- Self-assembly of a 5-fluorouracil-dipeptide hydrogel
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The self-assembly of 5-fluorouracil dilysine conjugates into self-supporting hydrogels, comprised of entangled nanofibers or rigid nanotubes with diameters of 10 and 16 nm, respectively, is reported. The rate of release of 5-Fu from the conjugates was highly dependent on concentration in solution, whereas, release from the fully formed hydrogels was significantly slower. The 5-Fu conjugate also exhibited promising in vitro cytotoxicity against human tumor cell lines A549, H460 and H23.
- Sun, Yuan,Kaplan, Jonah A.,Shieh, Aileen,Sun, Hui-Lung,Croce, Carlo M.,Grinstaff, Mark W.,Parquette, Jon R.
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- Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics
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Thiazolino fused 2-pyridone peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibers. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications.
- Krishnan, K. Syam,Bengtsson, Christoffer,Good, James A. D.,Mirkhanov, Shamil,Chorell, Erik,Johansson, Lennart B.-A.,Almqvist, Fredrik
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- Preferential binding of E. coli with type 1 fimbria to D-mannobiose with the Manα1→2Man structure
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Manα1→2Man, Manα1→3Man, Manα1→4Man, and Manα1→6Man were converted to the glycosylamine derivatives. Then, they were mixed with monobenzyl succinic acid to obtain their amide derivatives. After removing the benzyl group by hydrogenation, the succinylamide derivatives were coupled with the hydrazino groups on BlotGlyco beads in the presence of water-soluble carbodiimide. D-Mannobiose-linked beads were incubated with fluorescence-labeled Escherichia coli with type 1 fimbria, and the number of the fluorescent dots associated with the beads was counted in order to determine the binding preference among D-mannobiose isomers. The results showed that the bacteria bind strongly to Manα1→2Man1→beads, Man- α1→3Man1→beads, Manα1→4Man1→beads, and Manα1→6Man1→beads, in order. In the presence of 0.1 M methyl α-D-mannopyranoside, most of the bacteria failed to bind to these beads. These results indicate that E. coli with type 1 fimbria binds to all types of D-mannobiose isomers but preferentially to Manα1→2Man disaccharide.
- Ajisaka, Katsumi,Yuki, Kaoru,Sato, Kaori,Ishii, Nozomi,Matsuo, Ichiro,Kuji, Ryo,Miyazaki, Tatsuo,Furukawa, Kiyoshi
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- Strain-Promoted Reaction of 1,2,4-Triazines with Bicyclononynes
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Strain-promoted inverse electron-demand Diels-Alder cycloaddition (SPIEDAC) reactions between 1,2,4,5-tetrazines and strained dienophiles, such as bicyclononynes, are among the fastest bioorthogonal reactions. However, the synthesis of 1,2,4,5-tetrazines is complex and can involve volatile reagents. 1,2,4-Triazines also undergo cycloaddition reactions with acyclic and unstrained dienophiles at elevated temperatures, but their reaction with strained alkynes has not been described. We postulated that 1,2,4-triazines would react with strained alkynes at low temperatures and therefore provide an alternative to the tetrazine cycloaddition reaction for use in in vitro or in vivo labelling experiments. We describe the synthesis of a 1,2,4-triazin-3-ylalanine derivative fully compatible with the fluorenylmethyloxycarbonyl (Fmoc) strategy for peptide synthesis and demonstrate its reaction with strained bicyclononynes at 37°C with rates comparable to the reaction of azides with the same substrates. The synthetic route to triazinylalanine is readily adaptable to late-stage functionalization of other probe molecules, and the 1,2,4-triazine-SPIEDAC therefore has potential as an alternative to tetrazine cycloaddition for applications in cellular and biochemical studies.
- Horner, Katherine A.,Valette, Nathalie M.,Webb, Michael E.
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- A General Strategy for the Preparation of Thalidomide-Conjugate Linkers
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The synthesis of small-molecule linkers for installation of thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These small-molecule tethers act as linkages between molecules, can also aid in cell permeability, and act as solubilizing agents. This work shows our progress in synthesizing conjugates with a variety of linker characteristics. The adaptability and manipulation of these and other linkers holds potential in improving synthetic control of chemical connectivities toward therapeutic development.
- Papatzimas, James W.,Gorobets, Evgueni,Brownsey, Duncan K.,Maity, Ranjan,Bahlis, Nizar J.,Derksen, Darren J.
