions between the two lanthanide centers.
- Kumar, Pawan,Biswas, Sourav,Swain, Abinash,Acharya, Joydev,Kumar, Vierandra,Kalita, Pankaj,Gonzalez, Jessica Flores,Cador, Olivier,Pointillart, Fabrice,Rajaraman, Gopalan,Chandrasekhar, Vadapalli
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- H2depda: An acyclic adjuvant potentiates meropenem activity in vitro against metallo-β-lactamase-producing enterobacterales
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Metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) pose an emerging threat to public health worldwide. An effective inhibitor of MBLs is therefore urgently needed for clinical use. In this study, two acyclic pyridine-containin
- Shi, Xiu-Fang,Wang, Ming-Ming,Huang, Shu-chao,Han, Jiang-Xue,Chu, Wen-Chao,Xiao, Chunling,Zhang, En,Qin, Shangshang
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- H2dpa derivatives containing pentadentate ligands: An acyclic adjuvant potentiates meropenem activity in vitro and in vivo against metallo-β-lactamase-producing Enterobacterales
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The emergence and dissemination of metallo-β-lactamases (MBLs) producing Enterobacterales is a great concern for public health due to the limited therapeutic options. No MBL inhibitors are currently available in clinical practice. Herein, we synthesized a series of H2dpa derivatives containing pentadentate-chelating ligands and evaluated their inhibitory activity against MBLs. Related compounds inhibited clinically relevant MBLs (Imipenemase, New Delhi metallo-β-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase) with IC50 values of 1–4.9 μM. In vitro, the most promising compounds, 5b and 5c, which had a chiral methyl at the acid adjacent to 5a, demonstrated potent synergistic activity against engineered strains, with fractional inhibitory concentration index values as low as 0.07–0.18. The addition of 5b and 5c restored meropenem efficacy against 42 MBL-producing Enterobacterales and Pseudomonas aeruginosa to satisfactory clinical levels. In addition, safety tests revealed that 5b/5c showed no toxicity in red blood cells, cell lines or mouse model. Further studies demonstrated that compounds 5b and 5c were non-competitive MBL inhibitors. In vivo compounds 5b and 5c potentiated meropenem efficacy and increased the survival rate from 0 to at least 83% in mice with sepsis caused by an NDM-1-positive clinical strain. The activity of the compounds exhibited consistency at the molecular, cellular, and in vivo levels. These data indicated that H2dpa derivatives 5b and 5c containing pentadentate-chelating ligands may be worthy of further study.
- Bai, Mengmeng,Chen, Fangfang,Du, Juan,Kong, Hongtao,Liu, Wentian,Qin, Shangshang,Yao, Hong,Zhang, En,Zhang, Tingting
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- Gallium Fluoride Complexes with Acyclic Bispicolinic Ligands as Potential New Fluorine-18 Labelled Imaging Agents
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The positron-emitting radionuclide, fluorine-18, is used to radiolabel molecules to develop tracers for diagnostic imaging with positron-emission tomography. There is growing interest in the potential of using strong coordinate bonds between electropositive Ga(III) and electronegative fluoride (≈ 557 kJ/mol) to provide new methods of incorporating fluorine-18 into molecules. The potential of gallium(III) complexes with acyclic pentadentate bispicolinic acid containing ligands (H2L1–3) to form ternary complexes with fluoride, [GaL1–3F] was investigated with a view to developing new methods for fluorine-18 radiolabelling. A solid-phase peptide synthesis approach was used to produce a bispicolinic acid chelator with a lysine residue. Characterisation of [GaL1X] (X = OH, Cl, F) by X-ray crystallography revealed that L1 acted as dianionic N2O2 donor to the Ga(III) with the fifth site occupied by a monodentate anion (OH–, Cl– or F–). Despite its high stability in aqueous mixture and [D6]DMSO and the straightforward synthesis of [GaL1F], it was only possible to form the radioactive analogue [18F][GaL1F] in low radiochemical yields.
- Donnelly, Paul S.,Haskali, Mohammad B.,Koay, HuiJing,Roselt, Peter D.,White, Jonathan M.
