- Two-component dendritic gel: Effect of stereochemistry on the supramolecular chiral assembly
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The self-assembly of diaminododecane solubilised by four different stereoisomeric dendritic peptides to form gel-phase materials in toluene was investigated. The second generation dendritic peptides were based on D- and L-lysine building blocks, and each contained three chiral centres. By designing dendritic peptides in which the configurations of the chiral centres were modified, and applying them as gelator units, the assembly of stereoisomers could be investigated. In all cases, the self-assembly of gelator units resulted in macroscopic gelation. However, the degree of structuring was modulated by the stereoisomers employed, an effect which changed the morphology and macroscopic behavior of the self-assembled state. Enantiomeric (L,L,L or D,D,D) gelator units formed fibrous molecular assemblies, whilst the racemic gel (50% L,L,L: 50% D,D,D) formed a flat structure with a "woven" appearance. Gelator units based on L,D,D or D,L,L dendritic peptides also formed fibrous assemblies, but small-angle X-ray scattering indicated significant morphological differences were caused by the switch in chirality. Furthermore, the macroscopic stability of the gel was diminished when these peptides were compared with their L,L,L or D,D,D analogues. In this paper it is clearly shown that individual stereocentres, on the molecular level, are directly related to the helicity within the fibre. It is argued that the chirality controls the pattern of hydrogen bonding within the assembly, and hence determines the extent of fibre formation and the macroscopic gel strength.
- Hirst, Andrew R.,Smith, David K.,Feiters, Martin C.,Geurts, Huub P. M.
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Read Online
- Synthesis and antibacterial bioactivities of cationic deacetyl linezolid amphiphiles
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Bacterial infections cause various life-threatening diseases and have become a serious public health problem due to the emergence of drug-resistant strains. Thus, novel antibiotics with excellent antibacterial activity and low cytotoxicity are urgently needed. Here, three series of novel cationic deacetyl linezolid amphiphiles bearing one lipophilic alkyl chain and one non-peptidic amide bond were synthesized and tested for antimicrobial activities. Several compounds showed excellent antibacterial activity toward drug-sensitive bacteria such as gram-negative bacteria Escherichia coli (E. coli), Salmonella enterica (S. enterica) and gram-positive Staphylococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis). Moreover, these amphiphilic molecules also exhibited strong activity against drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC (Klebsiella pneumoniae carbapenemase) and NDM-1 (New Delhi metallo-β-lactamase 1) producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MICs (minimum inhibitory concentrations) of the best compound 6e, ranged from 2 to 16 μg/mL and linezolid ranged from 2 to >64 μg/mL against these strains. Therefore, 6e is a broad-spectrum antimicrobial compound that may be a suitable lead as an antibiotic. The molecule 6e were found to function primarily by permeabilization and depolarization of bacterial membranes. Importantly, bacterial resistance against compound 6e was difficult to induce, and 6e was stable under plasma conditions and showed suitable activity in mammalian plasma. Thus, these compounds can be further developed into a potential new class of broad-spectrum antibiotics.
- Bai, Peng-Yan,Qin, Shang-Shang,Chu, Wen-Chao,Yang, Yi,Cui, De-Yun,Hua, Yong-Gang,Yang, Qian-Qian,Zhang, En
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Read Online
- End-Site-Specific Conjugation of Enoxaparin and Tetradeoxycholic Acid Using Nonenzymatic Glycosylation for Oral Delivery
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Heparin and low molecular weight heparins (LMWHs) have been the drug of choice for the treatment or the prevention of thromboembolic disease. Different methods are employed to prepare the LMWHs that are clinically approved for the market currently. In particular, enoxaparin, which has a reducing sugar moiety at the end-site of polysaccharide, is prepared by alkaline depolymerization. Focusing on this end-site-specific activity of LMWHs, we conjugated the tetraoligomer of deoxycholic acid (TetraDOCA; TD) at the end-site of enoxaparin via nonenzymatic glycosylation reaction. The end-site-specific conjugation is important for polysaccharide drug development because of the heterogeneity of polysaccharides. This study also showed that orally active enoxaparin and tetraDOCA conjugate (EnoxaTD) had therapeutic effect on deep vein thrombosis (DVT) without bleeding in animal models. Considering the importance of end-specific conjugation, these results suggest that EnoxaTD could be a drug candidate for oral heparin development.
- Park, Jooho,Jeon, Ok Cheol,Yun, Jisuk,Nam, Hwajung,Hwang, Jinha,Al-Hilal, Taslim A.,Kim, Kwangmeyung,Kim, Kyungjin,Byun, Youngro
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Read Online
- Photocleavable antimicrobial peptide mimics for precluding antibiotic resistance
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Cationic amphiphiles featuring a lysine-based hydrophilic moiety, an alkyl chain-based hydrophobic moiety, and an o-nitrobenzyl group-based linker were constructed facilely, which show alkyl chain-dependent antibacterial activity against both Gram-positive and Gram-negative bacteria, low cytotoxicity toward mammalian cells, and UV-cleavable properties, representing a novel type of environmental accumulation-free antimicrobial peptide mimic.
- Feng, Yang,Zhang, Yang-Yang,Li, Ke,Tian, Na,Wang, Wei-Bo,Zhou, Qian-Xiong,Wang, Xue-Song
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Read Online
- Biodegradable hydrogels for time-controlled release of tethered peptides or proteins
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Tethering drug substances to a gel network is an effective way of controlling the release kinetics of hydrogelbased drug delivery systems. Here, we report on in situ forming, biodegradable hydrogels that allow for the covalent attachment of peptides or proteins. Hydrogels were prepared by step-growth polymerization of branched poly(ethylene glycol). The gel strength ranged from 1075 to 2435 Pa; the degradation time varied between 24 and 120 h. Fluorescence recovery after photobleaching showed that fluorescently labeled bovine serum albumin (FITC-BSA) was successfully bound to the gel network during gel formation. Within 168 h, the mobility of the tethered molecules gradually increased due to polymer degradation. Using FITC-BSA and lysozyme as model proteins, we showed the potential of the developed hydrogels for time-controlled release. The obtained release profiles had a sigmoidal shape and matched the degradation profile very well; protein release was complete after 96 h.