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- Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties
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Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.
- Bellany, Fiona,Tsuchiya, Yugo,Tran, Trang M.,Chan, A.W. Edith,Allan, Helen,Gout, Ivan,Tabor, Alethea B.
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- From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
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Protein-protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation. We have confirmed the involvement of the E3 ligase CUL4A-DDB1 cereblon ubiquitination pathway, making these PROTACs a first step toward a new class of antiapoptotic B-cell lymphoma 2 family protein degraders.
- Papatzimas, James W.,Gorobets, Evgueni,Maity, Ranjan,Muniyat, Mir Ishruna,Maccallum, Justin L.,Neri, Paola,Bahlis, Nizar J.,Derksen, Darren J.
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- Peptide conjugates of 4-aminocyclophosphamide as prodrugs of phosphoramide mustard for selective activation by prostate-specific antigen (PSA)
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In our continued effort to develop prodrugs of phosphoramide mustard, conjugates of 4-aminocyclophosphamide (4-NH2-CPA) with three PSA-specific peptides were synthesized and evaluated as substrates of PSA. These include conjugates of cis-(2R,4R)-4-NH2-CPA with a tetrapeptide Succinyl-Ser-Lys-Leu-Gln-OH, a hexapeptide Succinyl-His-Ser-Ser-Lys-Leu-Gln-OH, and a pentapeptide Glutaryl-Hyp-Ala-Ser-Chg-Gln-OH. These conjugates were cleaved by PSA efficiently and exclusively after the expected glutamine residue to release 4-NH2-CPA, the activated prodrug form of phosphoramide mustard. The cleavage was most efficient for the pentapeptide conjugate 3 (Glutaryl-Hyp-Ala-Ser-Chg-Gln-NH-CPA), which showed a half-life of 55 min with PSA, followed by the hexapeptide conjugate 2 (Succinyl-His-Ser-Ser-Lys-Leu-Gln- NH-CPA) and the tertrapeptide conjugate 1 (Succinyl-Ser-Lys-Leu-Gln-NH-CPA) with half-lives of 6.5 and 12 h, respectively. These results indicate a potential of the conjugate 3 as an anticancer prodrug of phosphoramide mustard for selective PSA activation.
- Jiang, Yongying,Hu, Longqin
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- Esterification of dicarboxylic acids with benzyl alcohol under the action of the microwave radiation
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Reaction of dicarboxylic acid with benzyl alcohol under the microwave irradiation proceeds faster as compared to the thermal conditions. The main reaction products are alkyl dicarboxylates, and the monoester and dibenzyl ether are formed as the side products. A proposal about the nature of the nonthermal effect in the reactions stimulated by the microwave irradiation is considered.
- Aver'yanov,Batrakova,Samuilov,Spiridonova,Kochnev,Galibeev,Gnezdilov
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- Biotin and glucose dual-targeting, ligand-modified liposomes promote breast tumor-specific drug delivery
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Breast cancer is the second leading cause of cancer-related deaths in women. Ligand-modified liposomes are used for breast tumor-specific drug delivery to improve the efficacy and reduce the side effects of chemotherapy; however, only a few liposomes with high targeting efficiency have been developed because the mono-targeting, ligand-modified liposomes are generally unable to deliver an adequate therapeutic dose. In this study, we designed biotin-glucose branched ligand-modified, dual-targeting liposomes (Bio-Glu-Lip) and evaluated their potential as a targeted chemotherapy delivery system in vitro and in vivo. When compared with the non-targeting liposome (Lip), Bio-Lip, and Glu-Lip, Bio-Glu-Lip had the highest cell uptake in 4T1 cells (3.00-fold, 1.60-fold, and 1.95-fold higher, respectively) and in MCF-7 cells (2.63-fold, 1.63-fold, and 1.85-fold higher, respectively). The subsequent cytotoxicity and in vivo assays further supported the dual-targeting liposome is a promising drug delivery carrier for the treatment of breast cancer.
- Fu, Qiuyi,Guo, Li,Huang, Mengyi,Peng, Yao,Pu, Yanchi,Wu, Yong,Zheng, Yongxiang
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- Chemoselective hydrolysis of tert-butyl esters in acetonitrile using molecular iodine as a mild and efficient catalyst
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A simple, mild and efficient method for the hydrolysis of tert-butyl esters using molecular iodine as a catalyst is described. Acid labile protecting groups, such as N-Boc, OBn, OAc and double bonds, are compatible under the reaction conditions.