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- Functional Polypyridine Co Complex as an Efficient Catalyst for Photo-Induced Water Oxidation
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A novel mononuclear cobalt complex 1 was synthesized by treatment of CoCl2·6H2O with a COOMe functionalized TPA ligand (TPA=tris(2-pyridylmethyl)amine). In a basic borate buffer, 1 acts as an efficient catalyst for water oxidation, which is confirmed by an extinct catalytic oxidant wave in electrochemistry. Visible light-driven water oxidation has been achieved by 1 with a TON of 127.7 and a TOF of 3.8 s?1respectively in a homogeneous system. In comparison to the reference RC with naked TPA, the higher efficiency of 1 evidences COOMe on ligand can improve the catalytic efficiency, leading to an effective pathway towards construction of a robust and stable artificial photosynthesis system.
- Wang, Hongyan,Xin, Zhijuan,Xiang, Ruijuan,Liu, Si,Gao, Xuewang,Li, Chengbo
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- Metal ion based chiral fluorescence sensor selective for dihydrogenphosphate
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A Cu(II) based conformationally restricted chiral fluorescence sensor (receptor 2) has been designed and synthesized for selective sensing of anions. The anion recognition property of the Cu2+-complex has been studied in acetonitrile by fluorescence methods which show remarkable sensitivity toward dihydrogen phosphate via fluorescence modulation of the Cu2+-complex over the other anions examined.
- Goswami, Shyamaprosad,Sen, Debabrata,Das, Nirmal Kumar
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- Homometallic DyIII Complexes of Varying Nuclearity from 2 to 21: Synthesis, Structure, and Magnetism
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The synthesis, structure, and magnetic properties of four DyIII coordination compounds isolated as [Dy2(LH2)2(μ2-η1:η1-Piv)]Cl?2 MeOH?H2O (1), [Dy4(LH)2(μ3-OH)2(Piv)4(MeOH)2]?4 MeOH?2 H2O (2), [Dy6(LH2)3(tfa)3(O3PtBu)(Cl)3]Cl4?15.5 H2O?4 MeOH?5 CHCl3 (3) and [Dy21(L)7(LH)7(tfa)7]Cl7?15 H2O?7 MeOH?12 CHCl3 (4) are reported (Piv=pivalate, tfa=1,1,1-trifluoroacetylacetone, O3PtBu=tert-butylphosphonate). Among these, 3 displays an equilateral triangle topology with a side length of 9.541 ? and a rare pentagonal-bipyramidal Dy3+ environment, whereas complex 4 exhibits a single-stranded nanowheel structure with the highest nuclearity known for a homometallic lanthanide cluster structure. A tentative model of the dc magnetic susceptibility and the low-temperature magnetization of compounds 1 and 2 indicates that the former exhibits weak ferromagnetic intramolecular exchange interaction between the Dy3+ ions, whereas in the latter both intramolecular ferromagnetic and antiferromagnetic magnetic exchange interactions are present. Compounds 1, 3, and 4 exhibit frequency-dependent ac signals below 15 K at zero bias field, but without exhibiting any maximum above 2 K at frequencies up to 1400 Hz. The observed slow relaxation of the magnetization suggests that these compounds could exhibit single molecule magnet (SMM) behavior with either a thermal energy barrier for the reversal of the magnetization that is not high enough to block the magnetization above 2 K, or there exists quantum tunneling of the magnetization (QTM).
