- Battlement-shaped 1D coordination polymer based on a bis(N-methylimidazole- 2-yl)butadiyne ligand
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Bis(N-methylimidazole-2-yl)butadiyne (bmib) has been prepared starting from N-methylimidazole following two different pathways. Bmib fluoresces and is capable of forming 1D coordination polymers by clamping together metal units. The molecular structure of a zinc coordination polymer based on bmib and zinc acetate resembles a battlement of a fortress.
- Waidmann, Thomas,Fritsch, Nico,Tucher, Johannes,Rudolf, Marc,Glaser, Felix,Guldi, Dirk M.,Burzlaff, Nicolai
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- Synthesis and biological evaluation of heterocyclic privileged medicinal structures containing (benz)imidazole unit
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Abstract: New heterocyclic privileged medicinal scaffolds involving 4H-pyran, 1,4-dihydropyridine, quinazoline, and 2-aminochromene bearing a (benz)imidazole unit were prepared in good to excellent yields, and evaluated for their in vitro hepatotoxicity on HepG2 cells and antioxidant activity using DPPH radical-scavenging assay. From these results, 2-amino-4-(1-methyl-1H-imidazol-2-yl)-4H-benzo[h]chromene-3-carbonitrile has been identified as a racemic, readily available imidazole derivative, significantly less hepatotoxic than tacrine at 100?μM concentration. One compound was found to be a potent antioxidant agent. The catalytic effect of the 1-methylimidazole unit, in the synthesis of some heterocycle, was also demonstrated. Crystal X-ray structures are reported for six compounds. Graphical abstract: [Figure not available: see fulltext.]
- Boulebd, Houssem,Zama, Sana,Insaf, Bataiche,Bouraiou, Abdelmalek,Bouacida, Sofiane,Merazig, Hocine,Romero, Alejandro,Chioua, Mourad,Marco-Contelles, José,Belfaitah, Ali
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- Structure-Activity Relationships for Reactivators of Organophosphorus-Inhibited Acetylcholinesterase: Quaternary Salts of 2-imidazole
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A series of 1,3-disubstituted-2-imidazolium halides were prepared and evaluated in vitro with respect to their ability to reactivate acetylcholinesterase inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methylphosphonofluoridate (GD).The compounds conform to the general formula +*Cl-, where R = CH3, (CH2)3CH3, (CH2)7CH3, CH2C6H5, CH2C10H7, (CH2)3C6H5, CH(CH3)2, CH2C(CH3)3, and CH(CH3)C(CH3)3.For comparison we also evaluated three known pyridinium reactivators, 2-PAM, HI-6, and toxogonin.The imidazolium aldoximes exhibit oxime acid dissociation constants (pKa) in the range 7.9-8.1, bracketing the value of 8.0, believed to be optimal for acetylcholinesterase reactivation.With imidazolium compound in excess over inhibited enzyme, the kinetics of reactivation are well behaved for EPMP-inhibited AChE and depend on the nature of the alkyl ether group R.For GD-inhibited AChE, maximal reactivation was used to compare compounds becouse rapid phosphonyl enzyme dealkylation and enzyme reihibition complicate interpretation of kinetic constants.
- Bedford, Clifford D.,Harris, Ralph N.,Howd, Robert A.,Miller, Alexi,Nolen, Harold W.,Kenley, Richard A.
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- Functional mimics of copper enzymes. Synthesis and stereochemical properties of the copper(II) complexes of a trinucleating ligand derived from L-histidine
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The ligand piperazine-1,4-bis[4-(N-(1-acetoxy-3-(1-methyl-1H-imidazol- 4-yl))-2-propyl)-N-(1-methyl-1H-imidazol-2-ylmethyl)aminobutyl] (PHI) was synthesized by a multistep procedure starting from N(T)-methyl-L-histidine, piperazine-1,4-bis[4-(4-oxo-4-butanoic) acid] and 1-methyl-1H-imidazole-2- carbaldehyde. This ligand has two potential tridentate, aminobis(imidazole) (A sites), and one bidentate, piperazine (B site), binding sites for metal ions and was employed for the synthesis of the binuclear [Cu2PHI]4+ and the trinuclear [Cu3PHI]6+ complexes, the latter of which features a coordination environment mimicking that present in the trinuclear clusters of the blue copper oxidases. For comparison purposes, the mononucleating ligand L-N(α)-(1-methyl-1H-imidazol-2-ylmethyl)-N(τ)-methylhistidine methyl ester (IH) and its complex [CuIH]2+ have been also prepared. These copper(II) model complexes are the first reported which are directly derived from chiral L-histidine residues. A detailed analysis of the UV-vis, CD and EPR spectra of the complexes has established that the Cu(II) centers bound to PHI A sites are square-pyramidal in solution, with the amino and one imidazole donor in the equatorial plane and the additional imidazole group bound axially. This arrangement implies the adoption of an unusual conformation of λ chirality by the L-histidine residue and is determined by the attempts to minimize steric interference between the substituents at the tertiary amine donor group and the histidine residue bearing the C-α substituent acetoxymethylene group of the bound PHI ligand. For the less sterically crowded secondary amine group of the bound IH ligand, the histidine C-α substituent can occupy a pseudoaxial position, so that in the complex [CuIH]2+ the 'normal' arrangement with three equatorial nitrogen donors and δ chirality in the L- histidine chelate ring occurs.
