- Synthesis and conformational evaluation of p-tert-butylthiacalix[4]arene-crowns
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Bridging of p-tert-butylthiacalix[4]arene afforded 1,3-dihydroxythiacalix[4]arene-monocrown-5 (3b), 1,2-alternate thiacalix[4]arene-biscrown-4 and -5 (4a,b), and 1,3-alternate thiacalix[4]arene-biscrown-5 and -6 (5a,b), depending on the metal carbonates and oligoethylene glycol ditosylates used. Starting from 1,3-dialkylated thiacalix[4]arenes, the corresponding bridging reaction gave 1,3-alternate, partial-cone, and cone conformers 10-19, depending on the substituents present. Temperature-dependent studies revealed that the conformationally flexible 1,3-dimethoxythiacalix-[4]arene-crowns 10a-c exclusively occupy the 1,3-alternate conformation. Demethylation exclusively gave the cone 1,3-dihydroxythiacalix[4]arene-crowns (3a,c), which could not be obtained by direct bridging of thiacalix[4]arene. The different structures were assigned on the basis of several X-ray crystal structures and extensive 2-D 1H NMR studies.
- Van Leeuwen, Fijs W. B.,Beijleveld, Hans,Kooijman, Huub,Spek, Anthony L.,Verboom, Willem,Reinhoudt, David N.
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Read Online
- Catalytic Synthesis of PEGylated EGCG Conjugates that Disaggregate Alzheimer's Tau
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The naturally occurring flavonoid ( )-epigallocatechin gallate (EGCG) is a potent disaggregant of tau fibrils. Guided by the recent cryo-electron microscopy (cryoEM) structure of EGCG bound to fibrils of tau derived from an Alzheimer s brain donor, methods to site-specifically modify the EGCG D-ring with aminoPEGylated linkers are reported. The resultant molecules inhibit tau fibril seeding by Alzheimer s brain extracts. Formulations of aminoPEGylated EGCG conjugated to the (quasi)-brain-penetrant nanoparticle Ferumoxytol inhibit seeding by AD-tau with linker length affecting activity. The protecting groupfree catalytic cycloaddition of amino azides to mono-propargylated EGCG described here provides a blueprint for access to stable nanoparticulate forms of EGCG potentially useful as therapeutics to eliminate Alzheimer s-related tau tangles.
- El Khoury, Anton,Seidler, Paul M.,Eisenberg, David S.,Harran, Patrick G.
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p. 4263 - 4271
(2021/06/18)
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- Design and Synthesis of Oleanolic Acid Trimers to Enhance Inhibition of Influenza Virus Entry
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Influenza is a major threat to millions of people worldwide. Entry inhibitors are of particular interest for the development of novel therapeutic strategies for influenza. We have previously discovered oleanolic acid (OA) to be a mild influenza hemagglutinin (HA) inhibitor. In this work, inspired by the 3D structure of HA as a homotrimeric receptor, we designed and synthesized 15 OA trimers with different linkers and central region via the copper-catalyzed azide-alkyne cycloaddition reaction. All of the OA trimers were evaluated for their antiviral activities in vitro, and 12c, 12e, 13c, and 13d were observed to exhibit robust potency (IC50 in the submicromolar range) against influenza A/WSN/33 (H1N1) virus that was stronger than that observed with oseltamivir. In addition, these compounds also displayed strong biological activity against A/Hong Kong/4801/2014 and B/Sichuan/531/2018 (BV). The results of hemagglutination inhibition assays and surface plasmon resonance binding assays suggest that these OA trimers may interrupt the interaction between the HA protein of influenza virus and the host cell sialic acid receptor, thus blocking viral entry. These findings highlight the utility of multivalent OA conjugates to enhance the ligand-target interactions in anti-influenza virus drug design and are also helpful for studying antiviral drugs derived from natural products.
- Huang, Boxuan,Li, Weijia,Mu, Yu,Shao, Liang,Su, Yangqing,Sun, Mengsi,Xu, Huan,Yang, Fan,Yu, Fei,Zhang, Jihong,Zhang, Yuan
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p. 1759 - 1765
(2021/11/18)
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- Cu-tethered macrocycle catalysts: Synthesis and size-selective CO2-fixation to propargylamines under ambient conditions
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A novel air-stable, Cu-tethered macrocycle catalyst possessing a large inner cavity was successfully synthesized, creating a unique supramolecular catalytic system. The catalyst was utilized in the CO2-fixation reaction to propargylamines. The reaction proceeded more efficiently compared to the conventional CuI catalyst under atmospheric CO2 condition. Notably, owing to its topological effect, the Cu-tethered macrocycle catalyst exhibited unique substrate size selectivity.