- Biswas, Sourav,Das, Sourav,Acharya, Joydev,Kumar, Vierandra,van Leusen, Jan,K?gerler, Paul,Herrera, Juan Manuel,Colacio, Enrique,Chandrasekhar, Vadapalli
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- Observation of Slow Relaxation and Single-Molecule Toroidal Behavior in a Family of Butterfly-Shaped Ln4Complexes
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A family of five isostructural butterfly complexes with a tetranuclear [Ln4] core of the general formula [Ln4(LH)2(μ2-η1η1Piv)(η2-Piv)(μ3-OH)2]?x H2O?y MeOH?z CHCl3(1: Ln=DyIII, x=2, y=2, z=0; 2: Ln=TbIII, x=0, y=0, z=6; 3: Ln=ErIII, x=2, y=2, z=0; 4: Ln=HoIII, x=2, y=2, z=0; 5: Ln=YbIII, x=2, y=2, z=0; LH4=6-{[bis(2-hydroxyethyl)amino]methyl}-N′-(2-hydroxy-3-methoxybenzylidene)picolinohydrazide; PivH=pivalic acid) was isolated and characterized both structurally and magnetically. Complexes 1–5 were probed by direct and alternating current (dc and ac) magnetic susceptibility measurements and, except for 1, they did not display single-molecule magnetism (SMM) behavior. The ac magnetic susceptibility measurements show frequency-dependent out-of-phase signals with one relaxation process for complex 1 and the estimated effective energy barrier for the relaxation process was found to be 49 K. We have carried out extensive ab initio (CASSCF+RASSI-SO+SINGLE_ANISO+POLY_ANISO) calculations on all the five complexes to gain deeper insights into the nature of magnetic anisotropy and the presence and absence of slow relaxation in these complexes. Our calculations yield three different exchange coupling for these Ln4complexes and all the extracted J values are found to be weakly ferro/antiferromagentic in nature (J1=+2.35, J2=?0.58, and J3=?0.29 cm?1for 1; J1=+0.45, J2=?0.68, and J3=?0.29 cm?1for 2; J1=+0.03, J2=?0.98, and J3=?0.19 cm?1for 3; J1=+4.15, J2=?0.23, and J3=?0.54 cm?1for 4 and J1=+0.15, J2=?0.28, and J3=?1.18 cm?1for 5). Our calculations reveal the presence of very large mixed toroidal moment in complex 1 and this is essentially due to the specific exchange topology present in this cluster. Our calculations also suggest presence of single-molecule toroics (SMTs) in complex 2. For complexes 3–5 on the other hand, the transverse anisotropy was computed to be large, leading to the absence of slow relaxation of magnetization. As the magnetic field produced by SMTs decays faster than the normal spin moments, the concept of SMTs can be exploited to build qubits in which less interference and dense packing are possible. Our systematic study on these series of Ln4complexes suggest how the ligand design can help to bring forth such SMT characteristics in lanthanide complexes.
- Biswas, Sourav,Das, Sourav,Gupta, Tulika,Singh, Saurabh Kumar,Pissas, Michael,Rajaraman, Gopalan,Chandrasekhar, Vadapalli
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- Dipicolinate Complexes of Gallium(III) and Lanthanum(III)
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Three dipicolinic acid amine-derived compounds functionalized with a carboxylate (H3dpaa), phosphonate (H4dppa), and bisphosphonate (H7dpbpa), as well as their nonfunctionalized analogue (H2dpa), were successful
- Weekes, David M.,Ramogida, Caterina F.,Jaraquemada-Peláez, Maria De Guadalupe,Patrick, Brian O.,Apte, Chirag,Kostelnik, Thomas I.,Cawthray, Jacqueline F.,Murphy, Lisa,Orvig, Chris
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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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p. 4244 - 4254
(2021/04/06)
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- Getting a lead on Pb2+-amide chelators for 203/212Pb radiopharmaceuticals
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Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [nat/203Pb]Pb2+ ions for potential radiopharmaceutical applications. 1H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The 1H NMR spectrum of [Pb(DTPAm)]2+ revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)]2+ and [Pb(ampam)]2+, both of which showed fewer spectral changes indicative of less static behaviour. The solid-state coordination properties of each complex were also examined from single crystal structures that were studied by X-ray diffraction (XRD). In the solid-state, octadentate DTPAm coordinated Pb2+ to form an eight-coordinate hemidirected complex; octadentate EGTAm coordinated Pb2+ forming a ten-coordinate holodirected complex with a bidentate NO3- ion also coordinated to the metal centre; decadentate ampam completely encapsulated the Pb2+ ion to form a ten-coordinate holodirected complex with a C2 axis of symmetry. Potentiometric titrations were carried out to assess the thermodynamic stability of each metal-ligand complex. The pM values obtained for [Pb(DTPAm)]2+, [Pb(EGTAm)]2+ and [Pb(ampam)]2+ were 9.7, 7.2 and 10.2, respectively. The affinity of each chelator for Pb2+ ions was tested by [203Pb]Pb2+ radiolabeling studies to evaluate their prospects as chelators for [203/212Pb]Pb2+-based radiopharmaceuticals. DTPAm radiolabeled [203Pb]Pb2+ ions achieving molar activities as high as 3.5 MBq μmol-1 within 15 minutes, at 25 °C, whereas EGTAm and ampam produced lower molar activities of 0.25 MBq μmol-1 within 30 minutes, at 37 °C. EGTAm and ampam were therefore deemed unsuitable for [203/212Pb]Pb2+-based radiopharmaceutical applications, while DTPAm warrants further studies.
