Microcantilever biosensors based on conformational change of proteins

Microcantilevers (MCLs) hold a position as a cost-effective and highly sensitive sensor platform for medical diagnostics, environmental analysis and fast throughput analysis. MCLs are unique in that adsorption of analytes on the microcantilever (MCL) surface changes the surface characteristics of the MCL and results in bending of the MCL. Surface stress due to conformation change of proteins and other polymers has been a recent focus of MCL research. Since conformational changes in proteins can be produced through binding of anylates at specific receptor sites, MCLs that respond to conformational change induced surface stress are promising as transducers of chemical information and are ideal for developing microcantilever-based biosensors. The MCL can also potentially be used to investigate conformational change of proteins induced by non-binding events such as post-translational modification and changes in temperature or pH. This review will provide an overview of MCL biosensors based on conformational change of proteins bound to the MCL surface. The models include conformational change of proteins, proteins on membranes, enzymes, DNA and other polymers.     

RESTRICTED LIE ALGEBRAS WITH MAXIMAL 0-PIM

In this paper it is shown that the projective cover of the trivial irreducible module of a finite-dimensional solvable restricted Lie algebra is induced from the one dimensional trivial module of a maximal torus. As a consequence, the number of the isomorphism classes of irreducible modules with a fixed p-character for a finite-dimensional solvable restricted Lie algebra L is bounded above by p ^MT(L), where MT(L) denotes the maximal dimension of a torus in L. Finally, it is proved that in characteristic p > 3 the projective cover of the trivial irreducible L-module is induced from the one-dimensional trivial module of a torus of maximal dimension, only if L is solvable.     

Design, synthesis and pharmacological activity of novel enantiomerically pure phosphonic acid-based NAALADase inhibitors

Inhibitors of NAALADase have shown promise for a variety of diseases associated with glutamate excitotoxicity, and could be useful for the diagnosis and therapy of prostate cancer. A series of novel enantiomerically pure 2-(phosphonomethyl)pentanedioic acid (2-PMPA) based NAALADase inhibitors were synthesized. These compounds were prepared from previously reported (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl ester . Biological test results showed that the new compounds are good to outstanding NAALADase inhibitors. Compounds and showed activity similar to the known potent inhibitor (S)-2-PMPA. Fluorescently labeled inhibitor may potentially be used to study binding to prostate cancer cells by fluorescence microscopy, and siderophore-containing inhibitor may be useful for detection of prostate-derived cancer cells by magnetic resonance imaging (MRI).     

Mechanistic analysis and thermochemical kinetic simulation of the products from pyrolysis of poly(α-methylstyrene), especially the unrecognized role of phenyl shift

Mechanisms for pyrolysis of poly(α-methylstyrene) must rationalize high selectivity for monomer formation, negligible formation of volatile oligomers, and notably slow decrease in molecular weight compared with the rate of weight loss, i.e., unzipping dominates both back-biting and transfer. Backbone homolysis should form both a tert-benzylic radical R_tb and a prim radical R_p, with formation of the latter potentially supplemented in chain propagation steps emanating from the former. Hence product-forming pathways characteristic of each are expected to compete. Simulations of initial product distributions based on assigned rate constants for chain propagation steps indicate that R_tb is indeed predicted to efficiently unzip with minimal transfer or back-biting. However, R_p is predicted to give comparable amounts of transfer and back-biting with minimal unzipping, behavior inconsistent with experimental data. The proposed escape from this impasse is a previously unrecognized pathway, 1,2-phenyl shift in R_p to form a tert radical. If it undergoes β-scission, the net result is an inter-conversion of R_p to R_tb. Quantitative simulations suggest that this sequence is indeed highly competitive with other reactions of R_p and thus efficiently subverts the otherwise expected propagation of chains emanating from R_p.     

Structure factor for hard hyperspheres in higher dimensions

The structure factor for hard hyperspheres in two to eight dimensions is computed by Fourier transforming the pair correlation function obtained by computer simulation at a variety of densities. The resulting structure factors are compared to the known Percus-Yevick equations for odd dimensions and to the model proposed by Leutheusser [J. Chem. Phys. 84, 1050 (1986)] and Rosenfeld [J. Chem. Phys. 87, 4865 (1987)] in even dimensions. It is found that there is fine agreement among all these approaches at low to moderate densities but that the accuracy of the analytical models breaks down as the freezing transition is approached. The structure factor gives another insight into the decrease in the ordering of the hyperspheres as the dimension is increased.     

Reactions of nitroso hetero-Diels-Alder cycloadducts with azides: stereoselective formation of triazolines and aziridines

The addition of azides to acylnitroso hetero-Diels-Alder cycloadducts derived from cyclopentadiene affords exo-triazolines in excellent yield. The reaction is greatly affected by the level of alkene strain, while sterically demanding azides do not hinder the reaction. Conversion of the triazolines to aziridines is also described.     

