- Cationic N-confused porphyrin derivative as a better molecule scaffold for G-quadruplex recognition
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One N-confused porphyrin derivative was prepared and its first observation that it could stabilize G-quadruplex and possessed high selectivity over duplex DNA was made, furthermore, it was also proved to possess the capacity to induce a structural transition from the antiparallel to the mixed-type hybrid G-quadruplex structure.
- Du, Yuhao,Zhang, Dan,Chen, Wei,Zhang, Ming,Zhou, Yangyang,Zhou, Xiang
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- Synthesis and evaluation of novel α-aminoamides containing benzoheterocyclic moiety for the treatment of pain
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Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav 1.7 and anti-Nav 1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.
- Cheng, Jingchao,He, Junlin,Ren, Fengxia,Ren, Fengzhi,Shi, Weiguo,Tong, Kun,Yu, Zixing,Zhang, Ruotian,Zhang, Tao,Zhang, Yatong
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- A Chemoselective and Modular Post-Synthetic Multi-Functionalization of NHC-Platinum Complexes
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We report oxime ligation in combination with metal ligand exchange as a novel orthogonal and practical approach to the multifunctionalization of NHC-platinum complexes. This strategy, which enables strong diversity enhancement of metallodrug candidates, could also be applied to selective bioconjugation. We report oxime ligation in combination with metal ligand exchange as a novel orthogonal and practical approach to the multi-functionalization of NHC-platinum complexes.
- Dahm, Georges,Borré, Etienne,Guichard, Gilles,Bellemin-Laponnaz, Stéphane
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- Self-Assembly of a "cationic-cage": Via the formation of Ag-carbene bonds followed by imine condensation
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A new strategy for the synthesis of a "cationic-cage" (CC-Ag) has been developed via metal-carbene (M-CNHC) bond formation followed by imine bond condensation. Reaction of a trigonal trisimidazolium salt H3L(PF6)3 functionalized with three flexible N-phenyl-Aldehyde pendants with silver oxide yielded a trinuclear tricationic organometallic cage (OC-Ag). Subsequent treatment of the organometallic cage (OC-Ag) with 1,4-diaminobutane links the two tris-NHC ligands via imine bond condensation, which thus generates a 3D 'cationic-cage' (CC-Ag). Furthermore, post-synthetic replacement of the Ag(i) with Au(i) leading to the formation of CC-Au was achieved via trans-metalation, with the retention of the molecular architecture.
- Modak, Ritwik,Mondal, Bijnaneswar,Howlader, Prodip,Mukherjee, Partha Sarathi
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- Discovery of novel CA-4 analogs as dual inhibitors of tubulin polymerization and PD-1/PD-L1 interaction for cancer treatment
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A series of novel CA-4 analogs as dual inhibitors of tubulin polymerization and PD-1/PD-L1 were designed, synthesized and bio-evaluated. Among them, compound TP5 exhibited strongest inhibitory effects against five cancer cell lines with an IC50 value of 800 nM in HepG2 cells. In addition, mechanism studies revealed that TP5 could effectively inhibit tubulin polymerization, suppress HepG2 cells migration and colony formation, and cause cell arrest at G2/M phase and induce apoptosis. Furthermore, TP5 exhibited moderate anti-PD-1/PD-L1 activity with IC50 values of 48.76 μM in a homogenous time-resolved fluorescence (HTRF) assay. In vivo efficacy studies indicated that TP5 could significantly suppress tumor growth in an immune checkpoint humanized mouse model with a Tumor Growth Suppression (TGI) of 57.9% at 100 mg/kg without causing significant toxicity. Moreover, TP5 did not cause in vivo cardiotoxicity in BALB/c mice. These results suggest that the novel CA-4 analogs may serve as a starting point for developing more potent dual inhibitors of tubulin polymerization and PD-1/PD-L1.
- Yang, Xuchao,Cheng, Binbin,Xiao, Yao,Xue, Mingming,Liu, Ting,Cao, Hao,Chen, Jianjun
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- Rotationally Restricted 1,1′-Bis(phenylethynyl)ferrocene Subunits in Macrocycles
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The synthesis of macrocycles comprising a 1,1′-bis(phenylethynyl)ferrocene subunit was developed to increase the structural control over the spatial arrangement of the two cyclopentadienyl ligands of the ferrocene junction. The target structures were obtained through a modular strategy that enables the assembly of varying ring sizes from a common precursor. In particular, macrocycles were either formed by an ether formation reaction or by ring-closing metathesis reactions. The macrocycles were obtained in reasonable isolated yields, which allowed their thorough characterization by one- and two-dimensional NMR spectroscopy experiments, and the identity of one macrocycle was corroborated by single-crystal X-ray diffraction.
- Hoffmann, Viktor,Jenny, Nicolas,H?ussinger, Daniel,Neuburger, Markus,Mayor, Marcel
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- Synthesis and evaluation of novel α-aminoamides containing an indole moiety for the treatment of neuropathic pain
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The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted.