- Choudhary, Neha,Ingham, Aidan,Jaraquemada-Peláez, María De Guadalupe,Kostelnik, Thomas I.,McNeil, Brooke L.,Orvig, Chris,Patrick, Brian O.
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p. 11579 - 11595
(2021/08/30)
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- Reductive N-methylation of alkanolamines with paraformaldehyde in the presence of cobalt catalysts
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Herein a simple method for N-methylation of ethanolamines with paraformaldehyde as a dual methylation and reducing agent has been investigated. Two new cobalt complexes, Co[Methyl 6-(morpoline methyl) picolinate]2Cl2 and Co(2,6 bis morpholine methyl pyridine)Cl2 were prepared and applied as homogeneous catalyst in reductive methylation reaction. All experiments have progressed with excellent conversion and selectivity toward N,N dimethyl ethanolamine. On the other hand, Pyrolysis of prepared cobalt complexes on activated carbon at 550 °C leads to the formation of cobalt oxide nano-particles. These heterogeneous catalysts were shown similar activities in this reaction. Single-crystal X-ray crystallography, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) were used for characterization of prepared catalysts.
- Dindar, Sara,Janczak, Jan,Nemati Kharat, Ali,Zamanian, Sara
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- Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes
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Nuclear medicine leverages different types of radiometals for disease diagnosis and treatment, but these applications usually require them to be stably chelated. Given the often-disparate chemical properties of these radionuclides, it is challenging to find a single chelator that binds all of them effectively. Toward addressing this problem, we recently reported a macrocyclic chelator macrodipa with an unprecedented "dual-size-selectivity"pattern for lanthanide (Ln3+) ions, characterized by its high affinity for both the large and the small Ln3+ (J. Am. Chem. Soc, 2020, 142, 13500). Here, we describe a second-generation "macrodipa-type"ligand, py-macrodipa. Its coordination chemistry with Ln3+ was thoroughly investigated experimentally and computationally. These studies reveal that the Ln3+-py-macrodipa complexes exhibit enhanced thermodynamic and kinetic stabilities compared to Ln3+-macrodipa, while retaining the unusual dual-size selectivity. Nuclear medicine applications of py-macrodipa for chelating radiometals with disparate chemical properties were assessed using the therapeutic 135La3+ and diagnostic 44Sc3+ radiometals representing the two size extremes within the rare-earth series. Radiolabeling and stability studies demonstrate that the rapidly formed complexes of these radionuclides with py-macrodipa are highly stable in human serum. Thus, in contrast to gold standard chelators like DOTA and macropa, py-macrodipa can be harnessed for the simultaneous, efficient binding of radiometals with disparate ionic radii like La3+ and Sc3+, signifying a substantial achievement in nuclear medicine. This concept could enable the facile incorporation of a breadth of medicinally relevant radiometals into chemically identical radiopharmaceutical agents. The fundamental coordination chemistry learned from py-macrodipa provides valuable insight for future chelator development.
- Hu, Aohan,Aluicio-Sarduy, Eduardo,Brown, Victoria,Macmillan, Samantha N.,Becker, Kaelyn V.,Barnhart, Todd E.,Radchenko, Valery,Ramogida, Caterina F.,Engle, Jonathan W.,Wilson, Justin J.
