Biomimetic Synthesis of Meroterpenoids by Dearomatization‐Driven Polycyclization

A biomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)‐derived meroterpenoid scaffolds has yet to be reported despite great interest from the chemistry and biomedical research communities. A concise synthetic route with the potential to access DMOA‐derived meroterpenoids is highly desirable to create a library of related compounds. Herein, we report novel dearomatization methodology followed by polyene cyclization to access DMOA‐derived meroterpenoid frameworks in six steps from commercially available starting materials. Furthermore, several farnesyl alkene substrates were used to generate structurally novel, DMOA‐derived meroterpenoid derivatives. DFT calculations combined with experimentation provided a rationale for the observed thermodynamic distribution of polycyclization products.     

Construction of Bridged Polycyclic Systems by Polyene Cyclization

A stereoselective construction of bridged tri‐ and tetracyclic systems embedded in some 3,5‐dimethylorsellinic acid (DMOA)‐derived meroterpenoids was achieved by exploiting a polyene cyclization of suitably functionalized epoxyallylsilanes. Both the olefinic substituent on the epoxide and allylic trimethylsilyl (TMS) group were found to play pivotal roles in the success of the present reaction. The fact that the cyclization of monocyclized byproducts did not proceed strongly suggests that the reaction could be a concerted transformation.     

Reconstituted biosynthesis of fungal meroterpenoid andrastin A

Andrastins (andrastin A-D), produced by several Penicillium species, exhibit inhibitory activity against ras farnesyltransferase, suggesting that these compounds could be promising leads for antitumor agents. Although the genome sequence of Penicillium chrysogenum, an andrastin-producing species, is available, the genetic and molecular bases for the biosynthesis of andrastins have not been elucidated. Here we report the identification and characterization of the gene cluster for andrastin biosynthesis. We reconstituted the biosynthetic pathway in Aspergillus oryzae, a fungal expression host, by the co-expression of five genes, including that of a terpene cyclase, and of four genes encoding the tailoring enzymes, required for the generation of andrastins. Remarkably, we successfully obtained andrastin A, the most complex andrastin molecule, as the metabolite of nine gene products, thus confirming the potential of the fungal expression system to synthesize useful natural products.     

Terretonin D1, a new meroterpenoid from marine-derived Aspergillus terreus ML-44

A new meroterpenoid, named terretonin D1 (1), and three known ones, terretonin (2), terretonin A (3), and terretonin D (4), were isolated from marine-derived fungus Aspergillus terreus ML-44. The structure of 1 was elucidated by extensive spectroscopic methods, including 1D and 2D NMR, HR-ESI-MS, and the absolute configuration was determined by X-ray crystallographic analysis. The anti-inflammation activity of 1–4 was preliminarily tested, and all of them weakly inhibited the nitric oxide (NO) production of RAW264.7 macrophages stimulated by lipopolysaccharide (LPS), with inhibitory rates of 22–34% at 50?μg/mL.     

Characterisation of reversed-phase stationary phases for the liquid chromatographic analysis of basic pharmaceuticals by thermodynamic data

This paper describes the characterisation of reversed-phase liquid chromatography (RPLC) columns using thermodynamic measurements. Retention versus 1/T data were used to construct Van't Hoff plots. The slope of these plots indicates the standard enthalpy of transfer of the analyte from the mobile to the stationary phase. The standard entropy can be calculated from the intercept. Van't Hoff plots were linear for the investigated RPLC columns, meaning that for basic analytes over the temperature range studied no changes in the retention mechanism occurred. Enthalpies and entropies of transfer of basic analytes from the mobile to the stationary phase revealed information about the types of interaction of protonated and neutral compounds with the stationary phases. However, a clear view using the present set of basic compounds on how these thermodynamic data may explain the observed substantial differences in peak symmetry cannot be given. It is considered that addition of N,N-dimethyloctylamine (DMOA) to the eluent will results in a dynamically coating of the stationary phase. Addition of DMOA to the eluent resulted for protonated basic compounds in a reduction of both enthalpy and entropy. In practice, with DMOA in the eluent symmetrical peaks were obtained. It is assumed that this is due to blocking residual silanols and/or ion exclusion effects.     