- Li, Haotian,Fan, Shiyong,Cheng, Jingchao,Zhang, Ping,Zhong, Bohua,Shi, Weiguo
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- A Bifunctional Photosensitizer for Enhanced Fractional Photodynamic Therapy: Singlet Oxygen Generation in the Presence and Absence of Light
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The photosensitized generation of singlet oxygen within tumor tissues during photodynamic therapy (PDT) is self-limiting, as the already low oxygen concentrations within tumors is further diminished during the process. In certain applications, to minimize photoinduced hypoxia the light is introduced intermittently (fractional PDT) to allow time for the replenishment of cellular oxygen. This condition extends the time required for effective therapy. Herein, we demonstrated that a photosensitizer with an additional 2-pyridone module for trapping singlet oxygen would be useful in fractional PDT. Thus, in the light cycle, the endoperoxide of 2-pyridone is generated along with singlet oxygen. In the dark cycle, the endoperoxide undergoes thermal cycloreversion to produce singlet oxygen, regenerating the 2-pyridone module. As a result, the photodynamic process can continue in the dark as well as in the light cycles. Cell-culture studies validated this working principle in vitro.
- Turan, Ilke Simsek,Yildiz, Deniz,Turksoy, Abdurrahman,Gunaydin, Gurcan,Akkaya, Engin U.
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- Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation
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In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
- Relitti, Nicola,Saraswati, A. Prasanth,Chemi, Giulia,Brindisi, Margherita,Brogi, Simone,Herp, Daniel,Schmidtkunz, Karin,Saccoccia, Fulvio,Ruberti, Giovina,Ulivieri, Cristina,Vanni, Francesca,Sarno, Federica,Altucci, Lucia,Lamponi, Stefania,Jung, Manfred,Gemma, Sandra,Butini, Stefania,Campiani, Giuseppe
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- COMPOUNDS AND PHOTORESPONSIVE RELEASE CONTROL AGENTS
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PROBLEM TO BE SOLVED: To provide compounds having a photoreleasing protecting group which has excellent photoresponsivity to long-wavelength light and can release molecules to be time- and space-controlled even by one-photon excitation. SOLUTION: The compounds are represented by any of the formulas (1) to (3) in the figure. In the formulas (1) to (3), X is a pigment-containing group; Y is a releasable molecule-containing group; and R1, R2 and R3 are each independently a hydrogen atom or alkyl group. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPO&INPIT
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Paragraph 0057; 0058
(2020/10/14)
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- Amide derivative containing benzoheterocycle structure, and composition and application thereof
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The invention belongs to the technical field of medicines, and discloses an amide derivative containing a benzoheterocycle structure, and a composition and an application thereof. The amide derivativecontaining the benzoheterocycle structure is a compound represented by structural formula I and a nontoxic pharmaceutically acceptable salt thereof, or the amide derivative containing the benzoheterocycle structure is a compound represented by structural formula II or a nontoxic pharmaceutically acceptable salt thereof. The amide derivative containing the benzoheterocycle structure has good analgesic activity and good inhibition effect on a target sodium ion channel Nav1.7.
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- Self-reporting heavy atom-free photodynamic therapy agents
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Two novel, self-reporting distyryl BODIPY-based photodynamic therapy agents functionalized with singlet oxygen responsive imidazole and tertiary amine moieties are developed. Heavy atom-free photosensitizers are demonstrated to have efficient photodynamic action in MCF7 cells. The fluorescence intensity of the photosensitizers is shown to be reduced as a result of 1O2 generation without any significant change in photodynamic activity. This journal is
- Demirok, Naime,Erbas-Cakmak, Sundus,Kayadibi Koygun, Gozde,Turkoglu, Gulsen,Yurt, Mediha Nur Zafer
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p. 9433 - 9437
(2020/12/15)
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- IMIDAZO [2, 1-F] [1, 2, 4] TRIAZIN-4-AMINE DERIVATIVES AS TLR7 AGONIST
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Disclosed herein is an imidazo [2, 1-f] [1, 2, 4] triazin-4-amine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof useful as a TLR7 agonist, and a pharmaceutical composition comprising the same. Also disclosed herein is a method of treating cancer using the imidazo [2, 1-f] [1, 2, 4] triazin-4-amine derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as TLR7 agonist.
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Paragraph 0170-0171
(2020/08/22)
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- Synthesis of various cyclopropyl methyl bromide and its derivatives from ketones and/or aldehydes and some β-dicarbonyl compounds in the presence of BrCN and Et3N
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The ultimate goal in this paper has been developed for the synthesis of structurally various bromomethyl cyclopropane via an α-bromoketone and/or aldehydes with ethyl cyanoacetate or malononitrile and cyanogen bromide (BrCN) in the presence of Et3N to give products in excellent yields within about 3?s. All structures were characterized by IR, 1H-NMR, 13C-NMR, and Mass spectroscopy techniques. The reaction mechanism was discussed.
