Two new betaines from the Australian bryozoan Amathia lamourouxi

A chemical investigation of the eastern Australian endemic bryozoan Amathia lamourouxi led to the isolation of two unique betaine molecules, lamouroic acid trifluoroacetate and lamourimidazolinium trifluoroacetate. The structures of these molecules were determined using (+)-HRESIMS, 2D NMR and ECD analyses. The new compounds were screened for antiplasmodial, cytotoxic and antibacterial activity but were inactive at 40 μM. Lamouroic acid trifluoroacetate is structurally related to the ubiquitous marine compound homarine, that has previously been shown to possess feeding deterrent properties, and this suggests that the new compound may also have an ecological role in the bryozoan.     

The Double‐Bond Configuration of Corynanthean Alkaloids and Its Impact on Monoterpenoid Indole Alkaloid Biosynthesis

Experimental evidence is provided for the coherence of the double‐bond geometry and the occurrence of “secondary cyclizations” in the biosynthesis of monoterpenoid indole alkaloids. Biosynthetically, akuammiline, C‐mavacurine, and Strychnos alkaloids are proposed to be derived from the corynanthean alkaloid geissoschizine, a key intermediate in the biosynthetic pathway of these monoterpenoid indole alkaloids. This process occurs by so‐called “secondary cyclizations” from geissoschizine or its derivatives. Although corynanthean alkaloids like geissoschizine incorporate E or Z double bonds located at C19–C20, the alkaloids downstream in the biosynthesis exclusively exhibit the E double bond. This study shows that secondary cyclizations preferentially occur with the E isomer of geissoschizine or its derivatives. This is attributed to the flexibility of the quinolizidine system of the corynanthean alkaloids, which can adopt a cis or trans conformation. For the secondary cyclization to take place, the cis‐quinolizidine conformation is required. Experimental evidence supports the hypothesis that the E double bond of geissoschizine induces the cis conformation, whereas the Z double bond induces the trans conformation, which prohibits secondary cyclization of the Z compounds.     

A Supramolecular Approach toward Bioinspired PAMAM‐Dendronized Fusion Toxins

Nature has provided a highly optimized toolbox in bacterial endotoxins with precise functions dictated by their clear structural division. Inspired by this streamlined design, a supramolecular approach capitalizing on the strong biomolecular (streptavidin (SA))–biotin interactions is reported herein to prepare two multipartite fusion constructs, which involves the generation 2.0 (D2) or generation 3.0 (D3) polyamidoamine‐dendronized transporter proteins (dendronized streptavidin (D3SA) and dendronized human serum albumin (D2HSA)) non‐covalently fused to the C3bot1 enzyme from Clostridium botulinum, a potent and specific Rho‐inhibitor. The fusion constructs, D3SA‐C3 and D2HSA‐C3, represent the first examples of dendronized protein transporters that are fused to the C3 enzyme, and it is successfully demonstrated that the C3 Rho‐inhibitor is delivered into the cytosol of mammalian cells as determined from the characteristic C3‐mediated changes in cell morphology and confocal microscopy. The design circumvents the low uptake of the C3 enzyme by eukaryotic cells and holds great promise for reprogramming the properties of toxin enzymes using a supramolecular approach to broaden their therapeutic applications.

     

Ensemble methods for classification in cheminformatics

We describe the application of ensemble methods to binary classification problems on two pharmaceutical compound data sets. Several variants of single and ensembles models of k-nearest neighbors classifiers, support vector machines (SVMs), and single ridge regression models are compared. All methods exhibit robust classification even when more features are given than observations. On two data sets dealing with specific properties of drug-like substances (cytochrome P450 inhibition and "Frequent Hitters", i.e., unspecific protein inhibition), we achieve classification rates above 90%. We are able to reduce the cross-validated misclassification rate for the Frequent Hitters problem by a factor of 2 compared to previous results obtained for the same data set with different modeling techniques.     

Structural and oxidation-state changes at its nonstandard Ni-Fe site during activation of the NAD-reducing hydrogenase from Ralstonia eutropha detected by X-ray absorption, EPR, and FTIR spectroscopy

Structure and oxidation state of the Ni-Fe cofactor of the NAD-reducing soluble hydrogenase (SH) from Ralstonia eutropha were studied employing X-ray absorption spectroscopy (XAS) at the Ni K-edge, EPR, and FTIR spectroscopy. The SH comprises a nonstandard (CN)Ni-Fe(CN)(3)(CO) site; its hydrogen-cleavage reaction is resistant against inhibition by dioxygen and carbon monoxide. Simulations of the XANES and EXAFS regions of XAS spectra revealed that, in the oxidized SH, the Ni(II) is six-coordinated ((CN)O(3)S(2)); only two of the four conserved cysteines, which bind the Ni in standard Ni-Fe hydrogenases, provide thiol ligands to the Ni. Upon the exceptionally rapid reductive activation of the SH by NADH, an oxygen species is detached from the Ni; hydrogen may subsequently bind to the vacant coordination site. Prolonged reducing conditions cause the two thiols that are remote from the Ni in the native SH to become direct Ni ligands, creating a standardlike Ni(II)(CysS)(4) site, which could be further reduced to form the Ni-C (Ni(III)-H(-)) state. The Ni-C state does not seem to be involved in hydrogen cleavage. Two site-directed mutants (HoxH-I64A, HoxH-L118F) revealed structural changes at their Ni sites and were employed to further dissect the role of the extra CN ligand at the Ni. It is proposed that the predominant coordination by (CN),O ligands stabilizes the Ni(II) oxidation state throughout the catalytic cycle and is a prerequisite for the rapid activation of the SH in the presence of oxygen.     

Single-walled carbon nanotube purification, pelletization, and surfactant-assisted dispersion: a combined TEM and resonant micro-raman spectroscopy study

Resonant Raman spectroscopy and transmission electron microscopy were used to characterize the structural changes of three single-walled carbon nanotube samples processed with purification, pelletization, and surfactant-assisted dispersion. A two-stage purification process selectively removes metallic tubes as well as small-diameter ones, enriching large-diameter semiconducting tubes. Pelletizing reduces the intertube distance but greatly increases the intensity ratio of the D band to the G band. Single-walled nanotube (SWNT) bundle size decreases during ultrasonication dispersion aided by a surfactant. SWNT bundles composed of large-diameter tubes are prone to debundling.     

Investigating the Selectivity of Triacontyl Interphases

What causes the shape selectivity of C ₃₀ phases? This question can be answered by combining NMR and fluorescence spectroscopies with HPLC separations at various temperatures. The selectivities depend on the ratio of trans to gauche conformations of the alkyl chains, whose dynamic behavior was characterized with a two-dimensional solid-state NMR spectrum (shown on the right).