Potent platelet-derived growth factor-beta receptor (PDGF-betaR) inhibitors: Synthesis and structure-activity relationships of 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one derivatives

We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC50 = 0.05 micromol/l in CPA, 0.03 micromol/l in APA). Therefore, we tried to develop a novel and effective PDGF-betaR inhibitor by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with manganese(IV) oxide (MnO2) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC50 = 0.014 micromol/l in CPA, 0.007 micromol/l in APA) and selective [IC50 values against vascular endothelial growth factor receptor 2 (VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth factor receptor) and insulin growth factor I receptor (IGF-IR)/IC50 against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC50 = 0.004 micromol/l in CPA, 0.0008 micromol/l in APA, KDR: IC50 = 0.008 micromol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.     

Controlling 3(10)-helix and alpha-helix of short peptides in the solid state

L-Leu hexapeptide containing alpha-aminoisobutyric acid (Aib) forms a right-handed (P) 3(10)-helix, whereas that containing cyclic alpha,alpha-disubstituted amino acid Ac(5)c(dOM) assumes a right-handed (P) alpha-helix in the solid state.     

Direct measurement of fluid force on a particle in liquid by telemetry system

For real-time measurement of the fluid force acting on a particle which moves freely in liquid, we have made a “sensor particle” with a built-in wireless sensor. The sensor particle contains a 3-axis acceleration sensor, 3-axis magnetometer, microcomputer, wireless module and cells. The MEMS acceleration sensor detects the gravitational acceleration in addition to the dynamic acceleration of particle. In order to remove the gravity from acceleration signals, we applied the external magnetic field which is oriented in the same direction as the gravity field. The 3-axis magnetometer detects the direction of external magnetic field and consequently we can remove gravitational acceleration from the sensor signals with arbitrary attitude of particle. A preliminary experiment was performed for checking the accuracy of the measurement system. Firstly we measured the force acting on a settling particle toward a solid wall in liquid. The obtained signals of acceleration (force divided by mass) agrees well with the theoretical prediction of particle motion in liquid for each instant of time. The sensor particle also detects the lubrication force which is exerted on particle for a very short time when it comes close to the wall. Moreover, we applied our system to the gravitational settling of the particle assemblage and detected the fluid force acting on a particle in multi-particle system.     

Temperature dependent absorption spectra of Br(-), Br2(•-), and Br3(-) in aqueous solutions

The absorption spectra of Br(2)(?-) and Br(3)(-) in aqueous solutions are investigated by pulse radiolysis techniques from room temperature to 380 and 350 °C, respectively. Br(2)(?-) can be observed even in supercritical conditions, showing that this species could be used as a probe in pulse radiolysis at high temperature and even under supercritical conditions. The weak temperature effect on the absorption spectra of Br(2)(?-) and Br(3)(-) is because, in these two systems, the transition occurs between two valence states; for example, for Br(2)(-) we have (2)Σ(u) → (2)Σ(g) transition. These valence transitions involve no diffuse final state. However, the absorption band of Br(-) undergoes an important red shift to longer wavelengths. We performed classical dynamics of hydrated Br(-) system at 20 and 300 °C under pressure of 25 MPa. The radial distribution functions (rdf's) show that the strong temperature increase (from 20 to 300 °C) does not change the radius of the solvent first shell. On the other hand, it shifts dramatically (by 1 ?) the second maximum of the Br-O rdf and introduces much disorder. This shows that the first water shell is strongly bound to the anion whatever the temperature. The first two water shells form a cavity of a roughly spherical shape around the anion. By TDDFT method, we calculated the absorption spectra of hydrated Br(-) at two temperatures and we compared the results with the experimental data.     

