- 2-Aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLCBc
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Phosphatidylcholine preferring phospholipase C (PC-PLC) is an important enzyme that plays a key role in a variety of cellular events and lipid homoeostases. Bacillus cereus phospholipase C (PC-PLCBc) has antigenic similarity with the elusive mammalian PC-PLC, which has not thus far been isolated and purified. Therefore the discovery of inhibitors of PC-PLC Bc is of current interest. Here, we describe the synthesis and biological evaluation of a new type of compounds inhibiting PC-PLCBc. These compounds have been designed by evolution of previously described 2-aminohydroxamic acid PC-PLCBc inhibitors that block the enzyme by coordination of the zinc active site atoms present in PC-PLCBc [Gonzalez-Roura, A.; Navarro, I.; Delgado, A.; Llebaria, A.; Casas, J. Angew. Chem. Int. Ed. 2004, 43, 862]. The new compounds maintain the zinc coordinating groups and possess an extra trimethylammonium function, linked to the hydroxyamide nitrogen by an alkyl chain, which is expected to mimic the trimethylammonium group of the phosphatidylcholine PC-PLCBc substrates. Some of the compounds described inhibit the enzyme with IC 50's in the low micromolar range. Unexpectedly, the most potent inhibitors found are those that possess a trimethylammonium group but have chemically blocked the zinc coordinating functionalities. The results obtained suggest that PC-PLCBc inhibition is not due to the interaction of compounds with the phospholipase catalytic zinc atoms, but rather results from the inhibitor cationic group recognition by the PC-PLCBc amino acids involved in choline lipid binding.
- González-Bulnes, Patricia,González-Roura, Albert,Canals, Daniel,Delgado, Antonio,Casas, Josefina,Llebaria, Amadeu
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supporting information; experimental part
p. 8549 - 8555
(2011/02/25)
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- Synthesis of a library of polycationic lipid core dendrimers and their evaluation in the delivery of an oligonucleotide with hVEGF inhibition
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This article follows on from our previous work in the area of non-viral gene delivery using polycationic dendrimers (PCDs). Herein we report on the synthesis and efficacy of a new library of lipid core PCDs in the delivery of the anti-angiogenic oligonucleotide (ODN-1) to retinal pigment epithelial cells. ELISA was used to monitor hVEGF levels in cells transfected with dendriplexes, Cytofectin GSV and control (non-transfected). At 48 h, hVEGF titres had returned to that of the untransfected control for Cytofectin GSV however, a number of dendriplexes continued to exhibit a marked reduction in hVEGF titres.
- Parekh, Harendra S.,Marano, Robert J.,Rakoczy, Elizabeth P.,Blanchfield, Joanne,Toth, Istvan
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p. 4775 - 4780
(2007/10/03)
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- Syntheses of polycationic dendrimers on lipophilic peptide core for complexation and transport of oligonucleotides
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Synthesis of novel polycationic lipophilic peptide core(s) was accomplished and these agents successfully transfected human retinal pigment epithelium cells with ODN1 upon complexation with the oligonucleotide. The level of transfection was indirectly measured by the decreased production of the protein hVEGF (human vascular endothelial growth factor) in comparison to the transfection agent cytofectin GSV.
- Wimmer, Norbert,Marano, Robert J.,Kearns, Philip S.,Rakoczy, Elizabeth P.,Toth, Istvan
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p. 2635 - 2637
(2007/10/03)
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- Adsorption of Metal Ions to Surface-Template Resins Prepared with Amphiphilic Styrene Monomers Bearing Amino Carboxylic Acid
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Monomer-type functional surfactants, 2-(p-vinylbenzylamino)alkanoic acid (RnAc) and N,N-dialkyl derivatives (RRnNAc), have been used as both a ligand and an emulsifier for the preparation of surface-template resins. The surfactants adsorbed at the toluene-water interface and emulsified divinylbenzene-styrene in a Cu2+ or Zn2+ solution. Emulsion polymerization using a K2S2O8 initiator (80 °C) or by irradiation with γ-rays gave fine particles of 200-800 nm in diameter. Metal-imprinted resins prepared with RnNAc and RRnNAc showed a high adsorptive capacity for the metal ion (surface-template effect). Cu-imprinted resins prepared with R8NAc were 2.69-times as effective for Cu2+ in competitive sorption from a Cu2+-Zn2+ mixture and Zn-imprinted resins were 1.84-times as effective for Zn2+, compared with unimprinted resins. Because of the great emulsifying power, metal-imprinted resins prepared with R8NAc showed the most metal-selective adsorption and the largest capacity among resins prepared with RnNAc and RRnNAc.