- Brandl, Ferdinand,Hammer, Nadine,Blunk, Torsten,Tessmar, Joerg,Goepferich, Achim
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Read Online
- Synthesis and evaluation of a bis-3-chloropiperidine derivative incorporating an anthraquinone pharmacophore
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With the aim to attain an alkylating agent with enhanced DNA-affinity, we have successfully synthesised lysine-linked bis-3-chloropiperidine 1 bearing an anthraquinone moiety known to bind double-stranded DNA. Consistent with our expectations, compound 1 appears to intercalate into the DNA double helix, which can be observed by conformational changes of plasmid DNA suggesting alkylation and intercalation-induced DNA unwinding. The results of this work can provide a meaningful starting point for investigating the molecular mechanism of action of this novel DNA alkylating conjugate 1 with improved affinity for DNA.
- Zuravka, Ivonne,Sosic, Alice,Gatto, Barbara,G?ttlich, Richard
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Read Online
- Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics
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A series of fluoroquinolone conjugates was synthesised by linking the carboxylic acid functionality of the carboxylate-type siderophore staphyloferrin A and its derivatives to the piperazinyl nitrogen of ciprofloxacin and norfloxacin via amide bond formation. Four siderophore-drug conjugates were screened against a panel of bacteria associated with infection in humans. Whilst no activity was found against ciprofloxacin- or norfloxacin-resistant bacteria, one of the conjugates retained antibacterial activity against fluoroquinolone-susceptible strains although the structure of its lysine-based siderophore component differs from that of the natural siderophore staphyloferrin A. In contrast, three ornithine-based siderophore conjugates showed significantly reduced activity against strains that are susceptible to their respective parent fluoroquinolones, regardless of the type of fluoroquinolone attached or chirality at the ornithine Cα-atom. The loss of potency observed for the (R)- and (S)-ornithine-based ciprofloxacin conjugates correlates with their reduced inhibitory activity against the target enzyme DNA gyrase. The Royal Society of Chemistry.
- Milner, Stephen J.,Seve, Alexandra,Snelling, Anna M.,Thomas, Gavin H.,Kerr, Kevin G.,Routledge, Anne,Duhme-Klair, Anne-Kathrin
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Read Online
- Appended Aromatic Moieties in Flexible Bis-3-chloropiperidines Confer Tropism against Pancreatic Cancer Cells
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Nitrogen mustards (NMs) are an old but still largely diffused class of anticancer drugs. However, spreading mechanisms of resistance undermine their efficacy and therapeutic applicability. To expand their antitumour value, we developed bis-3-chloropiperidines (B-CePs), a new class of mustard-based alkylating agent, and we recently reported the striking selectivity for BxPC-3 pancreatic tumour cells of B-CePs bearing aromatic moieties embedded in the linker. In this study, we demonstrate that such tropism is shared by bis-3-chloropiperidines bearing appended aromatic groups in flexible linkers, whereas esters substituted by aliphatic groups or by efficient DNA-interacting groups are potent but nonselective cytotoxic agents. Besides, we describe how the critical balance between water stability and DNA reactivity can affect the properties of bis-3-chloropiperidines. Together, these findings support the exploitation of B-CePs as potential antitumour clinical candidates.
- Carraro, Caterina,Helbing, Tim,Francke, Alexander,Zuravka, Ivonne,Sosic, Alice,De Franco, Michele,Gandin, Valentina,Gatto, Barbara,G?ttlich, D. Richard
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p. 860 - 868
(2020/12/07)
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- LIPID-MODIFIED NUCLEIC ACID COMPOUNDS AND METHODS
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Disclosed herein, inter alia, are lipid-modified nucleic acid compounds of the following structure, their preparation, and their use: (I).
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Paragraph 0555-0556
(2019/12/25)
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- Rhamnolipid inspired lipopeptides effective in preventing adhesion and biofilm formation of Candida albicans
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Rhamnolipids are biodegradable low toxic biosurfactants which exert antimicrobial and anti-biofilm properties. They have attracted much attention recently due to potential applications in areas of bioremediation, therapeutics, cosmetics and agriculture, however, the full potential of these versatile molecules is yet to be explored. Based on the facts that many naturally occurring lipopeptides are potent antimicrobials, our study aimed to explore the potential of replacing rhamnose in rhamnolipids with amino acids thus creating lipopeptides that would mimic or enhance properties of the parent molecule. This would allow not only for more economical and greener production but also, due to the availability of structurally different amino acids, facile manipulation of physico-chemical and biological properties. Our synthetic efforts produced a library of 43 lipopeptides revealing biologically more potent molecules. The structural changes significantly increased, in particular, anti-biofilm properties against Candida albicans, although surface activity of the parent molecule was almost completely abolished. Our findings show that the most active compounds are leucine derivatives of 3-hydroxy acids containing benzylic ester functionality. The SAR study demonstrated a further increase in activity with aliphatic chain elongation. The most promising lipopeptides 15, 23 and 36 at 12.5 μg/mL concentration allowed only 14.3%, 5.1% and 11.2% of biofilm formation, respectively after 24 h. These compounds inhibit biofilm formation by preventing adhesion of C. albicans to abiotic and biotic surfaces.
- Jovanovic, Milos,Radivojevic, Jelena,O'Connor, Kevin,Blagojevic, Stevan,Begovic, Biljana,Lukic, Vera,Nikodinovic-Runic, Jasmina,Savic, Vladimir
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supporting information
p. 209 - 217
(2019/03/23)
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- Synthesis method for positive charge phospholipid
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The invention relates to a synthesis method for positive charge phospholipid. 1,2-Palmitodistearin is adopted as a raw material, and phospholipid DSPE is synthesized; then, lysine is connected to an amino of the DSPE; then, n beta-alanines are connected to two aminos of a BOC-lysine group in the product, finally, a salt is obtained, and a series of positive charge phospholipid is obtained.