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supporting information
p. 10429 - 10440
(2021/07/26)
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- H4HBEDpa: Octadentate Chelate after A. E. Martell
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H4HBEDpa, a new octadentate chelator inspired by the 1960s ligand HBED of Arthur E. Martell, has been investigated for a selection of trivalent metal ions useful in diagnostic and therapeutic applications (Sc3+, Fe3+, Ga3+, In3+, and Lu3+). Complex format
- Choudhary, Neha,Scheiber, Hayden,Zhang, Jiale,Patrick, Brian O.,De Guadalupe Jaraquemada-Peláez, María,Orvig, Chris
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p. 12855 - 12869
(2021/09/11)
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- Metal β - lactamase inhibitor pyridine dicarboxylic acid amine derivative and preparation method thereof
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The invention belongs to the technical field of pharmaceutical chemistry, and relates to a metal β - lactamase inhibitor pyridine dicarboxylic acid amine derivative and a preparation method and application thereof in the field of antibacterial. The invention has the following structural formula. The compound has good metal β - lactamase (NDM - 1). IMP-4 And VIM - 1) inhibitory activity. The antibacterial activity of the engineering strain for producing metal β - lactamase and the antibacterial activity of clinically isolated enterobacteriaceae bacteria on carbapenem antibiotics can be recovered, and the efficacy of the escherichia coli (production NDM - 1 type metal β - lactamase) resistant to carbapenem drug resistance can be improved by at least 1024 times. The combination of Compound 1 with meropenem can rapidly kill strains producing MBL. The compound toxicity experiment proves that the compound has very small in-vitro cell toxicity and in vivo toxicity, and the in vivo experiment shows that the compound and meropenem combined treatment can significantly improve the survival rate of the infection-producing metal β - lactamase Klebsiella pneumoniae. ink-jet printer A candidate medicament useful as a novel metal β - lactamase inhibitor.
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Paragraph 0027; 0029
(2021/10/05)
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- Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-β-lactamase-1
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New Delhi Metallo-β-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all β-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06–0.94 μM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time–kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 μg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.
- Bai, Meng-Meng,Cui, De-Yun,Han, Jiang-Xue,Kong, Hong-Tao,Liu, Yi-Shuang,Shen, Bo-Yuan,Wang, Cong-Cong,Xiao, Chun-Ling,Yan, Da-Chao,Yang, Yi,Zhang, En
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- Rapid Thermodynamically Stable Complex Formation of [nat/111In]In3+, [nat/90Y]Y3+, and [nat/177Lu]Lu3+ with H6dappa
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A phosphinate-bearing picolinic acid-based chelating ligand (H6dappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In3+, Lu3+, Y3+, Sc3+, La3+, Bi3+). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of H6dappa with four metal ions (In3+, Lu3+, Y3+, Sc3+) was deeply investigated via potentiometric and spectrophotometric (UV-vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand-ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([111In]In3+, [177Lu]Lu3+, [90Y]Y3+), and the serum stability of [111In][In(dappa)]3- was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that H6dappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/μmol and 28.2 GBq/μmol were achieved for [111In]In3+ and [177Lu]Lu3+, respectively. For H6dappa, high thermodynamic stability did not correlate with kinetic inertness-lability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.
- Jaraquemada-Pelaéz, Mariá De Guadalupe,Kostelnik, Thomas I.,Kubeil, Manja,Orvig, Chris,Southcott, Lily,Stephan, Holger,Wagner, Hannah K.,Wang, Xiaozhu
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p. 7238 - 7251
(2020/06/08)
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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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- Exploration of Structure-Activity Relationship of Aromatic Aldehydes Bearing Pyridinylmethoxy-Methyl Esters as Novel Antisickling Agents
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Aromatic aldehydes elicit their antisickling effects primarily by increasing the affinity of hemoglobin (Hb) for oxygen (O2). However, challenges related to weak potency and poor pharmacokinetic properties have hampered their development to treat sickle cell disease (SCD). Herein, we report our efforts to enhance the pharmacological profile of our previously reported compounds. These compounds showed enhanced effects on Hb modification, Hb-O2 affinity, and sickling inhibition, with sustained pharmacological effects in vitro. Importantly, some compounds exhibited unusually high antisickling activity despite moderate effects on the Hb-O2 affinity, which we attribute to an O2-independent antisickling activity, in addition to the O2-dependent activity. Structural studies are consistent with our hypothesis, which revealed the compounds interacting strongly with the polymer-stabilizing αF-helix could potentially weaken the polymer. In vivo studies with wild-type mice demonstrated significant pharmacologic effects. Our structure-based efforts have identified promising leads to be developed as novel therapeutic agents for SCD.