- Gholizadeh, Saeed,Safa, Kazem D.,Noroozi Pesyan, Nader
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p. 1239 - 1253
(2019/04/27)
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- GLUCOCORTICOID RECEPTOR AGONIST AND IMMUNOCONJUGATES THEREOF
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Provided herein are glucocorticoid receptor agonist immunoconjugates, glucocorticoid receptor agonists, and methods of using the same.
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Paragraph 0133-0134
(2019/06/14)
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- ANTI-CD40 ANTIBODY DRUG CONJUGATES
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Provided herein are anti-CD40 antibody drug conjugates comprising a radical of Formula (I), wherein R1, R2, and R3 are as defined herein. Further provided are anti-CD40 antibody drug conjugates of Formula (II), wherein Z, R, AA1, AA2, AA3, m, p, q, n, w, R1, R2, and R3 are as defined herein. Further provided are pharmaceutical compositions and kits thereof, and methods of using same.
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Paragraph 00139
(2019/06/17)
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- Reversing Chemoselectivity: Simultaneous Positive and Negative Catalysis by Chemically Equivalent Rims of a Cucurbit[7]uril Host
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Enzyme catalysis has always been an inspiration and an unattainable goal for chemists due to features such as high specificity, selectivity, and efficiency. Here, we disclose a feature neither common in enzymes nor ever described for enzyme mimics, but one that could prove crucial for the catalytic performance of the latter, namely the ability to catalyze and inhibit two different reactions at the same time. Remarkably, this can be realized by two identical, spatially resolved catalytic sites. In the future, such a synchronized catalyst action could be used not only for controlling chemoselectivity, as in the present case, but also for regulating other types of chemical reactivity.
- Rad, Nazar,Danylyuk, Oksana,Sashuk, Volodymyr
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p. 11340 - 11343
(2019/07/16)
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- Enhanced Solution and Solid-State Emission and Tunable White-Light Emission Harvested by Supramolecular Approaches
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Organic luminescent materials with high quantum yields and/or white-light-emitting properties in particular play a crucial role in labeling and optoelectronic devices. In this work we have synthesized a new 2,3,6,7-tetramethoxy-9,10-di-p-tolylanthracene-bridged pillar[5]arene dimer with persistent mazarine blue fluorescent emission and much higher quantum yields in both solution and the solid state in comparison with its corresponding emissive linker without pillarene units, which exhibits typical aggregation-caused quenching. According to the fluorescence data and single-crystal analyses, their contrasting fluorescent performances can be rationally ascribed to their different stacking structures and intermolecular interactions. Three fluorescent guests containing different chromophores and/or terminal binding sites have also been synthesized to interact with the pillar[5]arene dimer to construct supramolecular ensembles with highly controllable luminescence, taking advantage of the stimuli-responsive properties of the supramolecular host–guest interactions. Intriguingly, multicolor fluorescence, including white-light emission (0.31, 0.35), which is in high demand, has been achieved by tuning the molar ratio of the host and guest and/or by changing the solvent system. This strategy holds great potential for the design and development of fluorescent materials with high quantum yields, controllable emission wavelength, and good stimuli-responsiveness.
- Lou, Xin-Yue,Song, Nan,Yang, Ying-Wei
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p. 11975 - 11982
(2019/08/26)
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- PH clock instructed transient supramolecular peptide amphiphile and its vesicular assembly
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A new strategy to construct a transient supramolecular peptide amphiphile (SPA) and its vesicular aggregates is displayed. The construction of the amphiphile is assisted by the ternary complexation of cucurbit[8]uril and pH responsive imine bond formation. The transient assembly follows a pH clock set by urea/urease and hydrolysis of glucono delta-lactone (GdL). The transient assembly can be repeated for several cycles through feeding the system with the fuel (urea).
- Dowari, Payel,Das, Saurav,Pramanik, Bapan,Das, Debapratim
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p. 14119 - 14122
(2019/12/02)
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- SMALL MOLECULE INHIBITORS OF ALDH AND USES THEREOF
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This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a thiopyrimidinone structure which function as inhibitors of ALDH protein, and their use as therapeutics for the treatment of cancer and other diseases.
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Page/Page column 85
(2018/04/12)
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- Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria
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Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.
- Yang, Yiqing,Yu, You,Li, Xiaolu,Li, Jing,Wu, Yue,Yu, Jie,Ge, Jingpeng,Huang, Zhenghui,Jiang, Lubin,Rao, Yu,Yang, Maojun
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supporting information
p. 1994 - 2005
(2017/03/17)
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- GLUCOCORTICOID RECEPTOR AGONIST AND IMMUNOCONJUGATES THEREOF
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Provided herein are glucocorticoid receptor agonist immunoconjugates, glucocorticoid receptor agonists, and methods of using the same, e.g., to treat autoimmune or inflammatory diseases.