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Paragraph 0052-0063
(2019/05/04)
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- AMPHIPHILIC CONJUGATES OF TOBRAMYCIN LINKED TO A LYSINE-BASED PEPTOID MIMIC VIA A TETHER
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Amphiphilic conjugates of tobramycin linked to a lysine-based peptoid mimic via a tether are disclosed. Said lysine-based peptoid mimics comprise a positively-charged L-lysine, a hydrophobic aromatic core and an alkylene tether assembled through a tertiary amide linkage. Optimization of the resulting conjugate is provided using a C12 alkylene tether. These conjugates have utility as antibacterial agents, in particular when used in conjunction with another antibacterial agent (such as rifampicin or minocycline), where the combination results in a synergistic activity against drug-resistant bacteria (in particular extensively drug-resistant P. aeruginosa). As a result, these conjugates provide for effective antibiotic adjuvants that help overcome resistance of Gram-negative bacteria to antibiotics.
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Page/Page column 24
(2018/11/22)
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- Synthesis and bioactivities study of new antibacterial peptide mimics: The dialkyl cationic amphiphiles
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The emergence of infectious diseases caused by pathogenic bacteria is widespread. Therefore, it is urgently required to enhance the development of novel antimicrobial agents with high antibacterial activity and low cytotoxicity. A series of novel dialkyl cationic amphiphiles bearing two identical length lipophilic alkyl chains and one non-peptidic amide bond were synthesized and tested for antimicrobial activities against both Gram-positive and Gram-negative bacteria. Particular compounds synthesized showed excellent antibacterial activity toward drug-sensitive bacteria such as S. aureus, E. faecalis, E. coli and S. enterica, and clinical isolates of drug-resistant species such as methicillin-resistant S. aureus (MRSA), KPC-producing and NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE). For example, the MIC values of the best compound 4g ranged from 0.5 to 2 μg/mL against all these strains. Moreover, these small molecules acted rapidly as bactericidal agents, and functioned primarily by permeabilization and depolarization of bacterial membranes. Importantly, these compounds were difficult to induce bacterial resistance and can potentially combat drug-resistant bacteria. Thus, these compounds can be developed into a new class of antibacterial peptide mimics against Gram-positive and Gram-negative bacteria, including drug-resistant bacterial strains.
- Zhang, En,Bai, Peng-Yan,Cui, De-Yun,Chu, Wen-Chao,Hua, Yong-Gang,Liu, Qin,Yin, Hai-Yang,Zhang, Yong-Jie,Qin, Shangshang,Liu, Hong-Min
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p. 1489 - 1509
(2017/11/13)
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- Amphiphilic Tobramycin-Lysine Conjugates Sensitize Multidrug Resistant Gram-Negative Bacteria to Rifampicin and Minocycline
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Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics. Combination studies indicate the ability of these conjugates to synergize rifampicin and minocycline against MDR and extensively drug resistant (XDR) P. aeruginosa isolates and enhance efficacy of both antibiotics in the Galleria mellonella larvae in vivo infection model. Mode of action studies indicate that the amphiphilic tobramycin-lysine adjuvants enhance outer membrane cell penetration and affect the proton motive force, which energizes efflux pumps. Overall, this study provides a strategy for generating effective antibiotic adjuvants that overcome resistance of rifampicin and minocycline in MDR and XDR Gram-negative bacteria including P. aeruginosa.
- Lyu, Yinfeng,Yang, Xuan,Goswami, Sudeep,Gorityala, Bala Kishan,Idowu, Temilolu,Domalaon, Ronald,Zhanel, George G.,Shan, Anshan,Schweizer, Frank
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supporting information
p. 3684 - 3702
(2017/05/19)
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- NOVEL DRUG DELIVERY CONJUGATED MOIETY FOR ORAL ADMINISTRATION OF DRUG UNSUITABLE FOR ORAL ADMINISTRATION AND PREPARATION METHOD THEREOF
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The present invention provides a novel drug delivery conjugated moiety for oral administration of a drug that is not suitable for oral administration or a pharmaceutically acceptable salt thereof. When the drug delivery conjugated moiety of the present invention or a pharmaceutically acceptable salt thereof is combined with a drug, which is not suitable for oral administration, and is administered orally, it exhibits an excellent absorption rate without decreasing the biological activities of the drug. Moreover, the drug delivery conjugated moiety of the present invention or a pharmaceutically acceptable salt thereof can be easily prepared in a few steps, which is very advantageous in terms of mass production.
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Paragraph 74; 75
(2017/02/09)
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- Dialkyl cationic amphiphilic antibacterial peptide analogue with antibacterial activity and preparation method thereof
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The invention belongs to the field of medicinal chemistry, and discloses a dialkyl cationic amphiphilic antibacterial peptide analogue with antibacterial activity and a synthesis method thereof. Through four-step reaction, a target product can be simply and fast obtained. A major structure is shown as the accompanying drawing. In-vitro antibacterial activity experiments prove that the most compounds in the series show good antibacterial effects on staphylococcus aureus and escherichia coli; partial compounds show excellent antibacterial activity on super bacteria including MRSA (methicillin-resistance staphylococcus aureus), VRE (vancomycin-resistant enterococcus) and CRE (carbapenemase enterobacteriaceae). In-vitro red cell toxicity experiments also show the series of compounds have low red cell toxicity, so that the series of compounds are hopeful to be used as novel antibacterial candidate medicine. The formulas are shown in the description.