- Santagostini, Laura,Gullotti, Michele,Pagliarin, Roberto,Bianchi, Emanuela,Casella, Luigi,Monzani, Enrico
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- The synthesis of tripodal nitrogen donor ligands and their characterization as PdIIMe2 and PdIIIMe derivatives
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New tripod ligands containing pyridin-2-yl (py), N-methylimidazol-2-yl (mim), and pyrazol-1-yl (pz) groups have been made by addition of 2-bromopyridine to deprotonated (py)(mim)CH2 or (mim)2CH2 to form (py)2(mim)CH and (py)(mim)2CH, or by simple condensation reactions of (pz)2CO with (mim)CHO or (py)CHO to form (pz)2(mim)CH and (pz)2(py)CH.The ligands may have general application in coordination and organometallic chemistry, especially bis(pyrazol-1-yl)(pyridin-2-yl)methane , which can be readily synthesized and is an unsymmetrical tripod closely relatedto (pz)3CH and (py)3CH.Dimethylpalladium(II) and methyl(iodo)palladium(II) complexes of the ligands have been isolated, and compared with complexes of (pz)3CH, (py)3CH and (pz)4C.
- Byers, Peter K.,Canty, Allan J.,Honeyman, Thomas
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- Halogen-bond driven self-assembly of triangular macrocycles
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2-Iodoethynylpyridine and 2-iodoethynyl-1-methyl-imidazole self-assemble under halogen-bonding control into discrete macrocycles, viz. supramolecular triangles.
- Szell, Patrick M. J.,Siiskonen, Antti,Catalano, Luca,Cavallo, Gabriella,Terraneo, Giancarlo,Priimagi, Arri,Bryce, David L.,Metrangolo, Pierangelo
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- Tuning the optical properties of BODIPY dyes by N-rich heterocycle conjugation using a combined synthesis and computational approach
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The increased number of N-atoms induced a blueshift in absorption and a gain in fluorescence quantum yield, from 750 nm and ～0% for pyrrole to 635 nm and ～40% for triazole, respectively. DFT calculations indicated a decrease in HOMO energy levels with the
- Banala, Srinivas,Kiessling, Fabian,Merkes, Jean Michel,Ostlender, Tobias,Sun, Haitao,Wang, Fufang
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supporting information
p. 19641 - 19645
(2021/11/12)
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- BICYCLIC COMPOUNDS
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Provided herein are compounds and pharmaceutical compositions comprising said compounds that are useful for treating cancers. Specific cancers include those that are mediated by YAP/TAZ or those that are modulated by the interaction between YAP/TAZ and TEAD.
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Paragraph 00717
(2020/06/01)
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- Multi-substituted amine compound and its preparation and use (by machine translation)
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The invention belongs to the field of medical technology, in particular, the present invention provides the following formula I shown multi-substituted amine compound or its isomer or its pharmaceutically acceptable salt, ester, prodrug or hydrate, its pharmaceutical composition, preparation method thereof and its use in the preparation of medicine for treating aids in use. The compound or pharmaceutical composition containing the compound can be used as an inhibitor for inhibiting HIV integrase with LEDGF/p75 between protein - protein interaction and HIV integrase dimerization, then can be used for the treatment of aids. . (by machine translation)
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Paragraph 0711; 0715-0717
(2018/04/27)
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- Synthesis and in-vitro reactivation screening of imidazolium aldoximes as reactivators of sarin and VX-inhibited human acetylcholinesterase (hAChE)
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Post-treatment of organophosphate (OP) poisoning involves the application of oxime reactivator as an antidote. Structurally different oximes are widely studied to examine their kinetic and mechanistic behavior against OP-inhibited cholinesterase enzyme. A series of structurally related 1,3-disubstituted-2-[(hydroxyiminomethyl)alkyl]imidazolium halides (5a–5e, 9a–9c) were synthesized and further evaluated for their in-vitro reactivation ability to reactivate sarin- and VX-inhibited human acetylcholinesterase (hAChE). The observed results were compared with the reactivation efficacy of standard reactivators; 2-PAM, obidoxime and HI-6. Amongst the synthesized oximes, 5a, 9a and 9b were found to be most potent reactivators against sarin-inhibited hAChE while in case of VX only 9a exhibited comparable reactivity with 2-PAM. Incorporation of pyridinium ring to the imidazole ring resulted in substantial increase in the reactivation strength of prepared reactivator. Physicochemical properties of synthesized reactivators have also been evaluated.
- Sharma, Rahul,Gupta, Bhanushree,Sahu, Arvind Kumar,Acharya, Jyotiranjan,Satnami, Manmohan L.,Ghosh, Kallol K.