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Paragraph 00966; 00967; 00978; 00979
(2018/01/17)
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- Redox reaction between benzyl azides and aryl azides: concerted synthesis of aryl nitriles and anilines
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A unique and novel reaction between benzyl azides and aryl azides is described to synthesize aryl nitriles and anilines concurrently, which is catalyzed with a photoactivated diruthenium complex. N-Unsubstituted imines (N-H imines) are generated first from benzyl azides, followed by the hydrogen transfer reaction between N-H imines and aryl azides. A wide range of aryl nitriles and anilines were synthesized under neutral and mild reaction conditions.
- Kim, Yongjin,Rhee, Young Ho,Park, Jaiwook
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supporting information
p. 1636 - 1641
(2017/02/23)
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- DEUTERATED TOLL-LIKE RECEPTOR MODULATORS
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The present invention provides deuterated analogs of toll like receptor modulator compounds having the structures of formula (X) or (Y), processes for making those analogs, and their therapeutic methods of use.
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Paragraph 00133
(2017/03/14)
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- Direct Carboxylation of the Diazo Group ipso-C(sp2)-H bond with Carbon Dioxide: Access to Unsymmetrical Diazomalonates and Derivatives
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The direct carboxylation of the ipso-C(sp2)-H bond of a diazo compound with carbon dioxide under mild reaction conditions is described. This method is transition-metal-free, uses a weak base, and proceeds at ambient temperature under atmospheric pressure in carbon dioxide. The carboxylation exhibits high reactivity and is amenable to subsequent diversification. A series of unsymmetrical 1,3-diester/keto/amide diazo compounds are obtained with moderate to excellent yields (up to 99%) with good functional group compatibility.
- Liu, Qianyi,Li, Man,Xiong, Rui,Mo, Fanyang
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p. 6756 - 6759
(2017/12/26)
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- Novel alpha-amino amide derivatives and pharmaceutical use thereof
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The invention relates to novel alpha-amino amide derivatives and a pharmaceutical use thereof. Specifically, the invention relates to the alpha-amino amide derivatives represented by the structural formula I or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds as active ingredients, and the use of the derivatives or the pharmaceutically acceptable salts thereof for preparation of analgesic drugs.
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- Indole group-containing alpha-amino amide derivatives and pharmaceutical application thereof
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The invention relates to new indole group-containing alpha-amino amide derivatives represented by the structural formula I or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds as active ingredients, and an application of the derivatives or the pharmaceutically acceptable salts thereof in preparation of analgesic drugs. In the structural formula I, R is a hydrogen atom or C1-C5 straight-chain alkyl or branched-chain alkyl, and the configuration of carbon atoms connected to R is an R type or an S type.
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- METHODS OF PREPARING TOLL-LIKE RECEPTOR MODULATORS
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The present invention provides methods of preparing 4-amino-2-biitoxy-8-(3- (pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one and related compounds.
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Paragraph 0235
(2016/04/09)
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- METALPORPHYRIN COMPLEX, PREPARATION METHOD THEREFOR AND METHOD FOR PREPARING POLYCARBONATE
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The present invention provides a metalporphyrin complex having structure represented by formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from one of hydrogen, halogen, aliphatic group, substituted heteroaliphatic group, aryl and substituted heteroaryl; n is 1-6; L is quaternary ammonium functional group or quaternary phosphonium functional group; M is a metal element; and X is one of halogen, —NO3, BF4—, —CN, p-methyl benzoate, o-nitrophenol oxygen anion, 2,4-dinitrophenol oxygen anion, 2,4,6-trinitrophenol oxygen anion, 3,5-dichlorophenol oxygen anion and pentafluorophenol oxygen anion. The metalporphyrin complex provided in the present invention has two quaternary ammonium functional groups or two quaternary phosphonium functional groups, and compared with the prior art, the metalporphyrin complex shows higher catalytic activity in catalyzing polymerization reaction of carbon dioxide and an epoxide.
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Paragraph 0167-0169
(2016/08/07)
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- Facile synthesis of five 2D surface modifiers by highly selective photocyclic aromatization and efficient enhancement of oxygen permselectivities of three polymer membranes by surface modification using a small amount of the 2D surface modifiers
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A facile synthesis of novel five 2D (planar) surface modifiers having a triphenylbenzene derivatives as a 2D structure has been achieved by the highly selective photocyclic aromatization reaction. Efficient enhancement of oxygen permselectivities through the three polymer membranes has been achieved by adding a small amount (2-α graph were over or close to the upper boundary line by Robeson in 1991. Since all the membranes containing the 2D surface modifiers showed better permselectivities than the corresponding substrate membranes, it is very promising for the future.