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Paragraph 0065; 0066
(2017/09/01)
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- The anti-microbial activity of cationic amphiphilic compound linezolid alkali and its preparation method (by machine translation)
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The invention belongs to the field of pharmaceutical chemistry, has disclosed the use of antibacterial activity of linezolid alkali cation amphiphilic compound and its synthesis method. The invention through two steps or three-step reaction, simple, quickly obtain the three types of the target product, the main structure is shown as follows. In vitro antibacterial activity experiments prove that, the series of part of the compound to the sensitive strain such as Staphylococcus aureus, Enterococcus faecalis, large intestine and Salmonella enterica demonstrate good bacteriostatic effects, some compounds including methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE) and produces the carbon blue mildew alkene enzyme enterobacteriaceae bacterium including (CRE) "super-bacteria" also demonstrate excellent antibacterial activity. In vitro red cell toxicity test also showed that the series compound has a small red blood cell toxicity, therefore, the series of compounds expected to be used as a new antibacterial drug candidate. . (by machine translation)
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Paragraph 0035-0036
(2017/12/27)
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- Enantioselective hydrolysis of amino acid esters by non-chiral copper complexes equipped with bis (β-cyclodextrin)s
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Two non-chiral copper(II) complexes equipped with bis(β-cyclodextrin)s (bisCDs) were explored as hydrolase models for the enantioselective hydrolysis of two pairs of alkyl chain-possessing amino acid ester enantiomers. The two bisCD complexes are pyridine-linked with different CD cavity orientations, denoted as CuL1 (L1?=?2,6-bis(6-mono-amino-β-cyclodextrin-methyl)-pyridine) and CuL2 (L2?=?2,6-bis(3-mono-amino-β-cyclodextrin-methyl)-pyridine). Kinetic studies indicated that the “back-to-back” bisCD complex CuL1 showed higher catalytic efficiency and more pronounced enantioselectivity for all substrates than the “face-to-face” bisCD complex CuL2. Overall preference of L-isomers was observed for both complexes. In the presence of CuL1, the formation of catalyst-substrate Michaelis complexes during the hydrolysis was demonstrated by saturation kinetic study and Electrospray ionization mass spectrometry (ESI–MS) analysis. Enantiomer selectivity (vmaxL/vmaxD) value for N-Boc-N'-Boc-Lysine 4-nitrophenyl esters (Boc-Lys(Boc)-ONp), the longer alkyl-chain analogs, is twice of that for N-Boc-Alanine 4-nitrophenyl esters (Boc-Ala-ONp). The enantioselective hydrolysis of Boc-Lys(Boc)-ONp promoted by CuL1 was confirmed by chiral high-performance liquid chromatography (HPLC) analysis. The participation of CD cavities during enantioselective hydrolysis was investigated through inhibition assay. The enantioselectivity in hydrolyzing different amino acid esters promoted by CuL1 was compared. The mechanism involved in the cooperation of two adjacent CD cavities of bisCD was proposed.
- Xue, Shan-Shan,Zhao, Meng,Lan, Jing-Xing,Ye, Rui-Rong,Li, Yi,Ji, Liang-Nian,Mao, Zong-Wan
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p. 297 - 303
(2016/09/19)
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- PROCESS FOR THE PREPARATION OF LISDEXAMFETAMINE AND RELATED DERIVATIVES
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The present invention is directed to processes for the preparation of lisdexamfetamine and related derivatives, wherein the processes comprise coupling to racemic or enantiomerically enriched amphetamine and wherein the resulting product is advantageously enantiomerically or diastereomerically enriched in the desired stereoisomer.
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Paragraph 0206-0212
(2017/01/19)
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- Chalcone cationic antimicrobial peptide simulant with antimicrobial activity and preparation method thereof
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The invention belongs to the field of medicinal chemistry, and discloses a chalcone cationic antimicrobial peptide simulant with antimicrobial activity and a preparation method thereof. A target product is obtained simply and quickly through four steps of reaction, and the main structure is shown as formula I. An in vitro antimicrobial activity test proves that most of the series of compounds show good antibacterial effects on staphylococcus aureus and escherichia coli, and part of compounds also show excellent antimicrobial activity on superbacteria including methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and carbapenemases enterobacteriaceae (CRE). An in vitro erythrocyte toxicity test also shows that the series of compounds have less erythrocyte toxicity, and therefore, the series of compounds are expected to be used as a novel candidate antimicrobial drug. The formula I is shown in the description.
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Paragraph 0043; 0044; 0045
(2016/10/09)
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- Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; Synthesis of 5F203 hydrogels for local delivery
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Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R2 > 0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.
- Stone, Erica L.,Citossi, Francesca,Singh, Rajinder,Kaur, Balvinder,Gaskell, Margaret,Farmer, Peter B.,Monks, Anne,Hose, Curtis,Stevens, Malcolm F.G.,Leong, Chee-Onn,Stocks, Michael,Kellam, Barrie,Marlow, Maria,Bradshaw, Tracey D.
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supporting information
p. 6891 - 6899
(2015/11/11)
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- Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity
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A series of bis-3-chloropiperidines containing lysine linkers was synthesised as DNA alkylating model compounds by using a bidirectional synthetic strategy. These novel piperidine mustard based agents have been evaluated for their alkylating properties towards nucleic acids and were shown to alkylate and cleave DNA with strong preference for guanine residues. Our studies reveal that the introduction of aromatic groups in the side chain of the lysine linker has an impact on DNA alkylating activity. Analysis by ESI mass spectrometry enabled the verification of the reactive aziridinium ion formation. Overall, the results confirm our recently proposed reaction mechanism of bis-3-chloropiperidines.
- Zuravka, Ivonne,Roesmann, Rolf,Sosic, Alice,G?ttlich, Richard,Gatto, Barbara
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p. 1241 - 1250
(2015/03/04)
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- GSH- and pH-responsive drug delivery system constructed by water-soluble pillar[5]arene and lysine derivative for controllable drug release
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Novel GSH- and pH-responsive supramolecular vesicles constructed by an amphiphilic inclusion complex formed from water-soluble pillar[5]arene and lysine derivative have been successfully developed, which can efficiently encapsulate anticancer drug MTZ and show rapid MTZ-release in a simulated acidic tumor environment with high GSH concentration, and exhibit potent antitumor activity.
