Optimization of taxane binding to microtubules: binding affinity dissection and incremental construction of a high-affinity analog of paclitaxel

The microtubule binding affinities of a series of synthetic taxanes have been measured with the aims of dissecting individual group contributions and obtaining a rationale for the design of novel compounds with the ability to overcome drug resistance. As previously observed for epothilones, the positive and negative contributions of the different substituents to the binding free energies are cumulative. By combining the most favorable substitutions we increased the binding affinity of paclitaxel 500-fold. Insight into the structural basis for this improvement was gained with molecular modeling and NMR data obtained for microtubule-bound docetaxel. Taxanes with affinities for microtubules well above their affinities for P-glycoprotein are shown not to be affected by multidrug resistance. This finding strongly indicates that optimization of the ligand-target interaction is a good strategy to overcome multidrug resistance mediated by efflux pumps.     

Deciphering the Non‐Equivalence of Serine and Threonine O‐Glycosylation Points: Implications for Molecular Recognition of the Tn Antigen by an anti‐MUC1 Antibody

The structural features of MUC1‐like glycopeptides bearing the Tn antigen (α‐O‐GalNAc‐Ser/Thr) in complex with an anti MUC‐1 antibody are reported at atomic resolution. For the α‐O‐GalNAc‐Ser derivative, the glycosidic linkage adopts a high‐energy conformation, barely populated in the free state. This unusual structure (also observed in an α‐S‐GalNAc‐Cys mimic) is stabilized by hydrogen bonds between the peptidic fragment and the sugar. The selection of a particular peptide structure by the antibody is thus propagated to the carbohydrate through carbohydrate/peptide contacts, which force a change in the orientation of the sugar moiety. This seems to be unfeasible in the α‐O‐GalNAc‐Thr glycopeptide owing to the more limited flexibility of the side chain imposed by the methyl group. Our data demonstrate the non‐equivalence of Ser and Thr O‐glycosylation points in molecular recognition processes. These features provide insight into the occurrence in nature of the APDTRP epitope for anti‐MUC1 antibodies.     

HCOOH high-resolution spectroscopy in the 9.18 μm region

We report on highly accurate absolute frequency measurement against a femtosecond frequency comb of six saturated absorption lines of formic acid (HCOOH) with an accuracy of 1 kHz. We also report the frequency measurement of 17 other lines with an accuracy of 2 kHz. Those lines are in quasi coincidence with the 9R(36) to 9R(42) CO₂ laser emission lines and are probed either by a CO₂ or a widely tunable quantum cascade laser phase locked to a master CO₂ laser. The stability of HCOOH stabilized lasers is characterized by a fractional Allan deviation of 3.1 × 10⁻¹² τ^−1/2. They give suitable frequency references for Doppler-free two-photon spectroscopy.     

Observation of direct CP violation in B0 --> pi+pi- decays and model-independent constraints on the quark-mixing angle phi2

We report a new measurement of the time-dependent CP-violating parameters in B(0)-->pi(+)pi(-) decays with 535 x 10(6) BB pairs collected with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider operating at the Upsilon(4S) resonance. We find 1464+/-65 B(0)-->pi(+)pi(-) events and measure the CP-violating parameters S(pipi)=-0.61+/-0.10(stat)+/-0.04(syst) and A(pipi)=+0.55+/-0.08(stat)+/-0.05(syst). We observe large direct CP violation with a significance greater than 5 standard deviations for any S(pipi) value. Using isospin relations, we measure the Cabibbo-Kobayashi-Maskawa quark-mixing matrix angle phi(2)=(97+/-11) degrees for the solution consistent with the standard model and exclude the range 11 degrees 相似文献   

Rheological properties of a nematic cell oriented in a planar manner

We propose a simple model to investigate the rheological properties of a nematic cell oriented in a planar manner. The storage and loss modulus are evaluated in the case of strong and weak anchoring conditions. The contribution of the surface viscosity to the rheological parameters is also considered.     

The apparent molar heat capacity of aqueous hydrochloric acid from 10 to 140°C

The apparent molar heat capacity of aqueous HCl, C _p,, has been measured at temperatures of 25, 76, 103, 125 and 140°C and molalities from 0.1 to 1.02 mol-kg^–1 using a Picker flow microcalorimeter. The results were analyzed using the Pitzer and the Helgeson-Kirkham-Flowers models to derive standard state heat capacities. The fitted parameters were also used to extrapolate the standard EMF of the silver-silver chloride reference electrode at steam saturation from 0 to 200°C and the mean ionic activity coefficient, _± (HCl,aq) to 225°C, with an accuracy at the highest temperature of 2 mV and 4%, respectively. The results confirm that experimental values of C _p, to just over 100°C can be used to extrapolate standard state and excess Gibbs energies above 250°C, when the corresponding enthalpies at 25°C are accurately known.     

Modulating Weak Interactions for Molecular Recognition: A Dynamic Combinatorial Analysis for Assessing the Contribution of Electrostatics to the Stability of CH–π Bonds in Water

Electrostatic and charge‐transfer contributions to CH–π complexes can be modulated by attaching electron‐withdrawing substituents to the carbon atom. While clearly stabilizing in the gas phase, the outcome of this chemical modification in water is more difficult to predict. Herein we provide a definitive and quantitative answer to this question employing a simple strategy based on dynamic combinatorial chemistry.     

Influence of conducting polymers based on carboxylated polyaniline on in vitro CaCO3 crystallization

Conducting polymers are interesting materials of technological applications, while the use of polymers as additives controlling crystal nucleation and growth is a fast growing research field. In the present article, we make a first step in combining both topics and report the effect of conducting polymer derivatives, which are based on carboxylated polyanilines (c-PANIs), on in vitro CaCO3 crystallization by the Kitano and gas diffusion method. This is the first example of the mineralization control of CaCO3 by a rigid carboxylated polymer. Both the concentration of c-PANI and the presence of carboxylate groups have a strong influence on the CaCO3 crystallization behavior and crystal morphology. X-ray diffraction (XRD) analysis shows crystalline calcite particles confirmed by FTIR spectra. pH and Ca2+ measurements during CaCO3 crystallization utilizing the Kitano and a constant-pH approach show a defined nucleation period of CaCO3 particles. The measurements allow for the calculation of the supersaturation time development, and the kinetic data can be combined with time-dependent light microscopy. The presence of c-PANIs delays the time of nucleation indicative of calcite nucleation inhibition. Microscopy illustrates the morphologies of CaCO3 crystals at all crystallization stages, from homogeneous spherical amorphous CaCO3 (ACC) particles corresponding to the first steps of crystallization to transition stage calcite crystals also involving a dissolution-recrystallization process in a late stage of crystallization. The data show that it is not possible to conclude the crystallization mechanism even for a very simple additive controlled crystallization process without time-resolved microscopic data supplemented by the analysis of the species present in the solution. Finally, fluorescence analysis indicates that conducting polymer derivatives can be incorporated into precipitated calcite particles. This gives rise to CaCO3 particles with novel and interesting optical properties.