- Koide, Yoshifumi,Tsujimoto, Keigo,Shosenji, Hideto,Maeda, Mizuo,Takagi, Makoto
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p. 789 - 796
(2007/10/03)
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- Chemoselective N-deprotection of tert-butyl 2-(trifluoroacetylamino) esters under PTC conditions: Synthesis of tert-butyl 2-aminocarboxylates
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Trifluoroacetamide 1 is alkylated in good yields (77-83%) by tert-butyl 2-bromocarboxylates 3 under solid-liquid phase transfer catalysis (PTC) conditions [anhydrous K2CO3, triethyl(benzyl)ammonium chloride (TEBA; 10%), MeCN, 80°C]. The resulting tert-butyl 2-(trifluoroacetylamino) carboxylates 5 are chemoselectively hydrolysed in 75-95% yields to the corresponding tert-butyl 2-amino carboxylates, isolated as hydrochlorides 8, under liquid-liquid PTC conditions [CH2Cl2 or Et2O, aqueous 20% KOH, TEBA (10%), 25-40°C].
- Albanese, Domenico,Corcella, Francesco,Landini, Dario,Maia, Angelamaria,Penso, Michele
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p. 247 - 249
(2007/10/03)
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- Lipidic Peptides, I Synthesis, Resolution and Structural Elucidation of Lipidic Amino Acids and Their Homo- and Hetero-Oligomers
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The α-amino acids with long alkyl side chains, the so-called lipidic amino acids 1a-e, and their homo-oligomers, the lipidic peptides 1p-aj, represent a class of compounds which combine the structural properties of peptides and proteins with the characteristics of lipids and membranes.The amino acids were synthesised from the appropriate alkyl bromide and diethyl acetamidomalonate.Resolution was made chemically, by forming diastereomers of the amino acid esters with an optically pure α-pinene derivative.The protected homo-oligomers were synthesised in solution with the assistance of a water-soluble carbodiimide coupling agent.In order to modify the physical and chemical properties of the peptides, a series of protected hetero-oligomers were prepared, by similar methods, incorporating either other amino acids (3a-d, 7a-i) or side-chain-substituted lipidic amino acids (6a-d).
- Gibbons, William A.,Hughes, Richard A.,Charalambous, Mario,Christodoulou, Marika,Szeto, Alice,et al.
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p. 1175 - 1183
(2007/10/02)
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- Synthesis and anticandidal properties of polyoxin L analogues containing α-amino fatty acids
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Analogues of polyoxin L containing amino acids with saturated fatty acid like side chains were synthesized from the benzyloxycarbonyl-protected α-amino fatty acid p-nitrophenyl ester and uracil polyoxin C. Transfer hydrogenolysis using palladium black and formic acid gave diastereomeric, dipeptidyl polyoxin L analogues containing α-aminooctanoic acid (3), α-aminododecanoic acid (4), or α-aminohexadecanoic acid (5) as the amine terminal residue in 40-60% yield. Diastereomers of 3 and 5 were resolved by using high-performance liquid chromatography on a reversed-phase column and designated as 3a, 3b and 5a, 5b. Analogues 3-5 were excellent inhibitors of chitin synthetase from Candida albicans; 4, the best inhibitor, had an ID50 of 0.5 μM. The L,L diastereomers of 3 and 5 were 1-2 orders of magnitude more potent chitin synthetase inhibitors than their D,L homologues. None of the synthetic polyoxin L analogues inhibited transport of trimethionine, but 3a, 4, and 5b caused decreases of 71%, 87%, and 83%, respectively, in the initial rate of uptake of dileucine. Compounds 3-5 were significantly more stable to peptidase degradation than polyoxin L analogues containing naturally occurring α-amino acids. Compound 4 inhibited growth of C. albicans in culture at 40-80 μg/mL. All other analogues were less potent antifungals. The results suggest that synthetic polyoxins can be designed to have increased affinity for a peptide transport system and to have increased stability against intracellular degradation in C. albicans.
- Khare,Becker,Naider
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p. 650 - 656
(2007/10/02)
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