- Wang, Jianjun,Zang, Yu,Yin, Guanwu,Aoki, Toshiki,Urita, Hiroyuki,Taguwa, Ken,Liu, Lijia,Namikoshi, Takeshi,Teraguchi, Masahiro,Kaneko, Takashi,Ma, Liqun,Jia, Hongge
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p. 1384 - 1396
(2014/04/03)
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- Synthesis and evaluation of the antiparasitic activity of bis-(arylmethylidene) cycloalkanones
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A series of bis-(arylmethylidene)-cycloalkanones was synthesized by cross-aldol condensation. The activity of the compounds was evaluated against amastigotes forms of Trypanosoma cruzi and promastigotes forms of Leishmania amazonensis. The cytotoxicity of the active compounds on uninfected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their antiparasitic effects. Six compounds displayed trypanocidal activity against amastigotes intracellular forms of T. cruzi with IC50 values ranging from 7.0 to 249 μM. Besides these six compounds, eight other molecules exhibited significant leishmanicidal activity (IC50 values ranging from 0.6 to 110.4 μM). Two compounds can be considered as promising antiparasitic lead molecules because they showed IC50 values in the low-micromolar range (≤1.2 μM) with an adequate SI (≥19.9). To understand the mechanism of action of these compounds, two possible molecular targets were investigated: trypanothione reductase (TR) and cruzain.
- Braga, Saulo F.P.,Alves, érika V.P.,Ferreira, Rafaela S.,Fradico, Jordana R.B.,Lage, Paula S.,Duarte, Mariana C.,Ribeiro, Tatiana G.,Júnior, Policarpo A.S.,Romanha, Alvaro J.,Tonini, Maiko L.,Steindel, Mário,Coelho, Eduardo F.,De Oliveira, Renata B.
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p. 282 - 289
(2014/01/06)
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- A porphyrin molecule that generates, traps, stores, and releases singlet oxygen
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Tetraphenylporphyrin (H2TPP), covalently linked to four 2-pyridone moieties was synthesized (II) and studied. This composite molecule, in combination with light and ground state oxygen, has the ability to generate, trap, store, and release singlet oxygen. The process can be operated reversibly without detectable decomposition or side reactions using light with wavelength greater than 500 nm. Oxidation of the target molecule, 2-chloroethyl ethyl sulfide (CEES), by singlet oxygen released from the endoperoxide of the porphyrin-2-pyridone molecule (I) is demonstrated. Spectroscopic and kinetic data do not reveal evidence of perturbation between the porphyrin and pyridone ring systems of II. The decomposition kinetics for the endoperoxide adduct I are first order with activation parameters ΔH? = 26.7 (kcal/mol) and ΔG? = 24.0 (kcal/mol). Experimental and computational studies of unattached N-benzyl-2-pyridone peroxide are reported and compared to the experimental data for I.
- Changtong, Chuchawin,Carney, Daniel W.,Luo, Lan,Zoto, Christopher A.,Lombardi, John L.,Connors, Robert E.
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- Tunable self-assembly of triazole-linked porphyrin-polymer conjugates
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The convergence of supramolecular chemistry and polymer science offers many powerful approaches for building functional nanostructures with well-defined dynamic behaviour. Herein we report the efficient "click" synthesis and self-assembly of AB2- and AB4-type multitopic porphyrin-polymer conjugates (PPCs). PPCs were prepared using the copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) reaction, and consisted of linear polystyrene, poly(butyl acrylate), or poly(tert-butyl acrylate) arms attached to a zinc(II) porphyrin core via triazole linkages. We exploit the presence of the triazole groups obtained from CuAAC coupling to direct the self-assembly of the PPCs into short oligomers (2-6 units in length) via intermolecular porphyrinatozinc-triazole coordination. By altering the length and grafting density of the polymer arms, we demonstrate that the association constant of the porphyrinatozinc-triazole complex can be systematically tuned over two orders of magnitude. Self-assembly of the PPCs also resulted in a 6a K increase in the glass transition temperature of the bulk material compared to a non-assembling PPC. The modular synthesis and tunable self-assembly of the triazole-linked PPCs thus represents a powerful supramolecular platform for building functional nanostructured materials. Tunable building blocks: Triazole-linked porphyrin-polymer conjugates (PPCs) were prepared in high yield using the copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) "click" reaction. The triazole groups were introduced from CuAAC coupling to guide the self-assembly of the PPCs into short oligomers (2-6 units in length) via intermolecular porphyrinatozinc-triazole coordination. Association constants of the PPCs could be tuned by altering the polymer microenvironment around the porphyrin core, thus presenting a modular platform for designing self-assembled porphyrin-polymer materials. Copyright
- Roberts, Derrick A.,Schmidt, Timothy W.,Crossley, Maxwell J.,Perrier, Sebastien
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supporting information
p. 12759 - 12770
(2013/10/01)
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- A novel photodegradable hyperbranched polymeric photoresist
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We report the first synthesis of a photodegradable hyperbranched polyacetal, wherein every repeat unit carries a photo-labile 2-nitrobenzyloxy moiety. The pristine HBP serves as a positive photoresist to create micron-size patterns; furthermore, by changing the terminal groups to dipropargyl acetal, clickable photo-patterned substrates can be generated.