- Wu, Xuan,Li, Yan,Lin, Chen,Hu, Xiao-Yu,Wang, Leyong
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supporting information
p. 6832 - 6835
(2015/04/22)
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- One-pot orthogonal copper-catalyzed synthesis and self-assembly of l-lysine-decorated polymeric dendrimers
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Synthetic peptides, including cyclic peptides and peptidomimetics, provide stability, protection, and long circulation times compared to free-circulating peptides. Dendritic structures with amino acids or peptides attached to the peripheral layer represent one form of peptidomimetics (i.e., a hybrid peptide/dendrimer construct) that has found use in biological applications. Constructing such dendritic structures from linear polymeric building blocks provides a further advantage of generating a highly ordered and defined structure in the nanoparticle size range. However, the rapid synthesis of such well-defined structures is still a challenge. In this work, we demonstrate that through modulating the copper activity concomitantly of the nitroxide radical coupling (NRC) and the azide-alkyne cycloaddition (CuAAC) reactions, polymeric dendrimers decorated with l-lysine on the periphery could be made rapidly in one pot at 25 °C. Three polymeric dendrimers were constructed with high purity (>94%) and with varying l-lysine density coated on the peripheral generation layer. The self-assembly of these dendrimers in water gave similar sizes to that found in organic solvents, suggesting that the aggregation number of dendritic structures in water was very low and possibly consisting of unimolecular micelles. The findings support the conclusion that the self-assembly of a dendritic architecture in water produces nanoparticles with predictable and well-controlled sizes. This synthetic methodology and the self-assembly properties represent an important step toward synthesizing peptide-decorated dendrimers targeted toward therapeutic applications.
- Lu, Derong,Hossain, Md. D.,Jia, Zhongfan,Monteiro, Michael J.
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p. 1688 - 1702
(2015/03/31)
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- LYSINE OLIGOMER DERIVATIVE AND CARTILAGE TISSUE MARKER MADE THEREOF
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There is provided a lysine oligomer derivative, wherein an ε-amino group and a carboxyl group of lysines are linked via a peptide bond, and a group capable of generating or absorbing electromagnetic wave is bonded to a C-terminal carboxyl group, an N-terminal amino group and/or an α-amino group. This lysine oligomer derivative has the characteristic of specifically accumulating in the cartilage matrix and can generate or absorb an electromagnetic wave, and is, therefore, useful as a cartilage tissue marker.
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Paragraph 0043; 0044
(2015/03/28)
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- PH-SENSITIVE IMAGING AGENTS
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Composition and method for surface-functionalized SPION-based agents. Such agents can provide highly pH-sensitive MRI contrast in tissue.
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Paragraph 0321; 0322
(2014/05/20)
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- Small molecular antibacterial peptoid mimics: The simpler the better!
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The emergence of multidrug resistant bacteria compounded by the depleting arsenal of antibiotics has accelerated efforts toward development of antibiotics with novel mechanisms of action. In this report, we present a series of small molecular antibacterial peptoid mimics which exhibit high in vitro potency against a variety of Gram-positive and Gram-negative bacteria, including drug-resistant species such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. The highlight of these compounds is their superior activity against the major nosocomial pathogen Pseudomonas aeruginosa. Nontoxic toward mammalian cells, these rapidly bactericidal compounds primarily act by permeabilization and depolarization of bacterial membrane. Synthetically simple and selectively antibacterial, these compounds can be developed into a newer class of therapeutic agents against multidrug resistant bacterial species.
- Ghosh, Chandradhish,Manjunath, Goutham B.,Akkapeddi, Padma,Yarlagadda, Venkateswarlu,Hoque, Jiaul,Uppu, Divakara S.S.M.,Konai, Mohini M.,Haldar, Jayanta
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p. 1428 - 1436
(2014/03/21)
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- ANTIMICROBIAL COMPOUNDS, THEIR SYNTHESIS AND APPLICATIONS THEREOF
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The present disclosure relates to the field of medicinal chemistry and more particularly to the development of antimicrobial compounds. The disclosure relates to the synthesis and characterization of compounds comprising aromatic radical or an aliphatic radical, an alkyl amine and amino acid moiety wherein said compounds exhibit antimicrobial activity against various drug-sensitive and drug-resistant pathogenic 10 microorganisms.
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Page/Page column 49
(2014/07/08)
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- Efficacious anticancer drug delivery mediated by a pH-sensitive self-assembly of a conserved tripeptide derived from tyrosine kinase NGF receptor
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We present herein a short tripeptide sequence (Lys-Phe-Gly or KFG) that is situated in the juxtamembrane region of the tyrosine kinase nerve growth factor (Trk NGF) receptors. KFG self-assembles in water and shows a reversible and concentration-dependent switching of nanostructures from nanospheres (vesicles) to nanotubes, as evidenced by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The morphology change was associated with a transition in the secondary structure. The tripeptide vesicles have inner aqueous compartments and are stable at pH 7.4 but rupture rapidly at pH≈6. The pH-sensitive response of the vesicles was exploited for the delivery of a chemotherapeutic anticancer drug, doxorubicin, which resulted in enhanced cytotoxicity for both drug-sensitive and drug-resistant cells. Efficient intracellular release of the drug was confirmed by fluorescence-activated cell sorting analysis, fluorescence microscopy, and confocal microscopy. Package for special delivery: A biologically active tripeptide self-assembles to produce nanovesicles at lower concentrations and nanotubes at higher concentrations (see scheme). The nanovesicles rupture at pH≈6 and are highly efficient in doxorubicin delivery to both drug-sensitive and drug-resistant cancer cells. This system is highly promising as a stimulus-responsive biocompatible nanovehicle. Copyright
- Moitra, Parikshit,Kumar, Krishan,Kondaiah, Paturu,Bhattacharya, Santanu
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supporting information
p. 1113 - 1117
(2014/03/21)
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- PROCESS FOR PREPARATION OF LISDEXAMPHETAMINE AND SALTS THEREOF
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An improved, efficient, safe and convenient process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts by using novel mixed anhydride intermediate is provided. A process for preparation of diamino protected amide compound namely BOC protected lisdexamphetamine, a key intermediate in the preparation of lisdexamphetamine and its pharmaceutically acceptable salts by using novel mixed anhydride intermediate and its purification by crystallization are also provided. Further, novel mixed anhydride intermediate is provided too.