- Yadav,Balanarsaiah,Raghavendra,Satyanarayana
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- Synthesis of novel γ-ketoesters from succinic anhydride
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Four alkyl g-ketohexanoates (3a-3d) have been prepared from succinic anhydride employing a three step reaction strategy. In the first step using p-toluene sulfonic acid as catalyst, the ring of succinic anhydride was opened with isopropyl, isobutyl, isopentyl and benzyl alcohols, respectively to form alkyl hydrogen succinates (1a-1d). In the 2nd step these alkyl hydrogen succinates on treatment with SOCl2 yielded 4-alkoxy-4-ketobutanoyl chlorides (2a-2d). The acid halides thus obtained, on reaction with diethyl cadmium led to require g-ketoesters. All the synthesised compounds were characterized by recording and analyzing 1H, 13C NMR, IR spectra and mass measurements.
- Iqbal, Muhammad,Baloch, Imam Bakhsh,Baloch, Musa Kaleem
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- Photoredox Activation of Formate Salts: Hydrocarboxylation of Alkenes via Carboxyl Group Transfer
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A photoredox activation mode of formate salts for carboxylation was developed. Using a formate salt as the reductant, carbonyl source, and hydrogen atom transfer reagent, a wide range of alkenes can be converted into acid products via a carboxyl group tra
- Huang, Yan,Hou, Jing,Zhan, Le-Wu,Zhang, Qian,Tang, Wan-Ying,Li, Bin-Dong
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p. 15004 - 15012
(2021/12/14)
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- Design, Synthesis, and Activity Study of Water-Soluble, Rapid-Release Propofol Prodrugs
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In this work, a series of water-soluble propofol prodrugs were synthesized, and their propofol release rate and pharmacodynamic characteristics were measured. We found that inserting glycolic acid as a linker between propofol and the cyclic amino acid accelerated the release of propofol from prodrugs into the plasma while preserving its safety. In animal experiments, prodrugs (3e, 3g, and 3j) were significantly better than fospropofol (the only water-soluble propofol prodrug that has been used clinically) in terms of safety, onset, and duration time of anesthesia. Their molar dose, onset time, and anesthesia duration time were comparable to those of propofol, helping to maintain the clinical benefits of propofol. The experimental results showed the potential of such compounds as water-soluble prodrugs of propofol.
- Liu, Liang-Quan,Hong, Pei-Xi,Song, Xing-Hai,Zhou, Chang-Cui,Ling, Rui,Kang, Yi,Qi, Qing-Rong,Yang, Jun
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supporting information
p. 7857 - 7866
(2020/08/21)
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- COMPOUNDS AND COMPOSITIONS FOR OCULAR DELIVERY
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The present invention provides new prodrags of Sunitinib, Brinzolamide, and Dorzolamide and compositions to treat medical disorders, for example glaucoma, a disorder or abnormality related to an increase in intraocular pressure (TOP), a disorder requiring neuroprotection, age-related macular degeneration, or diabetic retinopathy.
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Page/Page column 108; 164-165; 184; 186
(2020/05/12)
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- Preparation and application of breast cancer targeted liposome modified by biotin and glucose
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The invention discloses a novel lipid material for realizing the delivery of a breast cancer targeted drug. The novel lipid material takes lysine as a connecting group and is connected with a cholesteric part, a biotin part and a glucose part. The affinity between biotin and glucose in the novel lipid material and biotin transporter (SMVT) and glucose transporter (GLUT1) can be utilized to realizethe double targeting function to breast cancer and play a stronger breast cancer targeting therapeutic role, wherein the biotin transporter (SMVT) and the glucose transporter (GLUT1) are highly expressed on the surface of breast cancer cells. The novel lipid material can be used in different dosage forms comprising liposomes, nanoparticles, micelles and the like, and the prepared paclitaxel-loaded liposome has obvious breast cancer targeting property and a wide application prospect.
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Paragraph 0023
(2020/03/11)
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- Further development of the tin-catalyzed transcarbamoylation reaction
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Studies carried out to further develop tin-catalyzed trans-carbamoylation reactions demonstrated that transcarbamoylation of cinnamyl alcohol in the context of allyl cyanate-to-isocyanate rearrangement can be efficiently carried out on a ten-gram scale and that tin-catalyzed transcarbamoylation is a valuable alternative to the method using trichloroacetyl isocyanate. In addition, methyl carbamate was found to be an economical carabamoyl donor in tin-catalyzed transcarbamoylation, which showed broad functional group tolerance and allowed a streamlined workup procedure. Finally, a unique synthetic method was developed for the preparation of carbamate-tethered terpene glycoconjugates.