- Kim, Nam-Kyun,Sogawa, Hiromitsu,Takata, Toshikazu
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supporting information
(2020/05/01)
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- Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
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The present invention relates to a degraducer for inducing the decomposition of target protein, a producing method thereof, and a pharmaceutical composition for preventing or treating target protein-related diseases by containing the degraducer as an active ingredient. A novel compound represented by chemical formula 1, ULB-L-PTM, by the present invention, as a degraducer compound inducing the decomposition of target protein using cereblon E3 ubiquitin ligase, is able to significantly achieve a target protein degradation-inducing activity with an excellent binding activity of a cereblon E3 ubiquitin ligase binder thereby, being able to achieve an excellent protein degradation activity by targeting protein or polypeptide related to various diseases. The bromodomain-containing pharmaceutical composition for preventing or treating protein-related diseases or conditions contains the novel compound represented by chemical formula 1 as an active ingredient and has a useful effect of providing a health functional food composition for prevention or improvement.(AA) Example 22 (nM, 24h)COPYRIGHT KIPO 2020
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Paragraph 1193; 1195-1197
(2020/05/01)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00962; 001074-001076
(2020/06/19)
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- A rings-in-pores net: Crown ether-based covalent organic frameworks for phase-transfer catalysis
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We herein present a new family of crown ether-based covalent organic frameworks (CE-COFs) for the first time. The CE-COFs show excellent phase-transfer catalytic performance in various nucleophilic substitution reactions.
- Guo, Wen-Di,Hu, Bingwen,Jiang, Wei-Ling,Lou, Xiaobing,Ma, De-Li,Qi, Qiao-Yan,Shen, Ji-Chuang,Shen, Ming,Yang, Hai-Bo,Zhao, Xin
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supporting information
p. 595 - 598
(2020/01/29)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 3472; 3473
(2019/07/10)
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- Formation of [2]- and [3]Rotaxanes through Bridging under Kinetic and Thermodynamic Control
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An efficient synthesis of a doubly stranded [3]rotaxane has been developed through bridging of a pseudo[3]rotaxane featuring two axle components. Reversible azine formation was effective as the bridging reaction. Kinetic and thermodynamic conditions provided the [2]- and [3]rotaxanes, respectively.
- Fujino, Takaaki,Naitoh, Hirotake,Miyagawa, Shinobu,Kimura, Masaki,Kawasaki, Tsuneomi,Yoshida, Kazuyuki,Inoue, Hajime,Takagawa, Hiroaki,Tokunaga, Yuji
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supporting information
p. 369 - 372
(2018/01/27)
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- Sandwich phosphate complexes of macrocyclic tris(urea) ligands and their rotation around the anion
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Four heteroditopic macrocyclic ligands incorporating both anion coordination sites (tris-urea units) and a cation binding fragment (polyether) were designed for possible application in molecular devices. Sandwich-type phosphate complexes were formed, which display a reversible rotation around the anion upon protonation/deprotonation of phosphate and binding of the cation (Emim+).
- Ji, Liguo,Yang, Zaiwen,Zhao, Yanxia,Sun, Meng,Cao, Liping,Yang, Xiao-Juan,Wang, Yao-Yu,Wu, Biao
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p. 7310 - 7313
(2016/06/09)
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- Novel C1-symmetric chiral crown ethers bearing rosin acids groups: Synthesis and enantiomeric recognition for ammonium salts
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Four types of novel C1-symmetric chiral crown ethers including 28-crown-8, 20-crown-6, 17-crown-5 and 14-crown-3 (9a-m) were synthesized and their enantiodiscriminating abilities with protonated primary amines (10-14) were examined by 1H NMR spectroscopy. 20-crown-6 crown ethers exhibited good chiral recognition properties toward these guests and showed different complementarity to some chiral guests, indicating that 20-crown-6 crown ethers could be used as a chiral NMR solvating agent to determine the enantiopurity of these guests. In addition, the binding model and binding site between the hosts and guests were also studied by the computational modeling and experimental calculation.