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Page/Page column 15-16
(2013/03/26)
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- Identification and characterization of a periplasmic aminoacyl- phosphatidylglycerol hydrolase responsible for Pseudomonas aeruginosa lipid homeostasis
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Background: Continuous adaptation of the bacterial membrane is required in response to changing environmental conditions. Results: Pseudomonas aeruginosa ORF PA0919 codes for an alanyl-phosphatidylglycerol hydrolase that is anchored to the periplasmic surface of the inner membrane. Conclusion: The elucidated enzymatic activity implies a new regulatory circuit for the fine tuning of cellular alanyl-phosphatidylglycerol concentrations. Significance: Lipid homeostasis is crucial for understanding antimicrobial susceptibility. Specific aminoacylation of the phospholipid phosphatidylglycerol (PG) with alanine (or with lysine) was shown to render various organisms less susceptible to antimicrobial agents and environmental stresses. In this study, we make use of the opportunistic pathogen Pseudomonas aeruginosa to decode ORF PA0919-dependent lipid homeostasis. Analysis of the polar lipid content of the deletion mutant ΔPA0919 indicated significantly enlarged levels of alanyl-PG. The resulting phenotype manifested an increased susceptibility to several antimicrobial compounds when compared with the wild type. A pH-dependent PA0919 promoter located within the upstream gene PA0920 was identified. Localization experiments demonstrated that the PA0919 protein is anchored to the periplasmic surface of the inner bacterial membrane. The recombinant overproduction of wild type and several site-directed mutant proteins in the periplasm of Escherichia coli facilitated a detailed in vitro analysis of the enzymatic PA0919 function. A series of artificial substrates (p-nitrophenyl esters of various amino acids/aliphatic acids) indicated enzymatic hydrolysis of the alanine, glycine, or lysine moiety of the respective ester substrates. Our final in vitro activity assay in the presence of radioactively labeled alanyl-PG then revealed hydrolysis of the aminoacyl linkage, resulting in the formation of alanine and PG. Consequently, PA0919 was termed alanyl-PG hydrolase. The elucidated enzymatic activity implies a new regulatory circuit for the appropriate tuning of cellular alanyl-PG concentrations.
- Arendt, Wiebke,Groenewold, Maike K.,Hebecker, Stefanie,Dickschat, Jeroen S.,Moser, Juergen
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p. 24717 - 24730
(2013/09/23)
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- Facile and universal immobilization of l-lysine inspired by mussels
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A novel functional molecule lysine-dopamine (LDA) was successfully synthesized and explored as a universal modifier for different types of surfaces, inspired by mussel adhesive moiety dopamine and bio-functional moiety l-lysine. The universal, robust, and efficient surface modification based on LDA was achieved through a facile and cost-effective dip-coating process, confirmed by Fourier transform infrared spectroscopy (FTIR), contact angle, X-ray photoelectron spectroscopy (XPS) and scanning electron microscope-energy dispersive spectroscopy (SEM-EDS) measurements. Meanwhile, LDA modification improved cell adhesion, promoted cell growth, and accelerated endothelialization on the substrate surface and provided plasma clot lysis activity. The results indicated that the surface biocompatibility was obviously improved by the one-step modification method for the immobilized l-lysine.
- Sun, Peiyu,Lu, Haoxiang,Yao, Xiong,Tu, Xiaoxiong,Zheng, Zhen,Wang, Xinling
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experimental part
p. 10035 - 10041
(2012/07/28)
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- ISOCYANATE MANUFACTURE
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The present invention encompasses the finding that improvements can be achieved in manufacture of isocyanates through the use of a substitute for or a precursor of phosgene. Methods and compositions utilized in accordance with the present invention can be useful in situations in which it is difficult to use phosgene, and in particular gaseous phosgene. In some embodiments, a substitute for or a precursor of phosgene used in accordance with the present invention for preparing isocyanates is or comprises diphosgene (ClCO2CCl3).
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Page/Page column 17-18
(2012/08/27)
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- Synthesis and cytotoxic activity of methyl glycyrrhetinate esterified with amino acids
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Methyl glycyrrhetinate was esterified at position C3 of ring A using different amino acids. A short, unbranched chain of four carbon atoms with two amino groups in positions 2 and 4 was shown to be the most active compound of this series (IC50 = 0:8 M on liposarcoma Lipo cells). These compounds trigger apoptosis as shown by an acridine orange/ethidium bromide assay, trypan blue tests and DNAladdering experiments.
- Csuk, Rene,Schwarz, Stefan,Siewert, Bianka,Kluge, Ralph,Stroehl, Dieter
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p. 731 - 746
(2012/11/13)
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- Synthesis and characterization of ramose tetralactosyllysyl-chitosan-5- fluorouracil and its in vitro release
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In order to improve drug loading and achieve a good release effect, this paper adopts the ramose method, choosing chitosan as the carrier and 5-fluorouracil (5-Fu) as a model drug. Ramose chitosan-lysyl-5-Fu(3) and ramose tetralactosyllysyl- chitosan-5-Fu(6) were synthesized successfully, then the in vitro release of (6) was researched. The results show that the drug loading of (3) and (6) are 9.17 and 1.63% (w/w), respectively. The in vitro release behavior of (6) in pH 7.4 phosphate buffer solution and pH 1.2 HCl-KCl solution were studied. The zero order release time that (6) maintains in alkaline and acidic media are 64 and 24 h, and the total release by 184 h are 71.97 and 82.34%, respectively. The performance is smooth throughout the whole stage of release, and the concentration of cumulative release is lower in the alkaline environment than in the acidic environment over the same time. Springer Science+Business Media B.V. 2012.
- Li, He-Ping,Qin, Long,Wang, Zhou-Dong,Li, Shan
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p. 1421 - 1429
(2012/11/14)
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- Design, synthesis and primary activity assay of tripeptidomimetics as histone deacetylase inhibitors with linear linker and branched cap group
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A novel series of tripeptidomimetics with spiro ring containing sulfur atoms as cap group and linear carbochain as linker was designed and synthesized as HDACs inhibitors. Several compounds possessed more potent HDAC8 inhibitory activity than clinically used drug SAHA, although their HDAC1 inhibitory activities and anti-proliferative activities against human breast cancer cell lines (MCF-7, MDA-MB-231) and prostate cancer cell line (PC-3) were not satisfactory. Among them, compounds 11l and 11k showed excellent potency against HDAC8 (IC50 values were 0.021 ± 0.004 μM and 0.035 ± 0.007 μM, respectively, whereas SAHA was 0.70 ± 0.12 μM), and good selectivity over HDAC1. Up to now, few hydroxamic acid derivatives with linear linker were reported to possess HDAC8 selectivity over HDAC1.
