Chemistry and Biology of Cylindrols: Novel Inhibitors of Ras Farnesyl-Protein Transferase from Cylindrocarpon lucidum

Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-transforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our continued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cylindrols A(1) to A(4), cylindrols B and B(1), and a number of known compounds, from Cylindrocarpon lucidum. The compounds were isolated by bioassay-guided separation using Sephadex LH-20, silica gel, and reverse phase HPLC. Structures were elucidated by extensive application of 2D NMR and X-ray crystallography. The determination of absolute stereochemistry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives which were critical for the evaluation of structure activity relationship. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 &mgr;M to >140 &mgr;M) against FPTase. The FPTase activity was noncompetitive with respect to both substrates. Isolation, structures, chemical transformations, and FPTase activity are discussed in detail.     

Artificial metalloenzymes: The powerful alliance between protein scaffolds and organometallic catalysts

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1-AMINO-1-ARYL- AND 1-AMINO-1-HETEROARYL-METHANEPHOSPHONIC ACIDS AND THEIR N-BENZHYDRYL–PROTECTED DIETHYL ESTERS: PREPARATION AND CHARACTERIZATION

n-Benzhydryl-protected diethyl[3.3pc] esters of 1-amino-1-aryl- (phenyl, cumyl, p-dimethylaminophenyl, piperonyl, 1′-naphthyl, 9′-anthryl, 1′-pyrenyl) and 1-amino-1-heteroaryl- (furyl, 2′-thienyl, 3′-thienyl, 2′-pyrrolyl)-methanephosphonic acids, prepared by the addition of diethyl phosphite to the corresponding benzhydryl imines, have been isolated, purified, and characterized. The presence of chiral α -carbon and prochiral phosphorus in these esters gives rise to complicated features in their NMR spectra, which are discussed. Hydrolysis of the crude 1-aryl compounds in situ gave modest yields of the corresponding aminophosphonic acids (except for 1′-pyrenyl). Of the 1-heteroaryl derivatives, only the 2′-thienyl compound gave the expected aminophosphonic acid; in other cases, alternative[-18pc] modes of decomposition may occur under hydrolytic conditions. NMR and mass spectral data are given for all products.     

Calcium Carbonate Dissolution from the Laboratory to the Ocean: Kinetics and Mechanism

The ultimate fate, over the course of millennia, of nearly all of the carbon dioxide formed by humankind is for it to react with calcium carbonate in the world's oceans. Although, this reaction is of global relevance, aspects of the calcite dissolution reaction remain poorly described with apparent contradictions present throughout the expansive literature. In this perspective we aim to evidence how a lack of appreciation of the role of mass-transport may have hampered developments in this area. These insights have important implications for both idealised experiments performed under laboratory conditions and for the measurement and modelling of oceanic calcite sediment dissolution.     

A Brief Review of the Anticancer Activity of α-Aminophosphonic Acid Derivatives and a Report on the in Vitro Activity of Some Dialkyl α-aryl- (or Heteroaryl)-α-(Diphenylmethylamino)Methanephosphonates

Abstract

Reports on the anticancer activity of representative α-aminophosphonic acid derivatives are briefly reviewed, with comments where possible on modes of action. Preliminary in vitro screening results are also presented for selected dialkyl α-aryl (or heteroaryl)-α-(diphenylmethylamino)methanephosphonates against the National Cancer Institute (NCI) 60-cell line panel of human tumor cells, which showed average response parameters for active compounds of GI₅₀ between 4.81 × 10^?6 and 2.40 × 10^?5 M, TGI between 1.88 and 6.28 × 10^?5 M, and LC₅₀ between 5.71 and 9.37 × 10^?5 M. The highest activity was shown by the α-phenyl compound for which GI₅₀ 10^?7 M was recorded against leukemia cell line MOLT-4.     