- Liu, Lu-Zhi,He, Chun-Huan,Yang, Lin,Huang, Yan,Wu, Qiang,Duan, Wen-Gui,Wang, Heng-Shan,Pan, Ying-Ming
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p. 9545 - 9553
(2015/03/05)
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- Synthesis of monoazacrown ethers under phase-transfer catalysis
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A procedure has been proposed for the synthesis of monoazacrown ethers by reaction of N-benzyldiethanolamine with oligo(ethylene glycol) bis-p-toluenesulfonates in a two-phase system aromatic hydrocarbon-50% aqueous alkali, followed by removal of the benzyl group by catalytic hydrogenolysis. The maximal yields of N-benzylaza-12-crown-4, -18-crown-6, and -21-crown-7 were achieved by adding 4-10 equiv of LiCl, BaBr2, and CsCl, respectively, to the reaction mixture, which probably indicated template effect. Pleiades Publishing, Ltd., 2012.
- Luk'yanenko,Basok,Kulygina, E. Yu.,Bogashchenko, T. Yu.,Yakovenko
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p. 1345 - 1352
(2013/02/22)
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- Synthesis and evaluation of homo-bivalent GnRHR ligands
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G protein coupled receptors (GPCRs) are important drug targets in pharmaceutical research. Traditionally, most research efforts have been devoted towards the design of small molecule agonists and antagonists. An interesting, yet poorly investigated class of GPCR modulators comprise the bivalent ligands, in which two receptor pharmacophores are incorporated. Here, we set out to develop a general strategy for the synthesis of bivalent compounds that are projected to bind to the human gonadotropin-releasing hormone receptor (GnRHR). Our results on the dimerisation of a known GnRHR antagonist, with as key step the Huisgen 1,3-cycloaddition, and their ability to bind to and antagonize GnRH-induced GnRHR stimulation, are presented here.
- Bonger, Kimberly M.,van den Berg, Richard J.B.H.N.,Heitman, Laura H.,IJzerman, Ad P.,Oosterom, Julia,Timmers, Cornelis M.,Overkleeft, Herman S.,van der Marel, Gijsbert A.
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p. 4841 - 4856
(2008/03/12)
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- Effect of crown ether ring size on binding and fluorescence response to saxitoxin in anthracylmethyl monoazacrown ether chemosensors
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Convenient macrocyclization synthetic routes for the preparation of different-sized monoaza anthracylmethyl crown ether chemosensors (15-crown-5, 18-crown-6, 21-crown-7, 24-crown-8, and 27-crown-9) are described. Evaluation of these crowns as chemosensors for saxitoxin revealed that the larger crowns have moderately higher binding constants, with the 27-crown-9 chemosensor having the largest binding constant (2.29 × 105 (mol/L)-1). Fluorescence enhancements of 100% were observed at saxitoxin concentrations of 5 μmol/L, which is close to the detection limit in mouse bioassay.
- Mao, Hua,Thorne, John B.,Pharr, Jennifer S.,Gawley, Robert E.
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p. 1273 - 1279
(2007/10/03)
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- The synthesis of tethered ligand dimers for PPARγ-RXR protein heterodimers
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The synthesis of heterodimeric compounds based on tethering the peroxisome proliferator-activated receptors (PPAR)γ agonist, Rosiglitazone and the RXR ligand Targetin is investigated. The synthesis of these compounds was accomplished via a convergent strategy, employed for preparing the appropriately-functionalized subunits of Rosiglitazone and Targetin and then attaching them to opposite ends of the tether. It was observed that a Mitsunobu reaction between the alcohol 5 and 4-hydroxy-benzaldehyde produced the ether 6 in a yield of 80%. It was concluded that the convergent strategy for the synthesis of these compounds could be easily adaptable to a larger and more diverse set of compounds as ligands for the PPARγ-RXR protein heterodimer.
- Mohler, Debra L.,Shen, Gang
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p. 2082 - 2087
(2008/02/03)
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- Novel synthesis of macrocycles with 1,1′-binaphthalene-2,2′-diol using intramolecular oxidative coupling
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A new series of BINOL-based macrocycles with two phenolic protons have been synthesized via oxidative coupling reaction using CuCl(OH)-TMEDA.