- Chatterjee, Saptarshi,Ramakrishnan
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p. 11041 - 11043
(2013/11/19)
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- GLUCOSE SENSOR MOLECULE
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The present invention provides a glucose sensor having a glucose receptor containing a binding site of formula (I): wherein X, n, m and R1 are defined herein. Also provided is a glucose sensor molecule for use in such a glucose sensor, the glucose sensor molecule containing the binding site of formula (I). The binding site has been found to have particularly good selectivity for glucose.
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- Water encapsulation in a polyoxapolyaza macrobicyclic compound
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A new heteroditopic macrobicyclic compound (t2pN 5O3) containing two separate polyoxa and polyaza compartments was synthesized in good yield through a [1 + 1] tripod-tripod coupling strategy. The X-ray crystal structure of H3t 2pN5O33+ revealed the presence of one encapsulated water molecule accepting two hydrogen bonds from two protonated secondary amines and donating a hydrogen bond to one amino group. The acid-base behavior of the compound was studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KCl. The results revealed unusual protonation behavior, namely a surprisingly low fourth protonation constant contrary to what was expected for the compound. 1H NMR and DOSY experiments, as well as molecular modeling studies, showed that the water encapsulation and the conformation observed in the solid state are retained in solution. The strong binding of the encapsulated water molecule, reinforced by the cooperative occurrence of a trifurcated hydrogen bond at the polyether compartment of the macrobicycle, account for the very low log K4 H value obtained.
- Mateus, Pedro,Delgado, Rita,Groves, Patrick,Campos, Sara R. R.,Baptista, Antonio M.,Brandao, Paula,Felix, Vitor
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experimental part
p. 6816 - 6824
(2012/09/25)
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- Harnessing "click"-type chemistry for the preparation of novel electronic materials
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Sequence-independent or "click"-type chemistry is applied for the preparation of novel π-conjugated oligomers. A variety of bi-functional monomers for Wittig-Horner olefination are developed and applied in a sequential protection-deprotection process for the preparation of structurally similar π-conjugated oligomers. Selected oligomers are incorporated as the organic semiconductors in light-emitting diodes and a field-effect transistor, demonstrating the potential of the approach. Sequence-independent or "click"-type chemistry is applied for the preparation of novel π-conjugated oligomers. A variety of bi-functional monomers for Wittig-Horner olefination are developed and applied in a sequential protection-deprotection process for the preparation of structurally similar π-conjugated oligomers. Selected oligomers are incorporated as the organic semiconductors in light-emitting diodes and a field-effect transistor, demonstrating the potential of the approach.
- Firstenberg, Michal,Shivananda, Kammasandra Nanjunda,Cohen, Irit,Solomeshch, Olga,Medvedev, Vladislav,Tessler, Nir,Eichen, Yoav
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experimental part
p. 634 - 643
(2012/01/12)
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- Design and photophysical properties of zinc(II) porphyrin-containing dendrons linked to a central artificial special pair
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The click chemistry synthesis and photophysical properties, notably photo-induced energy and electron transfers between the central core and the peripheral chromophores of a series of artificial special pair-dendron systems (dendron=G1, G2, G3; Gx=zinc(II) tetra-meso-arylporphyrin-containing polyimides) built upon a central core of dimethylxanthenebis(metal(II) porphyrin) (metal=zinc, copper), are reported. The dendrons act as singlet and triplet energy acceptors or donors, depending on the dendrimeric systems. The presence of the paramagnetic d9 copper(II) in the dendrimers promotes singlet-triplet energy transfer from the zinc(II) tetra-meso-arylporphyrin to the bis(copper(II) porphyrin) unit and slow triplet-triplet energy transfer from the central bis(copper(II) porphyrin) fragment to the peripheral zinc(II) tetra-meso-arylporphyrin. If bis(zinc(II) porphyrin) is the central core, evidence for chain folding is observed; this is unambiguously demonstrated by the presence of triplet-triplet energy transfer in the heterobimetallic systems, a process that can only occur at short distances.
- Bregier, Frederique,Aly, Shawkat M.,Gros, Claude P.,Barbe, Jean-Michel,Rousselin, Yoann,Harvey, Pierre D.
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scheme or table
p. 14643 - 14662
(2012/02/04)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula I wherein the variables are as defined herein.