- Hasegawa, Tomoyuki,Ichikawa, Yoshiyasu,Masuda, Toshiya,Minami, Takahiro,Morishita, Yukinori,Ochi, Rika,Sato, Hiroshi
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p. 2373 - 2378
(2020/08/19)
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- DIPEPTIDE MIMETICS OF NGF AND BDNF NEUROTROPHINS
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The invention relates to compounds having either agonist or antagonist activities for the neurotrophins NGF and BDNF and represented by monomeric or dimeric substituted dipeptides that are analogs of the exposed portions of loop 1 or loop 4 regions of these neurotrophins near or at a beta-turn of the respective loop. N-acylated substituents of these dipeptides are biostereoisomers of the amino acid residues preceding these dipeptide sequences in the neurotrophin primary structure. The dimeric structure is produced advantageously by using hexatnethylenediaanine to which dipeptides are attached via their carboxyl groups. The claimed compounds displayed neuroprotective and differentiation-inducing activities in cellular models and enhanced the amount of phosphorylated tyrosine kinase A and the heat shock proteins Hsp32 and Hsp70 in the concentration range of 10 -9 to 10 -5 M. They also displayed neuroprotective, anti-parkinsonian, anti-stroke, anti-ischemic, anti-depressant and anti-amnestic activities in animal models and were active in experimental models of Alzheimer's disease. These in vivo effects of the claimed compounds are displayed in the dose range of 0.01 to 10 mg/kg when administered intraperitoneally.
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Paragraph 0075
(2019/04/16)
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- Novel double brain tumor-targeted lipid material and application thereof
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The invention discloses a novel lipid material. The novel lipid material is used for prolonging the circulating time and increasing the transfer amount of medicine to brain tumor tissues in a target way. The novel lipid material is characterized in that polyethylene glycol is used as a bridge, one side of the bridge is connected with cholesterol, and one side of the bridge is connected with glucose and RGD (arginine-glycine-aspartic acid) peptide, so that the lack of brain tumor targeting ability by the lipid modified by the single glucose or the RGD peptide is overcome, and the brain tumor can be effectively targeted after blood brain barrier crossing. The novel lipid material can be used for different preparation types of lipids, nanoparticles, micelles and the like; the prepared paclitaxel-carrying lipid has obvious brain tumor targeting function, and broad application prospect.
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Paragraph 0021
(2018/12/02)
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- COMBINATION THERAPY
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The present disclosure provides certain combination therapy technologies that are particularly useful for treating one or more diseases, disorders, or conditions that may be related to abnormal metabolism. In some embodiments, provided technologies provides combinations of TCA cycle acids and ketone bodies. In some embodiments, provided technologies provides combinations of TCA cycle acids and other carboxylic acids.
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Paragraph 00263-00264
(2017/09/09)
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- Novel glucose-based brain-targeting prodrug with locking function
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The invention discloses a novel glucose-based TDS modified brain-targeting prodrug with a locking function. The prodrug is of a structure shown in a general formula (I) (described in the specification) or pharmaceutically acceptable salt of hydrate of the structure, wherein X is -NH-(CH2)m-O-, -NH-(CH2)m-NH-, -C(O)-(CH2)m-NH-, -C(O)-(CH2)m-O-, -O-(CH2)m-O-, -O-(CH2)m-NH-; Y is -C(O)-(CH2)n-C(O)-; m represents 2-6, n represents 1-4; Drug is a drug acting on a central nervous system. A series of prodrugs provided by the invention, on the basis of glucose brain targeting, are added with a TDS part, so that the prodrugs have the locking function, brain targeting and center concentration of the drug can be improved, the curative effect of the drug is enhanced, and distribution of the drug in peripheral organs is reduced while toxic and side effects of the drug are reduced.
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Paragraph 0035
(2016/10/10)
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- NEW BIS ESTERS OF IVY SAPOGENINS FOR RUMINANTS
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The present invention relates to synthetic bis esters of hederagenin, and their use in ruminants to improve ruminant growth performance, reduce rumen methane emission, reduce urine ammonia excretion, and/or to reduce rumen acetate to propionate ratio. Moreover, it also relates to a feed composition for ruminants comprising bis esters of hederagenin, and to novel bis esters of hederagenin.