- Ito, Satoshi,Koizumi, Kazuya,Fukuda, Katsuhiko,Kameta, Naohiro,Ikeda, Tsukasa,Oba, Toru,Hiratani, Kazuhisa
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p. 8563 - 8566
(2007/10/03)
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- Silver(I) oxide mediated highly selective monotosylation of symmetrical diols. Application to the synthesis of polysubstituted cyclic ethers
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(Matrix Presented) The reaction of symmetrical diols and oligo(ethylene glycol)s with a stoichiometric amount of p-toluenesulfonyl chloride in the presence of silver(I) oxide and a catalytic amount of potassium iodide led selectively to the monotosylate derivatives in high yields. Polysubstituted cyclic ethers were obtained readily upon treatment of the corresponding diols with an excess of silver oxide. The high selectivity was explained on the basis of the difference in acidity between the two hydroxy groups, which undergo an intramolecular hydrogen bonding.
- Bouzide, Abderrahim,Sauve, Gilles
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p. 2329 - 2332
(2007/10/03)
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- Synthesis of crown ethers based on a spiro acetal framework
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A novel class of crown ether derivatives incorporating a 1,7-dioxaspiro[5.5]undecane ring system have been prepared via alkylation of 3,5-diaxial diol 4 with polyethylene glycol ditosylates [di(toluene-p-sulfonates)]. The complexing properties of these cr
- Brimble, Margaret A.,Johnston, Andrew D.
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p. 265 - 269
(2007/10/03)
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- New Pyrimidino-Crown Ether Ligands
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Eight new macrocyclic ligands containing the pyrimidine subcyclic unit (3-10 Figure 1) have been prepared.Two of these new crown ethers are chiral.Pyrimidino-crowns 3-8 were prepared by treating the ditosylate derivative of the appropriate oligoethylene glycol with 4-methoxy-5-methyl-2,6-pyrimidinedimethanol in basic conditions.The yields were in the 30-50percent range giving the crowns as viscous oils.Chiral dimethyl-substituted pyrimidino-crown 9 was prepared from 4-methoxy-5-methyl-2,6-pyrimidinedimethyl ditosylate and chiral dimethyl-substituted tetraethylene glycol.Treatment of dimethyl 4-methoxy-5-methyl-2,6-pyrimidinedicarboxylate with the diamine derivative of chiral dibenzyl-substituted tetraethylene glycol gave the chiral dibenzyl-substituted pyrimidino-crown diamide 10.Starting 4-methoxy-5-methyl-2,6-pyrimidinedimethanol was prepared by a six step process from acetamidine hydrochloride and diethyl oxalpropionate.
- Redd, J.Ty,Bradshaw, Jerald S.,Huszthy, Peter,Izatt, Reed M.
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p. 1047 - 1052
(2007/10/02)
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- PROCEDURE FOR LARGE-SCALE PREPARATIONS OF OLIGOETHYLENE GLYCOL TOLUENESULPHONATES
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Phase transfer catalysis allows a synthesis of oligoethylene glycol di-p-toluenesulphonates IVa-e and V from the corresponding diols Ia-e and II, respectively, in yields >/= 95percent.A preferential tosylation of primary hydroxyl groups in the diols IIIa and IIIb can be also accomplished almost quantitatively under the phase-transfer conditions.
- Stibor, Ivan,Kocian, Oldrich,Holy, Petr,Zavada, Jiri
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p. 2057 - 2060
(2007/10/02)
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- The Complexation of the Diquat Dication by Dibenzo-3n-crown-n Ethers
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Spectrophotometric investigations of equimolar mixtures of diquat bis(hexafluorophosphate) (2) and a range of dibenzo-3n-crown-n ethers in acetonitrile reveal the existence of charge-transfer absorption bands at ca. λmax 400 nm.These absorptions are attributable to intermolecular ?-? charge transfer between the electron-rich catechol units of the dibenzo-crown ethers and the electron-deficient bipyridinium ring system of the diquat dication.The qualitative conclusion from these experiments, that the most stable 1:1 complex is formed between dibenzo-30-crown-10 (14) and diquat bis(hexafluorophosphate) (2), led to the isolation from dichloromethane methanol-n-heptane of red crystals of 2 suitable for X-ray crystallography.Although the crystal structure analysis revealed that there are two independent sets of 1:1 complexes (I and II) in the unit cell, the gross structural features of the two complexes are very similar.In addition to the paralell alignment of their three aromatic rings to accommodate the stabilising intermolecular ?