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- Synthesis and characterization of copper(ii) complexes with multidentate ligands as catalysts for the direct hydroxylation of benzene to phenol
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Four copper(ii) complexes with multidentate ligands, 1 ([CuL1Cl2]), 2 ([Cu(HL2)Cl2]), 3 ([Cu2(L2)2](ClO4)2) and 4 ([CuL3(HOCH3)ClO4]) {L1 = N,N-bis((pyridin-2-yl)methyl) prop-2-yn-1-amine, HL2 = 2-((((1-methyl-1H-imidazol-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)phenol and HL3 = 2-((((1-methyl-1H-imidazol-2-yl)methyl)(pyridin-2-ylmethyl)amino)methyl)-2-t-butyl-phenol} are reported. The complexes were characterized by UV-vis spectroscopy, elemental analysis and electrochemical analysis. Complexes 1 and 3 were further characterized by X-ray single crystal diffraction analysis. The catalytic performances of these complexes were evaluated in the direct hydroxylation of benzene to phenol with hydrogen peroxide as an oxidant in aqueous acetonitrile media. Under optimized reaction conditions, complex 4 with the most negative reduction potential exhibited the highest conversion without considering the dinuclear complex 3. A correlation between the catalytic efficiency and the reduction potentials of these complexes was observed, that is the more negative the reduction potential, the higher the benzene conversion. A radical mechanism for the catalysis was confirmed by the fact that addition of radical scavengers such as TEMPO into the reaction mixture could severely suppress the catalysis.
- Wu, Li,Zhong, Wei,Xu, Beibei,Wei, Zhenhong,Liu, Xiaoming
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p. 8013 - 8020
(2015/05/05)
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- Dynamic Covalent Organocatalysts Discovered from Catalytic Systems through Rapid Deconvolution Screening
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The first example of a bifunctional organocatalyst assembled through dynamic covalent chemistry (DCC) is described. The catalyst is based on reversible imine chemistry and can catalyze the Morita-Baylis-Hillman (MBH) reaction of enones with aldehydes or N-tosyl imines. Furthermore, these dynamic catalysts were shown to be optimizable through a systemic screening approach, in which large mixtures of catalyst structures were generated, and the optimal catalyst could be directly identified by using dynamic deconvolution. This strategy allowed one-pot synthesis and in situ evaluation of several potential catalysts without the need to separate, characterize, and purify each individual structure. The systems were furthermore shown to catalyze and re-equilibrate their own formation through a previously unknown thiourea-catalyzed transimination process.
- Schaufelberger, Fredrik,Ramstr?m, Olof
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supporting information
p. 12735 - 12740
(2015/09/01)
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- Mechanochemical and conformational study of N-heterocyclic carbonyl-oxime transformations
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New mechanochemical pathways for the transformation of six N-heterocyclic carbonyl compounds into oximes using hydroxylamine hydrochloride were explored. Reactions were performed first without any base since the heterocyclic moieties (imidazole, benzimidazole, pyridine and quinuclidine) have an intrinsic basic nitrogen atom. This green, solvent free method was suitable for all compounds (up to quantitative yields) except for N-benzyl substituted imidazole and benzimidazole-2-carbaldehyde. For the slower reacting aldehydes, reactions with liquid assisted grinding and addition of sodium hydroxide were performed as well. Conformational analysis and quantum-chemical calculations revealed steric and electronic reasons for the lower reactivity of N-benzyl substituted derivatives.
- Primoi, Ines,Hrenar, Tomica,Baumann, Kreimir,Krito, Lucija,Krii, Ivana,Tomi, Srdlanka
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p. 153 - 160
(2015/02/19)
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- Cytotoxic effect of (1-methyl-1H-imidazol-2-yl)-methanamine and its derivatives in PtII complexes on human carcinoma cell lines: A comparative study with cisplatin
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The synthesis and pharmacological characterisation of (1-methyl-1H- imidazol-2-yl)-methanamine and its derivatives in PtII complexes are described. Six out of eleven new PtII complexes showed a significant cytotoxic effect on NCI-H460 lung cancer cell line with EC50 values between 1.1 and 0.115 mM, determined by MTT assay. Compound Pt-4a showed a particularly more potent cytotoxic effect than the previously described Pt II complex with 2,2′-bipyridine, [Pt(bpy)Cl2], with an EC50 value equal to 172.7 μM versus 726.5 μM respectively, and similar potency of cisplatin (EC50 = 78.3 μM) in NCI-H460 cell line. The determination of the intracellular and DNA-bound concentrations of 195Pt, as marker of the presence of the complexes, showed that the cytotoxic compound Pt-4a readily diffused into the cells to a similar extent of cisplatin and directly interacted with the nuclear DNA. Pt-4a induced both p53 and p21Waf expression in NCI-H460 cells similar to cisplatin. A direct comparison of the cytotoxic effect between compound Pt-4a and cisplatin on 12 different cancer cell lines demonstrated that compound Pt-4a was in general less potent than cisplatin, but it had a comparable cytotoxic effect on non-small-cell lung cancer NCI-H460 cells, and the colorectal cancer cells HCT-15 and HCT-116. Altogether, these results suggested that the PtII complex with 1-methyl-1H-imidazol-2-yl)-methanamine (compound Pt-4a), displayed a significant cytotoxic activity in cancer cells. Similarly to cisplatin this compound interacts with nuclear DNA and induces both p53 and p21waf, and thus it represents an interesting starting point for future optimisation of new PtII complexes forming DNA adducts.