- Zhang, Yingjie,Feng, Jinhong,Jia, Yuping,Xu, Yingying,Liu, Chunxi,Fang, Hao,Xu, Wenfang
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experimental part
p. 5387 - 5397
(2011/12/14)
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- PROCESS FOR THE SYNTHESIS OF AMPHETAMINE DERIVATIVES
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The invention relates to a process for preparing acylated amphetamine, methamphetamine and dexamphetamine derivatives by reacting the parent amine with the to be coupled acid or a salt of the to be coupled acid which acid is protected or not protected, in the presence of an alkylphosphonic acid anhydride as coupling agent and - provided the acid (V2) was protected - the cleavage of the protecting group(s), in a one-pot reaction or in two or more separate steps.
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Page/Page column 8-10
(2010/04/28)
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- Novel 3-phenylpropane-1,2-diamine derivates as inhibitors of aminopeptidase N (APN)
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Aminopeptidase N (APN) is an essential peptidase involved in the process of tumor invasion and metastasis. Here we describe a novel class of inhibitor with 3-phenylpropane-1,2-diamine as scaffold to APN. Preliminary activity evaluation with enzyme inhibition studies showed that compound 12i exhibited potent and selective inhibitory activity towards APN with the IC50 value 15.5 ± 1.2 μM.
- Shang, Luqing,Wang, Qiang,Fang, Hao,Mu, Jiajia,Wang, Xuejian,Yuan, Yumei,Wang, Binghe,Xu, Wenfang
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scheme or table
p. 9984 - 9990
(2009/04/06)
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- ABUSE-RESISTANT AMPHETAMINE PRODRUGS
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The invention describes compounds, compositions, and methods of using the same comprising a chemical moiety covalently attached to amphetamine. These compounds and compositions are useful for reducing or preventing abuse and overdose of amphetamine. These compounds and compositions find particular use in providing an abuse-resistant alternative treatment for certain disorders, such as attention deficit hyperactivity disorder (ADHD), ADD, narcolepsy, and obesity. Oral bioavailability of amphetamine is maintained at therapeutically useful doses. At higher doses bioavailability is substantially reduced, thereby providing a method of reducing oral abuse liability. Further, compounds and compositions of the invention decrease the bioavailability of amphetamine by parenteral routes, such as intravenous or intranasal administration, further limiting their abuse liability.
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Page/Page column 28-29; 2/70
(2008/06/13)
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- AMINO ACID PRODRUGS
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The present invention is directed to a prodrug comprised of an amino acid bonded to a medicament or drug having a hydroxy, amino, carboxy or acylating derivative thereon. The prodrug has the same utility as the drug from which it is made, but it has enhanced therapeutic properties. In fact, the prodrugs of the present invention enhance at least two therapeutic qualities, as defined herein. The present invention is also directed to pharmaceutical compositions containing same.
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Page/Page column 68; 148
(2008/06/13)
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- Synthesis of a methacrylic monomer containing an L-lysine-based dendron
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Procedures were developed for preparing a polylysine dendron of second generation, containing terminal Boc-protected amino groups and a free focal amino group; from this substance, a previously unknown methacrylic monomer linked to the L-lysine-based dendron was prepared.
- Khimich,Tennikova
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p. 1003 - 1007
(2007/10/03)
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- Novel methods for the delivery of polynucleotides to cells
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Process are described for the delivery of a polynucleotide to a cell. The process comprises forming a salt stable complex between the polynucleotide and a cationic surfactant. Ternary complexes are also made by associating an amphipathic compound with the binary complex. The resultant complexes are suitable for delivery of the polynucleotide to cells in vitro and in vivo.
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- Syntheses of dendritic branches based on L-lysine: is the stereochemistry preserved throughout the synthesis?
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This paper reports the syntheses of individual dendritic branches based on L-lysine and functionalised with either Boc or Bz surface groups. Convergent and divergent synthetic approaches were employed and the preservation of stereochemistry during the syntheses was monitored using polarmetry, NMR and HPLC. In addition, racemic dendritic branches based on D,L-lysine were synthesised for comparative purposes. It was observed that the preservation of stereochemistry in the dendritic peptide was dependent on the method of synthesis, with divergent methodology being preferred. The results are discussed in terms of the known stereochemical outcomes of traditional peptide coupling processes, and are generalised to the synthesis of other dendritic peptides. Such observations about the chirality of dendritic peptides are of relevance to chemists developing dendritic systems for applications where single enantiomer dendrimers would clearly be preferred, such as enantioselective catalysis or pharmaceutical chemistry.
- Driffield, Malcolm,Goodall, David M,Smith, David K
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p. 2612 - 2620
(2007/10/03)
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- Calixarene amino acids; building blocks for calixarene peptides and peptide-dendrimers
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A modular strategy towards receptor macromolecules is presented, which combines synthetically diverse peptide synthesis with highly functional calixarene chemistry. The design and synthesis of calix[4]arene amino acids 1a-f, calix-lysines, is described, which were used as construction blocks to assemble nanoscale, multivalent entities - calix-peptides 2 and calix-peptide-dendrimers 3.
- Hu, Heng,Kinsel, Gary R.,Zhang, Jiang,Li, Meiling,Rudkevich, Dmitry M.
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p. 5837 - 5848
(2007/10/03)
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- 1,3-Diarylprop-2-en-1-ones, compositions containing them and use thereof
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1,3-Diarylprop-2-en-1-ones and derivatives, compositions containing them, manufacturing process and use. Substituted 1,3-diarylprop-2-en-1-ones with therapeutic activity may be used in oncology.