- Pagare, Piyusha P.,Ghatge, Mohini S.,Chen, Qiukan,Musayev, Faik N.,Venitz, Jurgen,Abdulmalik, Osheiza,Zhang, Yan,Safo, Martin K.
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p. 14724 - 14739
(2020/11/30)
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- Phosphonate-assisted tetranuclear lanthanide assemblies: Observation of the toroidic ground state in the TbIII analogue
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The reaction of LnCl3·6H2O with a multidentate flexible Schiff base ligand (LH4), H2O3PtBu and trifluoroacetic acid (tfaH) afforded a series of homometallic tetranuclear complexes, [Ln4(LH2)2(O3PtBu)2(μ2-η1η1tfa)2][2Cl] (Ln = DyIII (1), TbIII (2) and GdIII (3)). The tetranuclear lanthanide core contains two structurally different lanthanide centres, one being in a distorted trigonal dodecahedron geometry and the other in a distorted trigonal prism. Complexes 1-3 were investigated via direct and alternating current (DC and AC) magnetic susceptibility measurements. Only 1 revealed a weak single-molecule magnet (SMM) behaviour. Alternating current (ac) magnetic susceptibility measurements on 1 reveal a frequency-dependent out-of-phase signal. However, the absence of distinct maxima in the χ′′ peak (within the temperature/frequency range of our experiments) prevented deduction of the experimental energy barrier for magnetization reversal (Ueff) and the relaxation time. We have carried out extensive ab initio (CASSCF + RASSI-SO + SINGLE-ANISO + POLY-ANISO) calculations on complexes 1-2 to gain deeper insights into the nature of magnetic anisotropy. Our calculations yielded only one exchange coupling parameter between the two LnIII centres bridged by the ligand (neglecting the exchange between the LnIII centres that are not proximal wrt each other). All the extracted J values indicate a weakly antiferromagnetic coupling between the metal centres (J = -0.025 cm-1 for 1 and J = -0.015 cm-1 for 2). Calculated exchange coupled Ucal values of ～5 and ～1 cm-1 in 1 and 2 respectively nicely corroborated the experimental observations regarding weak and no SMM characteristics. Our calculations indicated the presence of a net single-molecule toroidal (SMT) behaviour in complex 2. On the other hand, fitting the magnetic data (susceptibility and magnetization) in the isotropic cluster 3 revealed weak AFM exchange couplings of J1 = 0.025 cm-1 and J2 = -0.020 cm-1 which are consistent with those for GdIII ions.
- Biswas, Sourav,Kumar, Pawan,Swain, Abinash,Gupta, Tulika,Kalita, Pankaj,Kundu, Subrata,Rajaraman, Gopalan,Chandrasekhar, Vadapalli
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p. 6421 - 6434
(2019/05/24)
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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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- AROMATIC ALDEHYDES WITH SUSTAINED AND ENHANCED IN VITRO AND IN VIVO PHARMACOLOGIC ACTIVITY TO TREAT SICKLE CELL DISEASE
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Compounds and methods for preventing and/or treating one or more symptoms of sickle cell diseases (SCD) by administering at least one of the compounds are provided. The compounds are based on vanillin which is chemically modified to increase bioavailability and activity, e.g. so that the compounds bind to the F helix of hemoglobin (Hb) and prevent adhesion of red blood cells (RBCs).