- Ferri, Nicola,Cazzaniga, Stefano,Mazzarella, Luca,Curigliano, Giuseppe,Lucchini, Giorgio,Zerla, Daniele,Gandolfi, Raffaella,Facchetti, Giorgio,Pellizzoni, Michela,Rimoldi, Isabella
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p. 2379 - 2386
(2013/05/09)
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- Facile preparation of aromatic esters from aromatic bromides with ethyl formate or DMF and molecular iodine via aryllithium
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Various aromatic bromides were treated with n-BuLi and subsequently with ethyl formate, followed by the reaction with ethanol and molecular iodine in the presence of K2CO3 to provide the corresponding aromatic ethyl esters in good yields. Moreover, aromatic bromides could be transformed into the corresponding aromatic methyl esters in good yields by the treatment with n-BuLi and subsequently with DMF, followed by the reaction with methanol, molecular iodine, and K2CO3. Some aromatics could be also converted into the corresponding aromatic esters in good yields by the treatment with n-BuLi, and subsequently with ethyl formate or DMF, followed by the reaction with molecular iodine and K2CO3. The present reactions offer a novel route for the transition-metal-free, carbon-monoxide-free, and therefore environmentally benign one-pot conversion of aromatic bromides and aromatics into aromatic esters.
- Ushijima, Sousuke,Moriyama, Katsuhiko,Togo, Hideo
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experimental part
p. 4701 - 4709
(2012/07/28)
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- Pyruvamide Compounds as Inhibitors of Dust Mite Group 1 Peptidase Allergen and Their Use
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The present invention pertains generally to the field of therapeutic compounds and more specifically to certain pyruvamide compounds of the formula (X) (for convenience, collectively referred to herein as “PVA compounds”), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.
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- Syntheses, protonation constants and antimicrobial activity of 2-substituted N-alkylimidazole derivatives
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A series of N-alkylimidazole-2-carboxylic acid, N-alkylimidazole-2- carboxaldehyde and N-alkylimidazole-2-methanol derivatives [alkyl = benzyl, methyl, ethyl, propyl, butyl, heptyl, octyl and decyl] have been synthesized and the protonation constants determined. The antimicrobial properties of the compounds were tested against Gram-negative (Escherichi coli), Gram-positive (Staphylococcus aureus & Bacillus subtilis subsp. spizizenii) bacterial strains and yeast (C. albicans). Both the disk diffusion and broth microdilution methods for testing the antimicrobial activity showed that N-alkylation of imidazole with longer alkyl chains and the substitution with low pKa group at 2-position resulted in enhanced antimicrobial activity. Particularly, the N-alkylimidazole-2-carboxylic acids exhibited the best antimicrobial activity due to the low pKa of the carboxylic acid moiety. Generally, all the N-alkylimidazole derivatives were most active against the Gram-positive bacteria [S. aureus (MIC = 5-160 μg mL-1) and B. subtilis subsp. spizizenii (5-20 μg mL-1)], with the latter more susceptible. All the compounds showed poor antimicrobial activity against both Gram-negative (E. coli, MIC = 0.15 to >2500 μg mL-1) bacteria and all the compounds were inactive against the yeast (Candida albicans).
- Kleyi, Phumelele,Walmsley, Ryan S.,Gundhla, Isaac Z.,Walmsley, Tara A.,Jauka, Tembisa I.,Dames, Joanna,Walker, Roderick B.,Torto, Nelson,Tshentu, Zenixole R.
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p. 231 - 238
(2013/01/15)
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- Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: Effects of chelate design on pharmacokinetics
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Single amino acid chelate (SAAC) systems for the complexation of the M(CO)3 moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biological applications. However, the lipophilicity of the first generation of 99mTc(CO)3 complexes has resulted in substantial hepatobiliary uptake when examined either as lysine derivatives or integrated into biologically active small molecules and peptides. Here, we designed, synthesized, and evaluated novel polar functionalized imidazole derived SAAC systems (SAAC II) which have been chemically modified to promote overall 99mTc(CO)3L3 complex hydrophilicity with the intent of reducing non-target effects and enhancing renal clearance of prostate specific membrane antigen (PSMA) targeting small molecules. The 99mTc-labeled compounds were prepared, purified, and evaluated for stability, lipophilicity, and tissue distribution in LNCaP xenograft mice. The Glu-urea-Lys-C11 analogs were prepared with a variety of chelators to form (19R,23S)-1-(X)-2-((Y)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23, 25-tricarboxylic acid where X = Y = (methyl)pyridin-2-yl (6), X = Y = (methyl)-1H-imidazol-2-yl (7), X = (methyl)pyridin-2-yl, Y = carboxymethyl (8), X = Y = 1-(carboxymethyl)-1H-imidazol-2-yl (9), X = 1-(carboxymethyl)-1H- imidazol-2-yl, Y = carboxymethyl (10), and X = Y = 1-(1-(2-(bis(carboxymethyl) amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(carboxymethyl)amino) -2-oxoethyl)-1H-imidazol-2-yl) (11). 99mTc labeling was achieved at ligand concentrations as low as 10-6 M and the complexes were stable (>90%) for 24 h. These new SAAC II chelators were evaluated for their influence on binding of the Glu-urea-Lys-C11 analogs to PSMA-positive LNCaP cells and compared to pyridine- and N-methylimidazole-containing SAAC ligands. Tissue distribution of the 99mTc-complexes containing the more polar chelators, 9 and 11, demonstrated decreased liver (11% ID/g) accumulation at 1 h post-injection.