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- High-loading supports for oligonucleotide synthesis
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A simple protocol for the preparation of high-loading supports, suitable for large-scale synthesis of oligonucleotides, has been developed. The method involves the use of inexpensive reagents and is amenable to large-scale preparation of supports. The derivatized supports were successfully employed in an automated DNA synthesizer without any difficulty. The quality of the synthesized oligonucleotides was found to be comparable to that of the corresponding oligomers prepared with commercially available standard supports.
- Patnaik, Anupa K.,Rao, N Subba,Kumar, Pradeep,Sharma, Ashwani K.,Garg, Bhagwan S.,Gupta, Kailash C.
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p. 322 - 327
(2007/10/03)
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- Synthesis and assembly of poly(ethylene glycol) - Lipids with mono-, di-, and tetraacyl chains and a poly(ethylene glycol) chain of various molecular weights
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We synthesized a series of amphiphiles with poly(ethylene glycol) [MW 2000 (PEG20), 5000 (PEG50), 12 500 (PEG125)] as a headgroup and one, two, or four palmitoyl chains (1C16, 2C16, or 4C16), using a lysine monodendron as a connector. The relationship between the hydrophilic - hydrophobic balance of the multiacyl PEG-lipids and the physicochemical characteristics in self- or co-assembly with phospholipids were studied. The PEG-lipids were easily synthesized by combination of a general liquid-phase peptide synthesis and the acylation of an amino acid. The PEG part of the PEG - lipid films was crystallized to show a typical spherulite pattern. The thermal properties and microscopic observation revealed the phase separation of PEG and acyl chain parts. The critical micelle concentrations (cmcs) mainly depend on the number of acyl chains rather than the molecular weight of the PEG chain, although the area per molecule is dependent on the molecular weight of the PEG chain rather than the number of the acyl chains. The gel-to-liquid crystalline phase transition temperature was increased with the increasing number of acyl chains and the decreasing molecular weight of the PEG chain. The PEG - lipids in the aqueous dispersions assemble to take fibrous structures with bimolecular thickness because of the intermolecular hydrogen bonding. The PEG - lipids were immobilized onto the surface of the phospholipid vesicles by simply adding their aqueous dispersions to the vesicle dispersion; however, they dissociated from the vesicles on dilution of the mixed dispersion because they were incorporated into the vesicles in an equilibrium state. To prevent the dissociation of the PEG - lipids, at least two and four acyl chains were required for PEG with MW 5000 and 12 500, respectively. The aggregation of the vesicles by the addition of water-soluble polymers was significantly inhibited with the increasing molecular weight of the PEG chain. For the tight immobilization of the PEG - lipids with the long PEG chain onto the vesicular surface, an increased number of acyl chains is necessary, and the surface modification with the long PEG chains significantly increases the dispersion stability of the vesicles.
- Takeoka, Shinji,Mori, Katsura,Ohkawa, Haruki,Sou, Keitaro,Tsuchida, Eishun
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p. 7927 - 7935
(2007/10/03)
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- SYNTHESIS OF POLY(ETHYLENE GLYCOL) BLOCK COPOLYMERS AS POTENTIAL WATER-SOLUBLE DRUG CARRIERS
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The synthesis of a model water-soluble drug carrier based on poly(ethylene glycol) (PEG) block copolymers is described.In the copolymers, two blocks of PEG are linked by a biodegradable oligopeptide or amino acid linkage containing the glutamic acid residue. 4-Nitroaniline as a drug model is attached to the γ-carboxyl group of glutamic acid of the polymer carrier via an enzymatically degradable oligopeptide spacer.The oligopeptides used were potential substrates for chymotrypsin.The relationship between the structure of oligopeptides linking two PEG blocks and the rate of chymotrypsin-catalyzed polymer chain degradation as well as the relationship between the structure of the spacer and kinetics of drug model release from the carrier after incubation of chymotrypsin solution is discussed in detail.The results showed that by modifying the structure of oligopeptides in the polymer construct, changes in the rates of both polymer degradation and the drug model release can be achieved in a very broad range.
- Pechar, Michal,Strohalm, Jiri,Ulbrich, Karel
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p. 1765 - 1780
(2007/10/03)
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- Novel aminopimelic acids
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A) Compounds selected from the group consisting of a compound of the formula STR1 wherein U is STR2 m and n are individually 1 or 2 of one, the dotted lines is a single double bond optionally of cis or trans configuration, a is selected from the group consisting of hydrogen, methyl and methylene, Y is selected from the group consisting of hydrogen, residue of an amino acid with an α-or ω-carboxyl and a peptide or 2,3 or 4 amino acids with the amine optionally acylated with an optionally unsaturated aliphatic carboxylic acid of 6 to 24 carbon atoms or alkylated with alkyl of 1 to 8 carbon atoms, R is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon, alkenyl and alkynyl of 2 to 8 carbon atoms optionally substituted with at least one halogen with the proviso that if Y is hydrogen, alanine or proline and if a is hydrogen, U contains a double bond; and B) their non-toxic, pharmaceutically acceptable salts with bases or acids, the alkyl esters of 1 to 6 carbon atoms and their primary and secondary amides having remarkable immunomodulatric properties and anti-bacterial activity.
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- Lyotropic Lipo-Amino-Acids: Synthesis and Structural Study
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Lyotropic lipo-amino-acids Cn(AA) where AA is one of the following amino-acids: glycine, alanine, sarcosine, serine, tyrosine, lysine, hydroxyethylglutamine, hydroxypropylglutamine, hydroxypentylglutamine and glutamic acid, and Cn is a paraffinic chain with 12 or 18 carbon atoms have been synthesized.The study by X-ray diffraction of the lipo-amino-acids in concentrated water solution and in the anhydrous state has shown the existence of two types of mesophases: lamellar and hexagonal.The respective influence of the water concentration, the nature of the amino-acid and the length of the paraffinic chain on the domain of stability of the mesophases and on the values of their structural parameters has been established.
- Gallot, B.,Hassan, H. Haj
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p. 195 - 214
(2007/10/02)
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