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Page/Page column 33-34
(2019/10/15)
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- ANTICANCER COMPOUNDS
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The invention provides compounds having the general formula I: and salts thereof, wherein the variables RA, RB, RC, L1, L2, L3, A, B, C, X, Y, Z, E, m, n, and p have the meaning as describe
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Paragraph 0182
(2018/05/03)
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- Optimizing the readout of lanthanide-DOTA complexes for the detection of ligand-bound copper(I)
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The CuAAC 'click' reaction was used to couple alkyne-functionalized lanthanide-DOTA complexes to a range of fluorescent antennae. Screening of the antenna components was aided by comparison of the luminescent output of the resultant sensors using data normalized to account for reaction conversion as assessed by IR. A maximum 82-fold enhanced signal:background luminescence output was achieved using a Eu(III)-DOTA complex coupled to a coumarin-azide, in a reaction which is specific to the presence of copper(I). This optimized complex provides a new lead design for lanthanide-DOTA complexes which can act as irreversible 'turn-on' catalytic sensors for the detection of ligand-bound copper(I).
- Hanna, Jill R.,Allan, Christopher,Lawrence, Charlotte,Meyer, Odile,Wilson, Neil D.,Hulme, Alison N.
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- Metal beta-lactamase inhibitor open chain pyridine carboxylic acid derivative and preparation method thereof
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Belonging to the field of medicinal chemistry, the invention discloses a metal beta-lactamase inhibitor open chain pyridine carboxylic acid derivative and a preparation method thereof. The compound has the following structure shown as the specification. T
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- Polysubstituted pyridine medical intermediate and synthetic method thereof
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The invention belongs to the field of medicine intermediate technology, and specifically relates to a polysubstituted pyridine medical intermediate and a synthetic method thereof. The polysubstituted pyridine medical intermediate is a key intermediate in pharmaceutical synthesis, and has a huge market potential. The synthetic method has simple synthetic route, simple and easily available staring material, and has great meaning in synthesis of pyridine intermediate, development of pyridine medicament and research and development of novel medicament, and the product is cheap.
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- Macrocyclic Compounds And Metal Complexes For Bioimaging And Biomedical Applications
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The present disclosure provides a novel class of macrocyclic compounds and their metal complexes formed with transition metal ion, lanthanide metal ions and other metal ions (e.g., Al, Ga, Y, In, Sn, Tl, Pb and Bi) and their applications in the fields of contrast agents, artificial nucleases, fluorescence probes, nuclear medicines and other biomedical applications in the therapeutics or diagnostics.
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- NEW COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1) wherein R1, R2, R4, R6, E, n, Y1, Y2, Y3, Y4, Y5, L, B, R8, and m are as defined in the claims.
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- A red fluorescence 'off-on' molecular switch for selective detection of Al3+, Fe3+ and Cr3+: Experimental and theoretical studies along with living cell imaging
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A spirobenzopyran-quinoline (SBPQ) based sensor was synthesized which selectively detects trivalent ions viz. Al3+, Fe3+ and Cr3+ through a fluorescence turn on signal in the red region (～675 nm) with the detection limit in the order of 10-8 M. The potentiality of the probe was confirmed by employing it for fluorescence bio-imaging with Al3+ in three different types of live-cells.
- Goswami, Shymaprosad,Aich, Krishnendu,Das, Sangita,Das, Avijit Kumar,Sarkar, Deblina,Panja, Sukanya,Mondal, Tapan Kumar,Mukhopadhyay, Subhrakanti
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p. 10739 - 10741
(2013/11/06)
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- NEW COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1) wherein R1, R2, R4, R6, E, n, Y1, Y2, Y3, Y4, Y5, L, B, R8, and m are as defined in the claims.
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- H4octapa: An acyclic chelator for 111In radiopharmaceuticals
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This preliminary investigation of the octadentate acyclic chelator H 4octapa (N4O4) with 111In/ 115In3+ has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N 4O4) and DTPA (N3O5). The ability of H4octapa to radiolabel quantitatively 111InCl3 at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the 111In complex of H 4octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [111In(octapa)]- has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [ 111In(DOTA)]-, demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. 1H/13C NMR studies of the [In(octapa)]- complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In(DTPA)]2- and [In(DOTA)]- under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)]- complex to be log KML = 26.8(1). Through the same set of analyses, the [111/115In(decapa)] 2- complex was found to have nonoptimal stability, with H 5decapa (N5O5) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H 4octapa to be a valuable alternative to the macrocycle DOTA for use with 111In, and a significant improvement to the acyclic chelator DTPA.