Time-dependent radiolytic yield of OH• radical studied by picosecond pulse radiolysis

Picosecond pulse radiolysis measurements using a pulse-probe method are performed to measure directly the time-dependent radiolytic yield of the OH(?) radical in pure water. The time-dependent absorbance of OH(?) radical at 263 nm is deduced from the observed signal by subtracting the contribution of the hydrated electron and that of the irradiated empty fused silica cell which presents also a transient absoption. The time-dependent radiolytic yield of OH(?) is obtained by assuming the yield of the hydrated electron at 20 ps equal to 4.2 × 10(-7) mol J(-1) and by assuming the values of the extinction coefficients of e(aq)(-) and OH(?) at 782 nm (ε(λ=782 nm) = 17025 M(-1) cm(-1)) and at 263 nm (ε(λ=263 nm) = 460 M(-1) cm(-1)), respectively. The value of the yield of OH(?) radical at 10 ps is found to be (4.80 ± 0.12) × 10(-7) mol J(-1).     

Pin-point chemical modification of RNA with diverse molecules through the functionality transfer reaction and the copper-catalyzed azide-alkyne cycloaddition reaction

The internal modification of RNA has been successfully achieved by the functionality transfer reaction (FTR) and following click chemistry with diverse azide compounds. The benefits of the FTR have been demonstrated by its specificity, rapidity, broad applicability, and procedure simplicity.     

Reeb orbits trapped by Denjoy minimal sets

Let φ be any flow on T ⁿ obtained as the suspension of a smooth diffeomorphism of \({T^{n-1}}\) , and let \({\mathcal {A}}\) be any compact invariant set of φ. We realize \({(\mathcal{A}, \varphi|_{\mathcal{A}})}\) up to reparametrization as an invariant set of the Reeb flow of a contact form on \({\mathbb{R}^{2n+1}}\) equal to the standard contact form outside a compact set and defining the standard contact structure on all of \({\mathbb{R}^{2n+1}}\) . This uses the method from Geiges, Röttgen, and Zehmisch.     

Temperature effect on the surface phase transitions of monolayer films of C12E1 at air/water interface

The temperature-dependent conformational states of a monolayer film of ethylene glycol monododecyl ether (C₁₂E₁) at the air/water interface have been investigated using ellipsometry, surface tension, external reflection–absorption FTIR spectroscopy and two-dimensional infrared (2DIR) correlation analysis. The ellipticity coefficients and the entropy associated with C₁₂E₁ adsorption changed almost discontinuously at certain temperatures, which manifested the interfacial phase transitions. The phase transition and coexistence of two phases were further clarified using 2DIR correlation analysis with temperature perturbation. The asynchronous correlation maps revealed that both bands of asymmetric and symmetric C–H stretching vibration in one-dimensional IR were split into two components, which confirmed the coexistence of two phases at the interface.     

Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of (E)-chalcone

Stabilized short helical heptapeptides containing a combination of an α-aminoisobutyric acid as a helical promoter and l/d-serine derivatives to produce cross-linked units were synthesized. The cyclic peptide R₃,₇R-2, which had d-serine derivatives at its 3rd and 7th positions, formed a stable right-handed (P) α-helix in solution and the crystalline state. Furthermore, its N-terminal free helical peptide catalyzed the enantioselective epoxidation of (E)-chalcone to afford the epoxide in a high yield and moderate enantioselectivity.     

Enantioselective epoxidation of α,β-unsaturated ketones catalyzed by stapled helical l-Leu-based peptides

Stapled helical l-leucine-based heptapeptides were synthesized and used as catalysts for the enantioselective epoxidation of α,β-unsaturated ketones. All N-terminal free stapled peptides were successfully used as chiral catalysts. Among them, the use of H-hS₃,₇hS-10 gave epoxide products with high enantioselectivities of up to 99% ee. Furthermore, the dominant conformations of the N-terminal protected stapled peptides R₃,₇R-10 and hS₃,₇hS-10 were investigated by ¹H NMR, IR, CD spectra, and X-ray crystallographic analysis. The peptide R₃,₇R-10 formed a right-handed (P) α-helix in solution and in the crystalline state, while hS₃,₇hS-10 formed a right-handed (P) 3₁₀-helix in solution.