- Maresca, Kevin P.,Hillier, Shawn M.,Lu, Genliang,Marquis, John C.,Zimmerman, Craig N.,Eckelman, William C.,Joyal, John L.,Babich, John W.
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experimental part
p. 168 - 175
(2012/08/27)
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- A new N6 hexadentate ligand and a novel heptacoordinated N 6O-type Fe(III) compounds: Synthesis, characterization and structure of [Fe(dimpyen)(OH)](A)2 (A = PF6- or ClO 4-)
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In this contribution, we report the syntheses of a novel N6 donor set ligand, dimpyen = N1,N2-di[(1-methyl-1H-2-imidazolyl) methyl]-N1,N2-di(2-pyridilmethyl)-1,2-ethanediamine. This type of ligand was designed to modulate the properties of the metal ions bound to it. The reaction with Fe(II) gives off a new heptacoordinated iron(III) complex. We study the spectroscopic (UV-Vis), magnetic and electrochemical behavior and also made the structural determination with X-ray diffraction at 134 K and a heptacoordinated N6O-type derivative of Fe(III) is reported as well. This complex crystallize as perchlorate or hexafluorophosphate and the formula of these derivatives are [Fe(dimpyen)(OH)](PF6)2 (1) and [Fe(dimpyen)(OH)](ClO4)2 (2) which both crystallize with an intermediate geometry, between pentagonal bipyramidal and monocapped octahedral. The UV-Vis spectra in CH3CN solution show a shoulder at 306 nm assigned to one ligand-metal charge-transfer (LMCT) transition, in addition, a weaker and wide band assigned to the charge transfer HO-Fe transition (λmax at 404 nm with an extinction coefficient of 818 cm-1 M-1) is also observed. The magnetic studies corroborate a high-spin iron (III) species in all the temperature range considered. Measurements of cyclic voltammetric confirm a reversible system Fe(III) species, with E1/2 = -0.380 V/Fc+-Fc, this low potential value explains the high stability of the Fe(III) and the easy oxidation of Fe(II) by atmospheric O2(g) reaction.
- Ortega-Villar, Norma,Ugalde-Saldívar, Víctor M.,Flores-Pérez, Blas,Flores-Alamo, Marcos,Real,Moreno-Esparza, Rafael
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experimental part
p. 213 - 219
(2011/10/12)
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- Origins of stereoselectivity in optically pure phenylethaniminopyridine tris-chelates M(NN′)3n+ (M = Mn, Fe, Co, Ni and Zn)
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One-pot reactions of 2-pyridinecarboxaldehyde, chiral phenylethanamines and Fe(ii) give single diastereomer fac diimine complexes at thermodynamic equilibrium so that no chiral separations are required (d.r. > 200:1). The origins of this stereoselectivity are partly steric and partly a result of the presence of three sets of inter-ligand parallel-offset π-stacking interactions. Mn(ii), Co(ii), Co(iii), Ni(ii) and Zn(ii) give similar fac structures, alongside the imidazole analogues for Fe(ii). While most of the complexes are paramagnetic, the series of molecular structures allows us to assess the influence of the π-stacking present, and there is a strong correlation between this and the M-N bond length. Fe(ii) is close to optimal. For the larger Zn(ii) ion, very weak π-stacking leads to poorer measured stereoselectivity (NMR) but this is improved with increased solvent polarity. The mechanism of stereoselection is further investigated via DFT calculations, chiroptical spectroscopy and the use of synthetic probes.
- Howson, Suzanne E.,Allan, Laura E. N.,Chmel, Nikola P.,Clarkson, Guy J.,Deeth, Robert J.,Faulkner, Alan D.,Simpson, Daniel H.,Scott, Peter
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experimental part
p. 10416 - 10433
(2011/11/13)
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- Asymmetric Copper(II)-catalysed nitroaldol (Henry) reactions utilizing a chiral C1-symmetric dinitrogen ligand
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A series of stable chiral C1-symmetric dinitrogen ligands were conveniently synthesized in high yields by condensation of chiral amines [(-)-exo-bornylamine or (+)-(1S,2S,5R)-menthylamine] with various substituted imidazolecarbaldehydes. With the assistance of base, the ligand L1 in combination with CuCl2·2H2O (2.5 mol-% or 5.0 mol-%) can efficiently promote nitroaldol (Henry) reactions between a variety of aldehydes and nitromethane. Both aromatic and aliphatic aldehydes were tolerated in our catalytic system, affording the expected nitroalcohol products in high yields (up to 97%) and with good enantioselectivities (up to 96%) under mild reaction conditions. A series of chiral C1-symmetric dinitrogen ligands were conveniently synthesized in high yields by condensations of chiralamines with various substituted imidazolecarbaldehydes. The ligand L1 in conjunction with CuCl2·2H2O can efficiently promote nitroaldol (Henry) reactions between various aldehydes and nitromethane in high yields (up to 97%) and with good enantioselectivities (up to 96%).