- Price, Eric W.,Cawthray, Jacqueline F.,Bailey, Gwendolyn A.,Ferreira, Cara L.,Boros, Eszter,Adam, Michael J.,Orvig, Chris
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p. 8670 - 8683
(2012/06/29)
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- ANTIVIRAL COMPOUNDS AND USE THEREOF
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The invention relates to compounds, pharmaceutical compositions and methods useful for treating viral infection.
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Page/Page column 29
(2009/12/02)
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- Efficient synthesis of calix[6]tmpa: A new calix[6]azacryptand with unique conformational and host-guest properties
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A new C3v-symmetrical calix[6]azacryptand, that is, calix[6] tmpa (11), was synthesized by efficient [1+1] macrocyclization reactions. Remarkably, both linear and convergent synthetic strategies that were applied lead to equally good overall yields. Calix[6]tmpa behaves as a single proton sponge and appeared reluctant to undergo polyprotonation, unlike classical tris(2-pyridylmethyl)amine (tmpa) derivatives. It also acts as a good host for ammonium ions. Interestingly, it strongly binds a sodium ion and a neutral guest molecule, such as a urea, an amide, or an alcohol, in a cooperative way. A 1H NMR study indicated that the ligand, as well as its complexes, adopt a major flattened cone conformation that is the opposite of that observed with the previously reported calix[6]cryptands. Characterization of the monoprotonated derivative 11·H+ by X-ray diffraction also revealed the presence of a 1,3-alternate conformation, which is the first example of its kind in the calix[6]arene family. This conformer is probably also present in solution as a minor species. The important covalent constraint induced by the polyaromatic tmpa cap on the calixarene skeleton, and conversely from the calix core onto the tmpa moiety, is the likely basis for the unique conformational and chemical properties of this host.
- Zeng, Xianshun,Coquiere, David,Alenda, Aurelie,Garrier, Eva,Prange, Thierry,Li, Yun,Reinaud, Olivia,Jabin, Ivan
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p. 6393 - 6402
(2008/09/19)
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- Biaryloxymethylarenecarboxylic acids as glycogen synthase activators
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The present invention relates to compounds of formula (I) wherein Ar, Ar2, R2, R3, R4, m, p and s are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases that are associated with the activation of the glycogen synthase enzyme, such as diabetes.
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Page/Page column 23
(2008/06/13)
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- Biaryloxymethylarenecarboxylic acids as glycogen synthase activator
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The present invention relates to compounds of formula (I) wherein R1, R2, R3, R4, m, n, p and s are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases that are associated with the activation of the glycogen synthase enzyme, such as diabetes.
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Page/Page column 19
(2010/02/10)
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- New κ-Receptor Agonists Based upon a 2-piperidine Nucleus
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The syntheses of some 1--2-piperidines and their activities as κ-opioid receptor agonists are described.Selected structural modifications are made to the basic moiety and at the 2-, 3-, 4-, 5-, and 6-positions on the piperidine nucleus to enable structure-activity relationships to be delineated.As a result, some highly potent and selective κ-receptor agonists have been identified.In particular, this has been achieved by introduction of oxygen-containing functionality into the 4-position of the piperidine nucleus or the 3-position of the pyrrolidinylmethyl side chain.Thus, 1--2-piperidine (10) possesses high activity in the rabbit vas deferens (LVD, κ-specific tissue) (IC50 = 0.20 nM) and is a potent antinociceptive agent, as determined by the mouse acetylcholine-induced abdominal constriction test (MAC) (ED50 = 0.06 mg/kg, sc).The spirocyclic analogue 8--7-(1-pyrrolidinylmethyl)-1,4-dioxa-8-azaspirodecane (39) showed exceptionally potent activity: LVD, IC50 = 0.10 nM; MAC, ED50 = 0.001 mg/kg, sc.Both 10 and 39 displayed high selectivity for κ-opioid receptors over both μ- and δ-opioid receptor subtypes.
- Scopes, David I. C.,Hayes, Norman F.,Bays, David E.,Belton, David,Brain, John,et al.
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p. 490 - 501
(2007/10/02)
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