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Improved Activity (improved + activity)
Selected AbstractsSynthesis and In-Vitro Cytotoxicity Evaluation of Novel Naphtindolizinedione Derivatives, Part II: Improved Activity for Aza-AnaloguesARCHIV DER PHARMAZIE, Issue 2 2009Andrea Defant Abstract Our previous investigation on potential antitumor agents now got enriched by the evaluation of in-vitro activity against a full panel of NCI cancer cell lines for five new compounds. The concurrent presence in the molecular structure of a nitrogen atom in the aromatic system and a N,N -dimethylaminoethyl amide chain play a decisive role to enhance cytotoxicity. The N,N -anti compound 14 shows a higher activity than its N,N -syn isomer, exhibiting the best selective inhibition against the melanoma MALME-3M cell line, with a GI50 -value (= 30 nM) corresponding to a 330-fold increase in activity compared to the corresponding deaza-analogue. Compound 14 is efficiently synthesized by aminolysis of the ester obtained as a single regio-isomer by an one-pot three-component procedure involving metal-assisted cyclization under microwave irradiation conditions. [source] Replacement of Natural Cofactors by Selected Hydrogen Peroxide Donors or Organic Peroxides Results in Improved Activity for CYP3A4 and CYP2D6CHEMBIOCHEM, Issue 6 2006Amandine Chefson P450 enzymes made easier to use in synthesis. The use of cumene hydroperoxide with CYP2D6 or CYP3A4 leads to as much as a twofold increase in the rate of product formation compared to the use of the natural cofactors. [source] Design of a pH-sensitive pore-forming peptide with improved performanceCHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2004D.H. Haas Abstract:, GALA is a 30 residue synthetic peptide designed to interact with membranes in a pH-sensitive manner, with potential applications for intracellular drug and gene delivery. Upon reduction of the pH from neutral to acidic, GALA switches from random coil to , -helix, inserts into lipid bilayers, and forms oligomeric pores of defined size. Its simple sequence and well-characterized behavior make the peptide an excellent starting point to explore the effects of sequence on structure, pH sensitivity, and membrane affinity. We describe synthesis and characterization of two derivatives of GALA, termed GALAdel3E and YALA. GALAdel3E has a deletion of three centrally located glutamate residues from GALA, while YALA replaces one glutamate residue with the unusual amino acid 3,5-diiodotyrosine. Both derived peptides retain pH sensitivity, showing no ability to cause leakage of an encapsulated dye from unilamellar vesicles at pH 7.4 but substantial activity at pH 5. Unlike GALA, neither peptide undergoes a conformational change upon reduction of the pH, remaining , -helical throughout. Interestingly, the pH at which the peptides activate is shifted, with GALA becoming active at pH ,5.7, GALAdel3E at pH ,6.2, and YALA at pH ,6.7. Furthermore, the peptides GALAdel3E and YALA show improved activity compared with GALA for cholesterol-containing membranes, with YALA retaining the greatest activity. Improved activity in the presence of cholesterol and onset of activity in the critical range between pH 6 and 7 may make these peptides useful in applications requiring intracellular delivery of macromolecules, such as gene delivery or anti-cancer treatments. [source] Screening of a Modular Sugar-Based Phosphite,Oxazoline Ligand Library in Asymmetric Pd-Catalyzed Heck ReactionsCHEMISTRY - A EUROPEAN JOURNAL, Issue 12 2007Yvette Mata Abstract We have synthesised a library of phosphite,oxazoline ligands derived from readily available D -glucosamine. These ligands have been successfully screened in the palladium-catalysed Heck reaction of several substrates with high regio- (up to 99,%) and enantioselectivities (ee's up to 99,%) as well as with improved activities under standard thermal conditions. The results indicate that the catalytic performance is highly affected by the oxazoline and biarylphosphite substituents and the axial chirality of the biaryl moiety of the ligand. The Heck reactions were also performed under microwave irradiation conditions, allowing a considerably shorter reaction time (full conversion in minutes) maintaining the excellent regio- and enantioselectivities. [source] Synthesis and Antibacterial Activity of Novel 