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- Benzyl-substituted titanocene dichloride anticancer drugs: From lead to hit
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Through the reaction of Super Hydride (LiBEt3H) with 6-phenyl-substituted fulvenes followed by transmetallation to TiCl4 ten novel benzyl-substituted titanocene dichloride derivatives were synthesised. 6(4-morpholinomethyl-phenyl) fulvene (6g) and (bis-[(4-methoxymethyl-benzyl) cyclopentadienyl]titanium(IV) dichloride) (8a) were characterised by single crystal X-ray diffraction. All of the titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line and CAKI-1 human kidney cell human carcinoma cell line in an MTT based assay in order to determine their IC50 values. The titanocenes synthesised were found to have IC50 values ranging from 2.3 (±0.3) μM (comparable to cisplatin) to others which show no anti-proliferative activity on this cell line in standard DMSO formulations on LLC-PK cell line. Eight of the titanocenes were found to be completely water-soluble and had IC50 values of 6.5 (±0.7) μM to no activity when using medium only for formulation. On the CAKI-1 cell line, IC50 values of 7.8 (±1.4) μM to no activity were found using DMSO formulation, while IC50 values of 0.55 (±0.32) μM to no activity were measured using just medium as the formulation reagent. Some of the titanocenes show significant cytotoxicity improvement when compared directly to the lead compound Titanocene Y (bis-[(p-methoxybenzyl) cyclopentadienyl] titanium(IV) dichloride) and are more cytotoxic than cisplatin. Bis-[(4-diethylaminomethyl-benzyl)cyclopentadienyl]titanium(IV) dichloride (8d) at this preliminary stage seems to be the most promising of the ten compounds prepared and exhibits nanomolar activity against CAKI-1. Within the synthesis of several benzyl-substituted titanocene dichlorides is reported starting from 6-phenyl-substituted fulvenes. This synthesis has led to the discovery of new water-soluble benzyl-substituted titanocenes. Each compound had MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells and human CAKI-1 renal cancer cells completed, which show promising cytotoxic behaviour for some compounds comparable to or better cytotoxicities than cisplatin.
- Claffey, James,Müller-Bunz, Helge,Tacke, Matthias
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scheme or table
p. 2105 - 2117
(2010/09/12)
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- Dynamic combinatorial chemistry with hydrazones: Libraries incorporating heterocyclic and steroidal motifs
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We expand the possibilities in hydrazone based dynamic combinatorial chemistry with a series of new building blocks incorporating heterocyclic motifs. The synthetic procedure allows efficient access to building blocks with the general structure (MeO)2CH-Heterocycle-C(O)NHNH2, originating from heterocycles with an amine and an ester functionality. The equilibrium distribution of macrocyclic N-acyl hydrazones formed upon deprotection of the building blocks with TFA in organic solvents is reported. The mixing behaviour of these heterocycle-based building blocks with our cholate-based building blocks is described, particularly the observation of kinetic intermediates that disappear following 'proof-reading'. The Royal Society of Chemistry.
- Simpson, Mark G.,Pittelkow, Michael,Watson, Stephen P.,Sanders, Jeremy K. M.
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supporting information; experimental part
p. 1181 - 1187
(2010/06/13)
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- Novel monocyclam derivatives as HIV entry inhibitors: Design, synthesis, anti-HIV evaluation, and their interaction with the CXCR4 co-receptor
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The CXCR4 receptor has been shown to interact with the human immunodeficiency virus (HIV) envelope glycoprotein gp120, leading to fusion of viral and cell membranes. Therefore, ligands that can attach to this receptor represent an important class of therapeutic agents against HIV, thus inhibiting the first step in the cycle of viral infection: the virus-cell entry/ fusion. Herein we describe the in silico design, synthesis, and biological evaluation of novel monocyclam derivatives as HIV entry inhibitors. In vitro activity testing of these compounds in cell cultures against HIV strains revealed EC50 values in the low micromolar range without cytotoxicity at the concentrations tested. Docking and molecular dynamics simulations were performed to predict the binding interactions between CXCR4 and the novel monocyclam derivatives. A binding mode of these compounds is proposed which is consistent with the main existing site-directed mutagenesis data on the CXCR4 coreceptor. Moreover, molecular modeling comparisons were performed between these novel monocyclams, previously reported non-cyclam compounds from which the monocyclams are derived, and the well-known AMD3100 bicyclam CXCR4 inhibitors. Our results suggest that these three structurally diverse CXCR4 inhibitors bind to overlapping but not identical amino acid residues in the transmembrane regions of the receptor.
- Pettersson, Sofia,Perez-Nueno, Violeta I.,Mena, Maria Pau,Clotet, Bonaventura,Este, Jose A.,Borrell, Jose I.,Teixido, Jordi
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scheme or table
p. 1272 - 1281
(2011/02/21)
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- Towards control of dendrimer properties by reversible exchange of termini: Synthesis and characterization of diverse porphyrin dendrimers
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Porphyrin dendrimers with boronic ester, aldehyde, and pyridil termini were synthesized and fully characterized. These dendrimers have the potential to change their physical and chemical properties by reversible alteration of the reactive terminal groups.
- Shema-Mizrachi, Meital,Aharoni, Anna,Iliashevsky, Olga,Lemcoff
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experimental part
p. 1 - 8
(2010/04/05)
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- Synthesis, characterization and protein binding properties of supported dendrons
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Novel benzylether type aldehyde and acetal terminated dendrons were synthesized and attached to a silica gel support; a linear spacer was also introduced as a control material. The supported dendritic compounds were mainly characterized by solid state 13C CPMAS NMR, elemental analysis and X-ray photoelectron spectroscopy (XPS) and the presence of free aldehydes was determined by the purpald test. Bovine serum albumin (BSA) protein was coupled to the dendronized support by imine bond formation, followed by irreversible reduction of the carbon-nitrogen double bond. A significant positive dendritic effect was observed on the antibody binding capacity of immobilised BSA as measured by fluorescence immunoassay (FIA). The Royal Society of Chemistry 2009.