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Page/Page column 26
(2016/12/22)
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- FIBER COATED NANOPORES
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Provided herein are compositions, compounds, processes, and methods of use of 3D porous coating(s) on or near a nanopore(s) for analysis or detection of charged polymers such as nucleic acids, proteins, protein-nucleic acid complexes, small molecule-biological complexes, polymer-biological complexes, and/or polyelectrolytes.
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Paragraph 0493
(2016/07/05)
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- Hybrids of acylated homoserine lactone and nitric oxide donors as inhibitors of quorum sensing and virulence factors in Pseudomonas aeruginosa
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Pseudomonas aeruginosa is an opportunistic pathogen causing a variety of life-threatening diseases such as cystic fibrosis and nosocomial infections in burn victims. The ability of P. aeruginosa to cause infection is attributed to the production of virulence factors such as pyocyanin and elastases. These virulence factors are under the control of quorum sensing (QS) a cell to cell communication process controlled by small diffusible signalling molecules based on N-acyl-homoserine lactones (AHLs) known as autoinducers. The inhibition of QS and thereby virulence factors is seen as a potential new anti-infective strategy. Additionally, the role of nitric oxide (NO) in downstream processes in bacteria such as biofilm dispersal, motility, virulence and antimicrobial defence systems is gaining attention and could be used to control bacterial. Herein we report the design and synthesis of hybrid compounds based on AHL signalling molecules and NO donors as anti-infective agents. A series of AHL-NO hybrids were synthesised and potent inhibitors of QS and virulence factors of P. aeruginosa were identified. This research has led to conversion of agonist AHLs to antagonist AHLs with dual properties of QS inhibition and NO release.
- Kutty, Samuel K.,Barraud, Nicolas,Ho, Kitty K. K.,Iskander, George M.,Griffith, Renate,Rice, Scott A.,Bhadbhade, Mohan,Willcox, Mark D. P.,Black, David Stc,Kumar, Naresh
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p. 9850 - 9861
(2015/10/05)
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- DUAL ACTION NITRIC OXIDE DONORS AND THEIR USE AS ANTIMICROBIAL AGENTS
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The present invention relates generally to conjugates comprising a nitric oxide donor and an acyl homoserine lactone, fimbrolide, fimbrolide derivative, dihydropyrrolone or indole, and to the use of such conjugates as antimicrobial agents.
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Page/Page column 50; 51
(2014/05/24)
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- ABSORBABLE BRANCHED POLYESTERS AND POLYURETHANES
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The present invention relates to the discovery of a new class of hydrolysable isocyanates, hydrolysable branched polyols and branched absorbable polyesters and polyurethanes prepared therefrom. The resultant absorbable polymers are useful for drug delivery, stents, highly porous foam, reticulated foam, tissue engineering, tissue adhesives, adhesion prevention, bone wax formulations, medical device coatings, surface modifying agents and other implantable medical devices. In addition, these absorbable polymers can have a controlled hydrolytic degradation profile.
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Paragraph 0218-0220
(2014/05/25)
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- Synthesis of the polyketide (E)-olefin of the jamaicamides
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The jamaicamides, isolated in Jamaica from the cyanobacterium Lyngbya majuscula, are new mixed polyketide-peptides that are known to be sodium channel blockers. The polyketide moiety contains an (E)-vinyl chloride, an undetermined methyl stereocenter (C9), and an (E)-olefin. Herein, we report the synthesis of the (E)-olefin moiety of the polyketide of the jamaicamides utilizing a Kocienski-Julia coupling. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Watanabe, Satoshi,Watanabe, Sho,Aoki, Naoto,Usuki, Toyonobu
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supporting information
p. 1397 - 1403
(2013/05/22)
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- Peptidomimetic modification improves cell permeation of bivalent farnesyltransferase inhibitors
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Bivalent enzyme inhibitors, in which a surface binding module is linked to an active site binding module through a spacer, are a robust approach for site-selectively delivering a minimally-sized agent to a protein surface to regulate its functions, such as protein-protein interactions (PPIs). Previous research revealed that these agents effectively disrupt the interaction between farnesyltransferase (FTase) and the C-terminal region of K-Ras4B protein. However, the whole cell activity of these peptide-based agents is limited due to their low membrane permeability. In this study, we tested a peptidomimetic modification of these bivalent agents using a previously developed inhibitor, FTI-249, and evaluated their cell permeability and biological activity in cells. Confocal cell imaging using fluorescently-labeled agents showed that the peptidomimetic 3-BODIPY penetrated cells, while the peptide-based 1-BODIPY did not. Cell-based evaluation demonstrated that peptidomimetic 3 at a concentration of 100 μM inhibited HDJ-2 processing in cells, indicating that this peptidomimetic modification improves cell permeability, thus leading to enhanced whole cell activity of the bivalent compounds.