4,- O -Carbamoyl Erythromycin-A DerivativesARCHIV DER PHARMAZIE, Issue 8 2010Yunkun Qi Abstract Novel 4,- O -carbamoyl erythromycin-A derivatives were designed, synthesized, and evaluated for their in-vitro antibacterial activities. All of the 4,- O -carbamoyl derivatives showed excellent activity against erythromycin-susceptible Staphylococcus aureus ATCC25923, Streptococcus pyogenes, and Streptococcus pneumoniae ATCC49619. Most of the 4,- O -arylalkylcarbamoyl derivatives displayed potent activity against erythromycin-resistant S. pneumoniae encoded by the mef gene and greatly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene or the erm and mef genes. In particular, the 4,- O -arylalkyl derivatives 4c,4e and 4g were found to possess the most potent activity against all the tested erythromycin-susceptible strains, which were comparable to those of erythromycin, clarithromycin, or azithromycin. 4,- O -Arylalkyl derivatives 4e and 4g were the most effective against erythromycin-resistant S. pneumoniae encoded by the mef gene (0.25 and 0.25,µg/mL). 4,- O -Arylalkyl derivatives 4a and 4b exhibited significantly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene. In contrast, the 4,- O -alkylcarbamoyl derivatives hardly showed improved activity against all the tested erythromycin-resistant strains. [source] Atomic resolution studies of haloalkane dehalogenases DhaA04, DhaA14 and DhaA15 with engineered access tunnelsACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2010A. Stsiapanava The haloalkane dehalogenase DhaA from Rhodococcus rhodochrous NCIMB 13064 is a bacterial enzyme that shows catalytic activity for the hydrolytic degradation of the highly toxic industrial pollutant 1,2,3-trichloropropane (TCP). Mutagenesis focused on the access tunnels of DhaA produced protein variants with significantly improved activity towards TCP. Three mutants of DhaA named DhaA04 (C176Y), DhaA14 (I135F) and DhaA15 (C176Y + I135F) were constructed in order to study the functional relevance of the tunnels connecting the buried active site of the protein with the surrounding solvent. All three protein variants were crystallized using the sitting-drop vapour-diffusion technique. The crystals of DhaA04 belonged to the orthorhombic space group P212121, while the crystals of DhaA14 and DhaA15 had triclinic symmetry in space group P1. The crystal structures of DhaA04, DhaA14 and DhaA15 with ligands present in the active site were solved and refined using diffraction data to 1.23, 0.95 and 1.22,Å, resolution, respectively. Structural comparisons of the wild type and the three mutants suggest that the tunnels play a key role in the processes of ligand exchange between the buried active site and the surrounding solvent. [source] Probing active-site residues of pyranose 2-oxidase from Trametes multicolor by semi-rational protein designBIOTECHNOLOGY JOURNAL, Issue 4 2009Clara Salaheddin Abstract D -Tagatose is a sweetener with low caloric and non-glycemic characteristics. It can be produced by an enzymatic oxidation of D -galactose specifically at C2 followed by chemical hydrogenation. Pyranose 2-oxidase (P2Ox) from Trametes multicolor catalyzes the oxidation of many aldopyranoses to their corresponding 2-keto derivatives. Since D -galactose is not the preferred substrate of P2Ox, semi-rational design was employed to improve the catalytic efficiency with this poor substrate. Saturation mutagenesis was applied on all positions in the active site of the enzyme, resulting in a library of mutants, which were screened for improved activity in a 96-well microtiter plate format. Mutants with higher activity than wild-type P2Ox were chosen for further kinetic investigations. Variant V546C was found to show a 2.5-fold increase of kcat with both D -glucose and D -galactose when oxygen was used as electron acceptor. Because of weak substrate binding, however, kcat/KM is lower for both sugar substrates compared to wild-type TmP2Ox. Furthermore, variants at position T169, i.e., T169S and T169N, showed an improvement of the catalytic characteristics of P2Ox with D -galactose. Batch conversion experiments of D -galactose to 2-keto- D -galactose were performed with wild-type TmP2O as well as with variants T169S, T169N, V546C and V546C/T169N to corroborate the kinetic properties determined by Michaelis-Menten kinetics. [source] | |||||||||||||