Propagation of high-frequency gravitational waves in vacuum: Nonlinear effects

Linear and nonlinear perturbations of vacuum space-times are examined in the approximation of high frequencies. In order to do this, it is necessary to extend the concept of coordinate gauge transformations to the case of nonlinear terms. The generation of the second harmonic is studied by investigating perturbations of the tetrad components of the Weyl tensor. Propagation equations determining the amplitudes of these perturbations are derived. Finally, the relative motion in a system of test particles under the influence of both main wave and second harmonic as seen by a free falling observer is investigated. If inertial forces are absent, the second harmonic gives rise to oscillations in two transverse-traceless modes and in a transverse-scalar mode. The amplitude of the latter mode is proportional to the shear of the ray congruence along which the perturbations propagate.     

Mini Review of Poincar�� Invariant Quantum Theory

We review the construction and applications of exactly Poincaré invariant quantum mechanical models of few-degree of freedom systems. We discuss the construction of dynamical representations of the Poincaré group on few-particle Hilbert spaces, the relation to quantum field theory, the formulation of cluster properties, and practical considerations related to the construction of realistic interactions and the solution of the dynamical equations. Selected applications illustrate the utility of this approach.     

Study of latent fingermarks by matrix‐assisted laser desorption/ionisation mass spectrometry imaging of endogenous lipids

Identification of suspects via fingermark analysis is one of the mainstays of forensic science. The success in matching fingermarks, using conventional fingermark scanning and database searching, strongly relies on the enhancement method adopted for fingermark recovery; this in turn depends on the components present in the fingermarks, which will change over time. This work aims to develop a robust methodology for improved analytical detection of the fingermark components. For the first time, matrix‐assisted laser desorption/ionisation mass spectrometry imaging (MALDI‐MSI) has been used to image endogenous lipids from fresh and aged, groomed and ungroomed fingermarks. The methodology was initially developed using oleic acid which was detected along with its degradation products over a 7‐day period, at three different temperatures in a time‐course experiment. The optimised methodology was then transferred to the imaging analysis of real fingermark samples. Fingermark patterns were reconstructed by retrieving the m/z values of oleic acid and its degradation products. This allowed the three aged fingermarks to be distinguished. In order to prove that MALDI‐MSI can be used in a non‐destructive way, a simple washing protocol was adopted which returned a fingermark that could be further investigated with classical forensic approaches. The work reported here proves the potential and the feasibility of MALDI‐MSI for the forensic analysis of fingermarks, thus making it competitive with other MSI techniques such as desorption electrospray ionisation (DESI)‐MS. The feasibility of using MALDI‐MSI in fingermark ageing studies is also demonstrated along with the potential to be integrated into routine fingermark forensic analysis. Copyright © 2009 John Wiley & Sons, Ltd.     

Bayesian inference using a noninformative prior for linear Gaussian random coefficient regression with inhomogeneous within-class variances

A Bayesian inference for a linear Gaussian random coefficient regression model with inhomogeneous within-class variances is presented. The model is motivated by an application in metrology, but it may well find interest in other fields. We consider the selection of a noninformative prior for the Bayesian inference to address applications where the available prior knowledge is either vague or shall be ignored. The noninformative prior is derived by applying the Berger and Bernardo reference prior principle with the means of the random coefficients forming the parameters of interest. We show that the resulting posterior is proper and specify conditions for the existence of first and second moments of the marginal posterior. Simulation results are presented which suggest good frequentist properties of the proposed inference. The calibration of sonic nozzle data is considered as an application from metrology. The proposed inference is applied to these data and the results are compared to those obtained by alternative approaches.     

Determination of melamine in milk powder using gas chromatography-high-resolution isotope dilution mass spectrometry

A GC-high-resolution isotope dilution MS (IDMS) method for the quantification of melamine in milk powder is described. The developed technique is compared to the LC-IDMS/MS technique, typically used for the determination of melamine in various matrices. The accuracy of the GC-high-resolution IDMS method was demonstrated when a small degree of equivalence was obtained in a regional comparative study involving the determination of melamine in milk powder.