- Zhou, Yirong,Gong, Yuefa
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experimental part
p. 6092 - 6099
(2011/11/29)
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- Photoinduced electron-transfer-promoted redox fragmentation of N-alkoxyphthalimides
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A new photoinduced electron-transfer-promoted redox fragmentation of N-alkoxyphthalimides has been developed. Mechanistic experiments have established that this reaction proceeds through a unique concerted intramolecular fragmentation process. This distinctive mechanism imparts many synthetic advantages, which are highlighted in the redox fragmentation of various heterocyclic substrates.
- Zlotorzynska, Maria,Sammis, Glenn M.
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supporting information; experimental part
p. 6264 - 6267
(2012/01/15)
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- Novel polar single amino acid chelates for technetium-99m tricarbonyl-based radiopharmaceuticals with enhanced renal clearance: Application to octreotide
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Single amino acid chelate (SAAC) systems for the incorporation of the M(CO)3 moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biological applications. However, the lipophilicity of the first generation Tc(CO)3-dipyridyl complexes has resulted in substantial hepatobiliary uptake when either examined as lysine derivatives or integrated into biologically active small molecules and peptides. Here we designed, synthesized, and evaluated novel SAAC systems that have been chemically modified to promote overall Tc(CO)3L3 complex hydrophilicity with the intent of enhancing renal clearance. A series of lysine derived SAAC systems containing functionalized polar imidazole rings and/or carboxylic acids were synthesized via reductive alkylation of the ε amino group of lysine. The SAAC systems were radiolabeled with 99mTc, purified, and evaluated for radiochemical stability, lipophilicity, and tissue distribution in rats. The log P values of the 99mTc complexes were determined experimentally and ranged from -0.91 to -2.33. The resulting complexes were stable (>90%) for at least 24 h. Tissue distribution in normal rats of the lead 99mTc complexes demonstrated decreased liver (15 %ID/g) at 2 h after injection compared to the dipyridyl lysine complex (DpK). One of the new SAAC ligands, [99mTc]bis-carboxymethylimidazole lysine, was conjugated to the N-terminus of Tyr-3 octreotide and evaluated for localization in nude mice bearing AR42J xenografts to examine tissue distribution, tumor uptake and retention, clearance, and route of excretion for comparison to 111In-DOTA-Tyr-3-octreotide and 99mTc-DpK-Tyr-3- octreotide. 99mTc-bis-(carboxymethylimidazole)-lysine-Tyr-3- octreotide exhibited significantly less liver uptake and gastrointestinal clearance compared to 99mTc-DpK-Tyr-3-octreotide while maintaining tumor uptake in the same mouse model. These novel chelators demonstrate that lipophilicity can be controlled and organ distribution significantly altered, opening up broad application of these novel SAAC systems for radiopharmaceutical design.
- Maresca, Kevin P.,Marquis, John C.,Hillier, Shawn M.,Lu, Genliang,Femia, Frank J.,Zimmerman, Craig N.,Eckelman, William C.,Joyal, John L.,Babich, John W.
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experimental part
p. 1032 - 1042
(2011/03/17)
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- Hidden signatures: New reagents for developing latent fingerprints
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Aldehydes substituted with a quaternised pyridinium or quinolinium ring have been investigated for the development of latent fingerprints. Two routes were developed to a novel in situ formed azacyanine dye. This dye might form in the fingerprint where rea
- Plater, M. John,Barnes, Paul,McDonald, Lauren K.,Wallace, Sandy,Archer, Nia,Gelbrich, Thomas,Horton, Peter N.,Hursthouse, Michael B.
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experimental part
p. 1633 - 1641
(2009/06/28)
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- OLIGOHETEROAROMATIC LUMINISCENT ASSEMBLIES AS HIGH-AFFINITY DNA SEQUENCE-DIRECTED LIGANDS
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The present invention provides a novel class of oligoheteroaromatic assemblies with luminescence characteristics and composition based on integrated polyheterocyclic polyamide oligomers of multiple nitrogen-containing heteroaromatic of the general formula (I) This novel class of compounds of the present invention is capable of binding to targeted DNA sequence in the minor groove, and thus is useful for genomics applications. In particular, the compounds of the invention binds to the DNA at a binding stoichiometry of 2: 1 ternary complexation with very high affinity and sequence selectivity.