- Iliashevsky, Olga,Amir, Liron,Glaser, Robert,Marks, Robert S.,Lemcoff, N. Gabriel
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supporting information; experimental part
p. 6616 - 6622
(2010/05/19)
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- Optimization of the central linker of dicationic bis-benzimidazole anti-MRSA and anti-VRE agents
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A series of bis-benzimidazole diamidine compounds containing different central linkers has been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Seven compounds have shown potent antibacterial activities. The anti-MRSA and anti-VRE activities of compound 1h were more potent than that of the lead compound 1a and vancomycin.
- Hu, Laixing,Kully, Maureen L.,Boykin, David W.,Abood, Norman
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scheme or table
p. 3374 - 3377
(2010/02/28)
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- Triggered self-assembly of simple dynamic covalent surfactants
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(Figure Presented) A prototype surfactant system was developed with the unique feature that it can be switched between an aggregated, amphiphilic state and a nonaggregated, nonamphiphilic state using external stimuli. This switchable surfactant system uses the reversible formation of a dynamic covalent bond for pH- and temperature-triggered on/off self-assembly of micellar aggregates by reversible displacement of the equilibrium between nonamphiphilic building blocks and their amphiphilic counterparts. The potential for application in controlled-release systems is shown by reversible uptake and release of an organic dye in aqueous media.
- Minkenberg, Christophe B.,Florusse, Louw,Eelkema, Rienk,Koper, Ger J. M.,Van Esch, Jan H.
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supporting information; experimental part
p. 11274 - 11275
(2011/03/19)
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- Toward supramolecular polymers incorporating double cavity cucurbituril hosts
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We describe the synthesis of a series of guests (1-6) containing two adamantylammonium ions separated by xylylene spacing groups and their complexation properties toward double cavity cucurbituril host bis-ns-CB[10]. We observed the preferential formation of 1:1, 2:2, and oligomeric complexes rather than the desired n:n supramolecular polymers. Guest 7, which contains a longer biphenyl spacer successfully precludes the formation of the 1:1 complex but results in the formation of the 2:2 complex (bis-ns-CB[10]2·72) rather than supramolecular polymer. Guest 8, which contains adamantylammonium, p-xylylene diammonium, and hexanediammonium ion binding regions is shown to reversibly form 2:2 and 1:2 complexes (bis-ns-CB[10]2·82 and bis-ns-CB[10]·82) in response to changes in host:guest stoichiometry. Lastly, this equilibrium can be manipulated by the addition of exogenous CB[6], which selectively targets the hexanediammonium ion binding region of 8 and delivers the penta-molecular complex bis-ns-CB[10]·82·CB[6]2.
- Nally, Regan,Isaacs, Lyle
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scheme or table
p. 7249 - 7258
(2009/12/05)
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- A model for light-triggered porphyrin anticancer prodrugs based on an o-nitrobenzyl photolabile group
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A model for light-triggered porphyrin anticancer prodrug 1 was designed and synthesized. Upon photolysis, prodrug 1 can efficiently liberate the anticancer drug tegafur. The MTT assay demonstrates that prodrug 1 is significantly less toxic than its parent drug tegafur, and 1 can release tegafur upon photoactivation in vitro. The light-triggered porphyrin anti-cancer prodrug technique developed herein may find useful applications in chemotherapy to minimize the side effects of anticancer drugs because of the tumor affinity property of porphyrin and the light-controllable anticancer drug dosing. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Lin, Weiying,Peng, Daiwei,Wang, Bin,Long, Lingliang,Guo, Cancheng,Yuan, Jinbin
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supporting information; experimental part
p. 793 - 796
(2009/04/11)
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- Visible fluorescence chemosensor for saxitoxin
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Absorption spectra of a number of shellfish extracts have been obtained and reveal prominent absorptions in all samples at 210 and 260 nm and at 325 nm in some of them. These absorptions preclude the use of chromophores with similar absorptions in testing of shellfish samples for paralytic shellfish toxins. Two crown ether chemosensors featuring a boron azadipyrrin chromophore have been synthesized; both have absorption maxima at 650 nm, where all the shellfish extracts are transparent. The synthetic sensors feature either 18- or 27-membered crown ether rings and have been evaluated as visible sensors for the paralytic shellfish toxin saxitoxin. The binding constant for one of them is in the range of 3-9 × 105 M-1 and exhibits a fluorescence enhancement of over 100% at 680 nm in the presence of 40 μM saxitoxin.
- Gawley, Robert E.,Mao, Hua,Haque, M. Mahbubul,Thorne, John B.,Pharr, Jennifer S.
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p. 2187 - 2191
(2007/10/03)
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