- Machida, Shinnosuke,Tsubamoto, Mai,Kato, Nobuo,Harada, Kazuo,Ohkanda, Junko
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p. 4004 - 4010
(2013/07/27)
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- Dimeric argininamide-type neuropeptide y receptor antagonists: Chiral discrimination between Y1 and Y4 receptors
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The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y 4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R,R)-49): Ki = 230 nM (Y1R) and 290 nM (Y4R)). With a Ki value of 130 nM and a Kb value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists.
- Keller, Max,Kaske, Melanie,Holzammer, Tobias,Bernhardt, Guenther,Buschauer, Armin
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p. 6303 - 6322
(2013/10/22)
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- Bioavailable affinity label for collagen prolyl 4-hydroxylase
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Collagen is the most abundant protein in animals. Its prevalent 4-hydroxyproline residues contribute greatly to its conformational stability. The hydroxyl groups arise from a post-translational modification catalyzed by the nonheme iron-dependent enzyme, collagen prolyl 4-hydroxylase (P4H). Here, we report that 4-oxo-5,6-epoxyhexanoate, a mimic of the α-ketoglutarate co-substrate, inactivates human P4H. The inactivation installs a ketone functionality in P4H, providing a handle for proteomic experiments. Caenorhabditis elegans exposed to the esterified epoxy ketone displays the phenotype of a worm lacking P4H. Thus, this affinity label can be used to mediate collagen stability in an animal, as is desirable in the treatment of a variety of fibrotic diseases.
- Vasta, James D.,Higgin, Joshua J.,Kersteen, Elizabeth A.,Raines, Ronald T.
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p. 3597 - 3601
(2013/07/11)
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- Design and synthesis of novel amphiphilic Janus dendrimers for bone-targeted drug delivery
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In this paper, we synthesized a range of amphiphilic Janus dendrimers, which consisted of acidic amino acid and naproxen molecules as the peripheral groups, as novel potential bone-targeting dendritic drug delivery. These dendrimers take advantage of a dendritic display to carry multiple drug molecules and targeting moieties simultaneously. All of the dendrimers exhibited more than 80% binding rates to hydroxyapatite (HAP), especially the [G 2]-dendrimers (2a and 2b) showed dramatic binding rates (>95%). Moreover, the solubility of naproxen was remarkably enhanced by the dendritic drug delivery system, especially the naproxen concentration of 2b achieved 5.37 mg/ml, which is more than 28-fold over that of native drug. Furthermore, cell viability studies showed that all the dendrimers exhibited no significant cytotoxicity against HEK293 cells. These results provided an effective entry to the development of new bone-targeting drugs.
- Pan, Junzhu,Wen, Min,Yin, Dongqin,Jiang, Bo,He, Dongsheng,Guo, Li
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scheme or table
p. 2943 - 2949
(2012/06/01)
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- Novel dendritic naproxen prodrugs with poly(aspartic Acid) Oligopeptide: Synthesis and hydroxyapatite binding in vitro
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Novel bone-targeting prodrugs containing dendritic naproxen and poly(aspartic acid) oligopeptide were synthesized in a convergent approach and were characterized by NMR, mass spectral, and elemental analysis techniques. The modified naproxen prodrugs showed a high affinity to hydroxyapatite in vitro and provided an effective entry for the synthesis of a dendritic naproxen-poly(aspartic acid) oligopeptide conjugates used for bone targeting.