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Page/Page column 41; 79-80
(2010/11/27)
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- Series of Mn complexes based on N-centered ligands and superoxide - Reactivity in an anhydrous medium and SOD-like activity in an aqueous medium correlated to MnII/MnIII redox potentials
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Two crystal structures are described in this article: (a) the structure of a monomeric MnII complex with the tridentate N-centered N3 ligand tris[(1-methyl-2-imidazolyl)methyl]amine (TMIMA) ([Mn II(TMIMA)2]2+); and (b) the structure of a monomeric MnIII complex with the tridentate N-centered N2O ligand 2-{[(1-methyl-2-imidazolyl)methyl]amino}phenolate (PI-) [2] ([MnIII(PI)2]+) (5). The latter was isolated both in the MnII and in the MnIII state, although only MnIII crystals were successfully grown. They are part of a series of Mn complexes prepared as SOD mimics, namely [Mn(BMPG)(H 2O)]+ (2) {BMPG = N,N-bis[(6-methyl-2-pyridyl)methyl] glycinate}, [Mn(IPG)(MeOH)]+ (3) {IPG = N-[(1-methyl-2-imidazolyl) methyl]-N-(2-pyridylmethyl)glycinate}, [Mn(BIG)(H2O) 2]+ (4) {BIG = N,N-bis[(1-methyl-2-imidazolyl)methyl] glycinate}. The reactivity of MnII complexes 1 and 2 in an anhydrous medium is described and compared to that of complexes 3 and 4, the data for which was previously published. The cyclic voltammograms of the whole complex series were recorded in an aqueous medium (collidine buffer). Their SOD-like activities were estimated by the McCord-Fridovich test (IC50 with 22 μM cytc FeIII: 1.6±0.1 μMol L-1 for 1, 1.2±0.5 μmol L-1 for 2, 3.0±0.2 μmol L-1 for 3, 3.7±0.6 μmol L-1 for 4, 0.8±0.1 μmol L -1 for 5). IC50 values were converted into the corresponding kinetic constant kMcCF values. A linear correlation between Ea and log(kMcCF) was obtained, indicating that in this series the conversion to MnIII is probably the rate-limiting step. This is of substantial importance for further Mn-SOD mimic design in this series. Wiley-VCH Verlag GmbH & Co. KGaA 2005.
- Durot, Stephanie,Policar, Clotilde,Cisnetti, Federico,Lambert, Francois,Renault, Jean-Philippe,Pelosi, Giorgio,Blain, Guillaume,Korri-Youssoufi, Hafsa,Mahy, Jean-Pierre
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p. 3513 - 3523
(2007/10/03)
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- Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological activities of 1-benzazepine derivatives containing a sulfoxide moiety
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In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl
- Seto, Masaki,Miyamoto, Naoki,Aikawa, Katsuji,Aramaki, Yoshio,Kanzaki, Naoyuki,Iizawa, Yuji,Baba, Masanori,Shiraishi, Mitsuru
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p. 363 - 386
(2007/10/03)
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- 4(SPIROPIPERIDINYL)METHYL SUBSTITUTED PYRROLIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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3-Substituted pyrrolidines having a spiropiperidinylmethyl substituent on the 4-position of the ring are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
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- Design, synthesis and evaluation of imidazolylmethyl carbamate prodrugs of alkylating agents
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Two approaches to prodrugs of alkylating agents based on an imidazolylmethyl carbamate nucleus were explored. A 2-azido analogue (3) of the bis-carbamate carmethizole (1) displayed similar aerobic cytotoxicity to 1 in a panel of human and murine cell lines. Approaches to the 2-amino and 2- carbamoyl analogues are described. In the second approach an imidazolylmethanol was used as a 'trigger' linked via a carbamate to the alkylating agent N,N-bis(2-chlorethyl)amine (BCEA). Nitroimidazole and methylsulphinylimidazole carbamate prodrugs 6-8 were 5-20-fold less toxic than BCEA. Despite this deactivation in the prodrug form, little increase in cytotoxicity was observed under hypoxia. The data suggest that BCEA released on bioreduction is not sufficiently potent to contribute significant additional cytotoxicity. (C) 2000 Elsevier Science Ltd.
- Hay, Michael P.,Wilson, William R.,Denny, William A.
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p. 645 - 657
(2007/10/03)
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- Benzimidazole derivatives
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Disclosed are compounds represented by the following chemical formula (I) and pharmacologically acceptable salts thereof which are novel compounds useful as anticancer agents, antiviral agents or antimicrobial agents. STR1
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- Quinuclidinium-imidazolium compounds: Synthesis, mode of interaction with acetylcholinesterase and effect upon Soman intoxicated mice
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Four compounds were prepared: 3-oxo-1-methylquinuclidinium iodide (I), 2-hydroxyiminomethyl-1,3-dimethylimidazolium iodide (II) and two conjugates of I and II linked by -(CH2)3- (III) and -CH2-O-CH2- (IV). The aim was to evaluate separately the properties of I and II as opposed to III and IV, which contain both moieties in the same molecule. All four compounds were reversible inhibitors of acetylcholinesterase (AChE; EC 3.1.1.7). The enzyme/inhibitor dissociation constants for the catalytic site ranged from 0.073 mM (II) to 1.6 mM (I). The dissociation constant of I for the allosteric (substrate inhibition) site was 4.8 mM. Possible binding of the other compounds to the allosteric site could not be measured because II, III and IV reacted with the substrate acetylthiocholine (ATCh) and at high ATCh concentrations the non-enzymic reaction interfered with the enzymic hydrolysis of ATCh. The rate constants for the non-enzymic ATCh hydrolysis were between 23 and 37 l/mol per min. All four compounds protected AChE against phosphorylation by Soman and VX. The protective index (PI) of I (calculated from binding of I to both, catalytic and allosteric sites in AChE) agreed with the measured PI; this confirms that allosteric binding contributes to the decrease of phosphorylation rates. The PI values obtained with III and IV were higher than those predicted by the assumption of their binding to the AChE catalytic site only. The toxicity (i.p. LD50) of compounds I, II, III and IV for mice was 0.21, 0.68, 0.49 and 0.77 mmol/kg body wt. respectively. All four compounds protected mice against Soman when given (i.p.) together with atropine 1 min after Soman (s.c.). One-quarter of the LD50 dose fully protected mice (survival of all animals) against 2.52 (IV), 2.00 (I and III) and 1.58 (II) LD50 doses of Soman.