Expanding the scope of native chemical ligation – templated small molecule drug synthesis via benzanilide formation

We describe a reaction system that enables the synthesis of Bcr–Abl tyrosine kinase inhibitors (TKI) via benzanilide formation in water. The reaction is based on native chemical ligation (NCL). In contrast to previous applications, we used the NCL chemistry to establish aromatic rather than aliphatic amide bonds in coupling reactions between benzoyl and o-mercaptoaniline fragments. The method was applied for the synthesis of thiolated ponatinib and GZD824 derivatives. Acid treatment provided benzothiazole structures, which opens opportunities for diversification. Thiolation affected the affinity for Abl1 kinase only moderately. Of note, a ponatinib-derived benzothiazole also showed nanomolar affinity. NCL-enabled benzanilide formation may prove useful for fragment-based drug discovery. To show that benzanilide synthesis can be put under the control of a template, we connected the benzoyl and o-mercaptoaniline fragments to DNA and peptide nucleic acid (PNA) oligomers. Complementary RNA templates enabled adjacent binding of reactive conjugates triggering a rapid benzoyl transfer from a thioester-linked DNA conjugate to an o-mercaptoaniline-DNA or -PNA conjugate. We evaluated the influence of linker length and unpaired spacer nucleotides within the RNA template on the product yield. The data suggest that nucleic acid-templated benzanilide formation could find application in the establishment of DNA-encoded combinatorial libraries (DEL).

The templated native chemical ligation between benzoyl thioesters and o-mercaptoaniline fragments proceeds in water and provides benzanilides that have nanomolar affinity for Abl1 kinase.     

Polymerizations of olefins and diolefins catalyzed by monocyclopentadienyltitanium complexes containing a (dimethylamino)ethyl substituent and comparison with ansa-zirconocene systems

{[2-(dimethylamino)ethyl]cyclopentadienyl}titanium trichloride (Cp^NTiCl₃, 1 ) was activated with methylaluminoxane (MAO) to catalyze polymerizations of ethylene (E), propylene (P), ethylidene norbornene (ENB), vinylcyclohexene (VCH), and 1,4-hexadiene (HD). The dependence of homopolymerization activity ( A ) of 1 /MAO on olefin concentration ([M]ⁿ) is n = 2.0 ± 0.5 for E and n = 1.8 ± 0.2 for P. The value of n is 2.4 ± 0.2 for CpTiCl₃/MAO catalysis of ethylene polymerization; this system does not polymerize propylene. 1 /MAO catalyzes HD polymerization at one-tenth of A _H for 1-hexene, probably because of chelation effects in the HD case. The copolymerization of E and P has reactivity ratios of r_E = 6.4 and r_P = 0.29 at 20°C, and r_Er_P = 1.9, which suggests 1 /MAO may be a multisite catalyst. The copolymerization activity of CpTiCl₃/MAO is 50 times smaller than that of Cp^NTiCl₃/MAO. Terpolymerization of E/P/ENB has A of 10⁵ g of polymer/(mol of Ti h), incorporates up to 14 mol % (∼ 40 wt %) of ENB, and high MW's of 1 to 3 × 10⁵. All of these parameters are surprisingly insensitive to the ENB concentration. The E/P/VCH terpolymerization has comparable A value of (1.3 ± 0.3) × 10⁵ g/(mol of Ti h). The incorporation of VCH in terpolymer increases with increasing [VCH]. Terpolymerization with HD occurs at about one-third of the A of either ENB or VCH; the product HD–EPDM is low in molecular weight and contains less than 4% of HD. These terpolymerization results are compared with those obtained previously for three zirconocene precursors: rac-ethylenebis(1-η⁵-indenyl)dichlorozirconium ( 6 ), rac-(dimethylsilylene)bis(1-η⁵-indenyl)dichlorozirconium ( 7 ), and ethylenebis(9-η⁵-fluorenyl)dichlorozirconium ( 8 ). The last compound is a particularly poor terpolymerization catalyst; it incorporates very little VCH or HD and no ENB at all. 7 /MAO is a better catalyst for E/P/VCH terpolymerization, while 6 /MAO is superior in E/P/HD terpolymerization. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 319–328, 1998     

Density functional theory and pseudopotentials: A panacea for calculating properties of materials

Although our microscopic view of solids is still evolving, for a large class of materials one can construct a useful first principles or “standard model” of solids which is sufficiently robust to explain and predict many physical properties. Both electronic and structural properties can be studied, and the results of the first-principles calculations can be used to predict new materials, formulate empirical theories and simple formulas to compute material parameters, and explain trends. A discussion of the microscopic approach, applications, and empirical theories is given here, and some recent results on nanotubes, hard materials, and fullerenes are presented. © 1997 John Wiley & Sons, Inc.