- Pan, Junzhu,Ma, Lifang,Li, Bo,Li, Yanhua,Guo, Li
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scheme or table
p. 3441 - 3454
(2012/10/08)
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- Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo
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A codrug of the anti-Alzheimer drug tacrine and the natural product silibinin was synthesized. The codrug's biological and pharmacological properties were compared to an equimolar mixture of the components. The compound showed potent acetyl- and butyrylcholinesterase inhibition. In a cellular hepatotoxicity model, analyzing the influence on viability and mitochondria of hepatic stellate cells (HSC), the toxicity of the codrug was markedly reduced in comparison to that of tacrine. Using a neuronal cell line (HT-22), a neuroprotective effect against glutamate-induced toxicity could be observed that was absent for the 1:1 mixture of components. In subsequent in vivo experiments in rats, in contrast to the effects seen after tacrine treatment, after administration of the codrug no hepatotoxicity and no induction of the cytochrome P450 system were noticed. In a scopolamine-induced cognitive impairment model using Wistar rats, the codrug was as potent as tacrine in reversing memory dysfunction. The tacrine-silibinin codrug shows high AChE and BChE inhibition, neuroprotective effects, lacks tacrine's hepatotoxicity in vitro and in vivo, and shows the same pro-cognitive effects in vivo as tacrine, being superior to the physical mixture of tacrine and silibinin in all these regards.
- Chen, Xinyu,Zenger, Katharina,Lupp, Amelie,Kling, Beata,Heilmann, J?rg,Fleck, Christian,Kraus, Birgit,Decker, Michael
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experimental part
p. 5231 - 5242
(2012/09/25)
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- Self-assembled arrays of dendrimer-gold-nanoparticle hybrids for functional cell studies
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Dendrimer-controlled cell growth: A dendrimer-gold-nanoparticle hybrid array (see picture; PEG=polyethylene glycol), which can control the apparent dendrimer surface density, was used to investigate cell adhesion. The effect of the macromolecular architecture on the attachment and the morphological development of endothelial cells was studied. The dendrimer outperformed a linear counterpart, most likely modulated by the different interactions between the dendrimer and the proteins in the cell media. Copyright
- Lundgren, Anders,Hed, Yvonne,Oeberg, Kim,Sellborn, Anders,Fink, Helen,Loewenhielm, Peter,Kelly, Jonathan,Malkoch, Michael,Berglin, Mattias
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supporting information; experimental part
p. 3450 - 3453
(2011/05/06)
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- Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders
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The present invention provides prodrug compounds of diaryldiazepine drug compounds.
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Page/Page column 63
(2011/07/29)
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- The non-metathetic role of Grubbs' carbene complexes: From hydrogen-free reduction of α,β-unsaturated alkenes to solid-supported sequential cross-metathesis/reduction
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An efficient and high-yielding "hydrogen-free" reduction of α,β-unsaturated alkenes was carried out employing Grubbs' catalyst in a non-metathetic role and Et3SiH. Conditions were optimized under microwave irradiation. Application to the solid-phase organic synthesis allows a facile construction of sp3-sp3 carbon bonds through a sequential cross metathesis/olefin reduction.
- Poeylaut-Palena, Andres A.,Testero, Sebastian A.,Mata, Ernesto G.
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supporting information; experimental part
p. 1565 - 1567
(2011/03/20)
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- DIAZENIUMDIOLATE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
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Compounds of formula (I): wherein: R1 represents a hydrogen atom or a —COOR group, R2 represents a group G or a linear or branched (C1-C6)alkyl group substituted by a group G, wherein G represents a —(CH2)n-A-(CH2)m—B—(CR4R5)p—(CH2)o-R6 group as defined in the description, R3 represents a hydrogen atom, an alkyl group or an NO2 group.
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Page/Page column 4
(2010/12/29)
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- One-step transformation of tetrahydropyranyl ethers using indium(III) triflate as the catalyst
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A convergent one-step transformation of tetrahydropyranyl (THP) ethers is described. According to our earlier experiments, indium(III) triflate has proven to be an efficient catalyst for the transformation of THP ethers into their corresponding acetates.
- Mineno, Tomoko,Nikaido, Nana,Kansui, Hisao
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scheme or table
p. 1167 - 1170
(2010/03/31)
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- Synthesis and antibiofilm activity of a second-generation reverse-amide oroidin library: A structure-activity relationship study
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A second-generation library of 2-aminoimidazole-based derivatives incorporating a "reversed amide" (RA) motif in comparison to the marine natural product oroidin were synthesized and subsequently assayed for antibiofilm activity against the medically relevant Gram-negative proteobacteria P. aeruginosa and A. baumannii. Most notably, an in-depth activity profile is reported for the most active subclass of derivatives that bear linear aliphatic chains off the amide bond. Additionally, further structural modifications of the core template, such as removal of the amide bond or substitution with a triazole isostere, resulted in the discovery of analogues with antibiofilm activities that varied with respect to their inhibition and dispersal properties of P. aeruginosa and A. baumannii biofilms.