- Simeon-Rudolf, Vera,Reiner, Elsa,Skrinjaric-Spoljar, Mira,Radic, Bozica,Lucic, Ana,Primozic, Ines,Tomic, Srdanka
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p. 289 - 295
(2007/10/03)
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- Substituted heterocyclylisoquinolinium salts and compositions and method of use thereof
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Substitutued heterocyclylisoquinolinium salts, pharmaceutical compositions containing them and methods for the treatment or prevention of neurodegenerative disorders or neurotoxic injuries utilizing them.
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- A direct synthetic approach to novel quadrupolar [14]azolophanes
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A convergent '3+1' synthesis allowed a simple entrance to the first examples of [14]metaazolophanes 1 and [14l(meta-ortho)2azolophanes 2 built up from heterocyclic betaine subunits, illustrating a prototype of phanes constructed by both highly π-excessiveand highly π-deficient heteroaromatic moieties linked in a 1,3-alternating fashion.
- Alcalde, Ermitas,Alemany, Montserrat,Gisbert, Maria
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p. 15171 - 15188
(2007/10/03)
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- Non-oxidative Conversion of Ketone Carbonyls into Carboxy Carbonyls. Comparison of 2-Acylthiazoles and 2-Acylimidazoles in the Aldol Condensation and the Stereospecific Cleavage of an Example of the Latter to a β-Hydroxy Ester via the Azolium Salt
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The synthesis of some 2-acyl-thiazoles and -imidazoles is described.In the subsequent aldol condensation of these ketones, the imidazole congeners were much better behaved.N-Methylation of the imidazole aldols was only partially successful and suffered fr
- Davies, D. Huw,Hall, Jonathan,Smith, Edward H.
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p. 2691 - 2698
(2007/10/02)
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- Quaternary Salts of 2-imidazole. 4. Effect of Various Side-Chain Substituents on Therapeutic Activity against Anticholinesterase Intoxication
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A series of quaternary salt derivatives of 2--1-methylimidazole incorporating various side chains bearing ether, silyl, nitrile, ester, halogen, nitro, sulfone, amino, or aminosulfonyl substituents was prepared and evaluated in vivo
- Goff, Dane A.,Koolpe, Gary A.,Kelson, Andrew B.,Vu, Huynh M.,Taylor, Dorris L.,et al.
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p. 1363 - 1368
(2007/10/02)
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- Synthesis, Characterisation, and Reactivity of 1-(1-Methylimidazol-2-yl)ethenes
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Thermally labile 1-(1-methylimidazol-2-yl)ethenes, synthesised using the Wittig reaction, have been characterised as stable picrate or N-phenacyl salts.The free bases can be regenerated from the picrates on treatment with triethylamine and their reactivit
- Abarca-Gonzalez, Belen,Jones, R. Alan,Medio-Simon, Mercedes,Quilez-Pardo, Juan,Sepulveda-Arques, Jose,Zaballos-Garcia, Elena
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p. 321 - 331
(2007/10/02)
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- 6-(SUBSTITUTED)METHYLENE-PENICILLANIC AND 6-(SUBSTITUTED)HYDROXYMETHYL-PENICILLANIC ACIDS AND DERIVATIVES THEREOF
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Beta-lactamase inhibiting compounds of the formula: or a pharmaceutically acceptable acid addition or carboxylate salt thereof; where n is zero, 1 or 2; X.3 is H or Br, R1 is H, the residue of certain carboxy-protecting groups or the residue of an ester group readily hydrolyzable in vivo; one of R12 and R13 is H and the other is vinyl, certain aryl, alkylthio, alkylsulfonyl or certain heterocyclyl, aminomethyl, thiocarboxamido or amidino groups; one or R2 and R3 is H and the other is as disclosed for the other of R12 and R13, or is Cl or CH2 OH, and R18 is H or certain acyl groups; intermediates useful in their production, methods for their preparation and use, and pharmaceutical compositions containing them
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- Annelation Reactions of N-Heterocycles to Condensed Pyridones with Bridgehead Nitrogen
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The Horner-Wittig reaction of aromatic and heteroaromatic aldehydes with phosphono succinates gives the methylenesuccinates 2a-m and 4a-k in satisfactory yields.The compounds obtained have the E-configuration, as shown by 1H-NMR-spectroscopic and by chemi
- Linke, Siegfried,Kurz, Juergen,Lipinski, Dietmar,Gau, Wolfgang
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p. 542 - 556
(2007/10/02)
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