-? charge-transfer interaction, there is probably some further host-guest stabilisation to be gained on account of favourable electrostatic interactions between the phenolic oxygen atoms in the host and the nitrogen atoms in the pyridinium rings of the guest.Moreover, there is some evidence for weak C-H...O hydrogen bonding involving principally H-6 and H-6' on the bipyridinium ring system of the guest and certain -CH2OCH2- oxygen atoms in the host.As evidenced by 1H n.m.r. spectroscopy in CD3COCD3, these non-covalent bonding interactions are probably responsible for the formation of stable and ordered 1:1 complexes with similar gross structural features in solution, at least in the cases where dibenzo-30-crown-10 (14), dibenzo-33-crown-11 (15), and dibenzo-36-crown-12 (16) are the hosts.Further evidence for the 1:1 stoicheiometry of these solution complexes, as well as for the complex involving dibenzo-27-crown-9 (13), has come from equilibrium constant measurements for the association between the dibenzo-3n-crown-n (n = 9-12) hosts (13)-(16) and diquat bis(hexafluorophosphate) (2) in acetone.A quantitative treatment of the charge-transfer absorption bands at 400 nm, which affords Ka values of 410, 17500, 10800, and 2000 M-1 for n = 9, 10, 11, and 12, respectively, provides convincing quantitative evidence for (a) 1:1 stoicheiometry and (b) the relative stabilities of the 1:1 complexes in solution.In the case of dibenzo-24-crown-8 (11), a complex of 2:1 (guest-host) stoicheiometry is believed to be formed in acetone with a Ka value of 385000 M-2, as shown by a successfull quantitative treatment of the charge-transfer absorption data by an independent method.
- Colquhoun, Howard M.,Goodings, Eric P.,Maud, John M.,Stoddart, J. Fraser,Wolstenholme, John B.,Williams, David J.
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p. 607 - 624
(2007/10/02)
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- Molecular Design of Crown Ethers. 1. Effects of Methylene Chain Length: 15- to 17-Crown-5 and 18- to 22-Crown-6
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The ring-enlarged crown ethers, 16- and 17-crown-5 and 19- to 22-crown-6, were synthesized and their cation-binding abilities were evaluated by solvent extraction of aqueous alkali metal picrates.The cation-binding abilities of less symmetrical crown ethers, 3a-e and 4a,b, were generally lower than those of the common symmetrical crown ethers 15-crown-5 (5a) and 18-crown-6 (5b), for which the less symmetrical arrangement of the donor oxygen atoms must be responsible.Compared with 18-crown-6 (5b), the ring-extended crown ethers, 3d, 3e, and 4b, showed a significant shift in cation selectivity, probably due to the enlarged cavity size.The thermodynamic parameters for the extraction of sodium and potassium picrates with 3a, 3c, and 5a,b were calculated from the change of the extraction equilibrium constants (Kex) between 10-25 deg C.The stability of the cation-crown ether complexes was shown to be governed in general by the enthalpy change.However, a significant contribution of the entropy factor was found in unfavorable size combinations of K+ with 3a and Na+ with 3c.
- Ouchi, Mikio,Inoue, Yoshihisa,Kanzaki, Takashi,Hakushi, Tadao
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p. 1408 - 1412
(2007/10/02)
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- Neutral Ligands with Surfactant-Type Structure - Synthesis, Complexation, and Ion Transfer
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New lipophilic neutral ligands which combine crown ether and podand characteristics with structural features of surfactants (cf. formulas 1-12, 16-26) were synthesized.Their complexation behaviour was studied, their solid-to-liquid and liquid-to-liquid phase transfer properties as well as their efficiency in ion transport across a liquid model membrane.Crystalline stoichiometric complexes of the cycles 2a-4a and of 3e with NaSCN, Ba(SCN)2, and BaI2 can be isolated.Among the noncyclic representatives a crystalline complex is obtained only from 11 with BaI2.The ligand 8d behaves in aqueous solution as a typical surfactant showing micelle formation and cloud point.
- Weber, Edwin
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p. 770 - 801
(2007/10/02)
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- The Synthesis of Adrenaline Crown Ethers
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The syntheses of adrenaline-15-crown-5 and adrenaline-18-crown-6 starting from acetovanillone are reported, together with the properties of these compounds.Alkali and alkaline-earth metal complexes of these ligands have been prepared.A method of separating crown ethers based on their preferential complexation of barium is discussed.
- Fenton, David E.,Parkin, Donald,Newton, Roger F.
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p. 449 - 454
(2007/10/02)
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