- Eric Ballard,Richards, Justin J.,Wolfe, Amanda L.,Melander, Christian
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experimental part
p. 10745 - 10761
(2009/12/04)
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- (1-Nosyl-5-nitroindol-3-yl)methyl ester: A novel protective group for carboxylic acids
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(Chemical Equation Presented) The usefulness of (1-nosyl-5-nitroindol-3-yl) methyl esters as a novel protective group for carboxylic acid is fully demonstrated. The novel protective group is stable under a broad range of conditions and can easily be deprotected under the mild conditions used for removal of the nosyl (Ns) group. It is orthogonal to the existing protective groups for carboxylic acids such as t-butyl and allyl esters.
- Nishimura, Takuya,Yamada, Kouhei,Takebe, Tohru,Yokoshima, Satoshi,Fukuyama, Tohru
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supporting information; experimental part
p. 2601 - 2604
(2009/05/26)
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- LIPOPHILIC ANTICANCER DRUG COMPOUNDS, COMPOSITIONS AND RELATED METHODS
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Lipophilic anticancer drug compounds, compositions that include the compounds, and methods for treating a cell proliferative disease using the compounds.
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Page/Page column 11
(2008/06/13)
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- Amide derivatives and methods of their use
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Amide derivatives of the general formulae Ia and Ib: are disclosed. Pharmaceutical compositions containing these compounds, and methods for their use, inter alia, for treating and/or preventing gastrointestinal disorders, pain, and pruritus are also disclosed.
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Page/Page column 38
(2008/06/13)
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- Efficient and simple NaBH4 reduction of esters at cationic micellar surface
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(Chemical Equation Presented) A simple, efficacious, and biocompatible methodology for reducing esters with sodium borohydride at an aqueous cationic micellar surface under ambient conditions has been developed. The present method holds promise for future use in selective functional group reduction and stereocontrolled alcohol synthesis.
- Das, Debapratim,Roy, Sangita,Das, Prasanta Kumar
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p. 4133 - 4136
(2007/10/03)
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- Montmorillonite clay: A novel reagent for the chemoselective hydrolysis of t-butyl esters
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A mild and highly selective hydrolysis of t-butyl esters has been achieved in high yields using montmorillonite KSF in refluxing acetonitrile. The method is compatible with a variety of protecting and functional groups such as BOC, Cbz, propargyl, allyl, benzyl, t-butyl ethers, allyl, methyl and benzyl esters present in the molecule.
- Yadav,Reddy, B. V. Subba,Rao, K. Sanjeeva,Harikishan
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p. 826 - 828
(2007/10/03)
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- Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators
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Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.
- Moridani, Majid Y.,Tilbrook, Gary S.,Khodr, Hicham H.,Hider, Robert C.
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p. 349 - 364
(2007/10/03)
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- Phenolic modification as an approach to improve the pharmacology of the 3-acyloxy-2-benzylpropyl homovanillic amides and thioureas, a promising class of vanilloid receptor agonists and analgesics
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In order to improve the analgesic activity and pharmacokinetics of thioureas 2 and 3, which we previously developed as potent vanilloid receptor (VR) agonists, we prepared and characterized phenolic modifications of them and of their amide surro-gates (7, 8). The aminoethyl analogue of the amide template 13 was a potent analgesic with an EC50 =0.96 μg/kg in the AA-induced writhing test and with better in vivo stability than the parent phenol. Copyright
- Lee, Jeewoo,Lee, Jiyoun,Kang, Myung-Sim,Kim, Kang-Pil,Chung, Suk-Jae,Blumberg, Peter M.,Yi, Jung-Bum,Park, Young Ho
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p. 1171 - 1179
(2007/10/03)
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- Vanilloid analogues containing resinferatoxin pharmacophores as potent vanilloid receptor agonists and analgesics, compositions and uses thereof
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The present invention is related to new vanilloid analogues containing resiniferatoxin pharmacophores, pharmaceutical compositions comprising such analogues, and their uses as vanilloid receptor agonists and potent analgesics. The present invention provides a pharmaceutical composition for treating acute, chronic, inflammatory or neuropathic pains or for treating bladder hypersensitivity.
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- Novel bifunctional chelating compounds containing hydroxamic acid residues
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New types of hydroxamic acid-based bifunctional chelators are provided. These chelators are designed to chelate metal ions that can be detected either by their paramagnetic or radioactive properties. Conjugation with peptides or protein can be achieved by the presence of a linker moiety in the molecular structure of these chelators.
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