A Unique Tryptophan C‐Prenyltransferase from the Kawaguchipeptin Biosynthetic Pathway

Cyanobactins are a rapidly growing family of linear and cyclic peptides produced by cyanobacteria. Kawaguchipeptins A and B, two macrocyclic undecapeptides reported earlier from Microcystis aeruginosa NIES‐88, are shown to be products of the cyanobactin biosynthetic pathway. The 9 kb kawaguchipeptin (kgp) gene cluster was identified in a 5.26 Mb draft genome of Microcystis aeruginosa NIES‐88. We verified that this gene cluster is responsible for the production of the kawaguchipeptins through heterologous expression of the kgp gene cluster in Escherichia coli. The KgpF prenyltransferase was overexpressed and was shown to prenylate C‐3 of Trp residues in both linear and cyclic peptides in vitro. Our findings serve to further enhance the structural diversity of cyanobactins to include tryptophan‐prenylated cyclic peptides.     

Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy‐Resistant L858R/T790M/C797S Mutant

The treatment of non‐small‐cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third‐generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine‐mutated L858R/T790M/C797S EGFR.     

Bis‐clickable Mesoporous Silica Nanoparticles: Straightforward Preparation of Light‐Actuated Nanomachines for Controlled Drug Delivery with Active Targeting

Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co‐condensation of TEOS with variable amounts (2–5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on‐demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans‐to‐cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on‐command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin‐loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not.     

Osmotically induced morphological changes of extruded dioctadecyldimethylammonium chloride (DODAC) dispersions

Extruded vesicles, which are often used as models for living cells, can change their morphology when they are diluted into a hyperosmotic medium. Different morphological changes were observed with extruded dioctadecyldimethylammonium chloride (DODAC) vesicles after dilution with a nonionic (sucrose) and ionic (CaCl2) osmotic agent above and below the gel-to-liquid crystalline transition temperature. By means of turbidimetry, dynamic light scattering, and cryo-transmission electron microscopy, it was seen that the vesicles only deflated when they were in the gel state, whereas in the liquid crystalline state, an ionic osmotic agent could induce twinning of the vesicles, reminiscent to endocytosis. The latter could occur as a result of the combined effects of reduced repulsion, local dehydration, and reduced bending rigidity induced by the ionic agent.     

On the keto-enol tautomerization of malonaldehyde: an effective fragment potential study

Recent studies have mapped the keto-enol tautomerization of malonaldehyde through a general transition structure that leads exclusively to the Z isomer of the enol. However, it will be shown that a competing general transition structure exists that leads to both the E and Z isomers of the enol at the B3LYP/6-31G(d,p) and MP2/6-31G(d,p) levels of theory. Both the RHF- and DFT-based effective fragment potential methods have been used to model solvation effects, and the results are compared with full ab initio calculations. It is found that two bridging water molecules with two discrete DFT-based effective fragment potential solvent waters at the MP2/6-31G(d,p) level of ab initio theory provides the most computationally effective model for solvent effects in this system. It is shown that the relative energies for this QM/MM model differ from the full MP2/6-31G(d,p) energies by an average absolute relative difference of 2.2 kcal mol-1 across the reaction path when the zero-point vibrational energy correction is included.     

Antiprotozoal Activities of Epimeric Aminobicycles

Summary. We synthesized several 4-aminobicyclo[2.2.2] octan-2-ols and 4-amino-2-azabicyclo[3.2.2]nonanes from epimerized 4-amino-bicyclo[2.2.2]octan-2-ones. The new compounds were tested for their activity against Trypanosoma b. rhodesiense, the causative organism of East African sleeping sickness, and Plasmodium falciparum K ₁, a multiresistant protozoan parasite which causes Malaria tropica. The results are compared to the activities of their formerly synthesized stereoisomers and structure–activity relationships are discussed.     

Di‐ and tri‐organotin derivatives of 3S,4S‐3‐[(R)‐1‐(tert‐butyl‐dimethylsilyloxy)ethyl]‐4‐[(R)‐1‐carboxyethyl]‐2‐azetidinone: synthesis,characterization and in vitro antitumour activity

Di‐n‐butyl‐, triphenyl and tri‐n‐butyltin derivatives of 3 S, 4 S ‐3‐[( R )‐1‐(tert‐butyldimethyl‐­<?tw=103.5%>silyloxy)ethyl‐4‐[( R )‐1‐carboxyethyl]‐2‐azetidi<?tw>‐­none were synthesized and characterized. Their antitumour activity was screened against seven tumoural cell lines of human origin. Copyright © 1999 John Wiley & Sons, Ltd.     

Multiple rate-determining steps for nonideal and fractal kinetics

We show that the kinetic model of a single rate-determining step in a reaction mechanism can be extended to systems with multiple overall reactions for which the elementary reactions obey nonideal or fractal kinetics. The following assumptions are necessary: (1) The system studied is either closed or open, but no constraints exist preventing the evolution toward equilibrium. (2) Elementary reactions occur in pairs of forward and backward steps. (3) The kinetics of the elementary steps are either nonideal or fractal and are compatible with equilibrium thermodynamics. (4) The number of reaction routes is identical with the number of rate-determining steps. If these hypotheses are valid, then the overall reaction rates can be explicitly evaluated: they have a form similar to the kinetic equations for the elementary reactions and the apparent reaction orders and fractal coefficients can be expressed analytically in terms of the kinetic parameters of the elementary reactions. We derive a set of relationships which connect the equilibrium constants of the reaction routes, the corresponding overall rate coefficients, and the stoichiometric numbers of the rate-determining steps. We also derive a set of generalized Boreskov relations among the apparent activation energies of the forward and backward overall processes, the corresponding reaction enthalpies, and the stoichiometric coefficients of the rate-determining steps. If the elementary reactions obey fractal kinetics, the same is true for the rate-determining steps. The fractal exponents of the forward and backward overall reactions are linear combinations of the fractal exponents of the fractal elementary reactions. Similar to the theory of single rate-determining steps, our approach can be used for selecting suitable reaction mechanisms from experimental data.