Single nucleus versus single‐cell gel electrophoresis: Kinetics of DNA track formation

Single‐cell gel electrophoresis, or the comet assay, is usually performed with nucleoids prepared after a lysis of either whole cells (more often) or isolated cell nuclei (rarely). Electrophoretic properties of the second type of nucleoids have never been investigated carefully. We measured the kinetics of the DNA exit from nuclei‐derived nucleoids in comparison with cell‐derived nucleoids. The results show that general organization of the nuclei‐derived nucleoids is not changed very much in comparison with nucleoids commonly obtained from whole cells. At the same time, in contrast to the cell‐derived nucleoids, for which the exit is stepwise and cooperative, the DNA exit from the nuclei‐derived nucleoids can be described by a simple monomolecular kinetics. This difference is probably due to agarose penetration into nuclei (but not into cells) before polymerization of the agarose gel. We suggest that single‐nucleus gel electrophoresis may be a way for the comet assay standardization.     

Studies on New Hydrophobically Modified Water-soluble Cellulosic Graft Terpolymers

Hydrophobically modified water-soluble ion-containing cellulosic polymer possessing intra-or intermolecular modes of hydrophobic associations has been recently the object of our research^[1-4]. Based on the preparation of the surface-active monomer, dimethyloctyl (2-methacryloxyethyl)ammonium bromide (DMOA), new cellulosic graft terpolymers (NCGT) have been synthesized by grafting acrylamide (AM) and DMOA onto carboxymethyl cellulose (CMC) using potassium persulfate and dimethylaminoethyl methacrylate as the initiating system, and characterized by FTIR, elementary analysis, titration and GPC. To obtain the optimum reaction conditions, the influence of the feed ratio and addition order of raw materials, the concentration of initiators, temperature and pH on the grafting have been investigated.     

Effects of Counter Ions in Ion-Pair Liquid Chromatography of Hydrophobic Amines on Non-Polar Bonded Phases

Abstract

The retention behaviour of alprenolol and related hydrophobic amines in ion-pair adsorption systems has been examined with particular emphasis on the influence of different mono-and divalent counter ions (dihydrogenphosphate, bromide, perchlorate, dimethylcyclohexyl sulphate, sulphate and ethylenediaminetetraacetate). N,N-dimethyloctylamine (DMOA) and 1-pentanol were used as modifiers in the aqueous eluent and LiChrosorb RP-8 as stationary phase.

The retention is evaluated according to a two-site adsorption model and equilibrium constants are given for ion pair adsorption of DMOA. The retention of alprenolol has been evaluated in terms of ion exchange with DMOA and the ion-exchange constants are shown to be of the same magnitude and independent of the nature of the counter ion used. The ion-pair adsorption and the ion-exchange approaches are analogous expressions for the distribution process governing the retention.     

Side‐chain supramolecular polymers with induced supramolecular chirality through H‐bonding interactions

Side‐chain supramolecular polymers that show columnar mesomorphism have been prepared through H‐bonding interactions between a polyvinylpyridine polymer as H‐acceptor and different H‐donors derived from benzoic acid. These compounds have been designed according to a promesogenic structure, that is, either disk‐like or banana‐like, to promote stacking and therefore the formation of columnar arrangements. IR studies confirmed the formation of H‐bonds and demonstrated that the H‐bond intensity decreases upon increasing temperature. The mesophase organizations were studied by polarized optical microscopy, differential scanning calorimetry, and X‐ray diffraction. Associations containing poly‐3‐methyl‐4‐vinylpyridine showed supramolecular optical activity, as evidenced by circular dichroism studies on thin films. It is proposed that these supramolecular polymers adopt a helical structure that can be biased toward a given handedness by virtue of the configuration of the stereogenic centers in the peripheral tails of the acids. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5528–5541, 2008     

Biphenyl‐Derived Phosphepines as Chiral Nucleophilic Catalysts: Enantioselective [4+1] Annulations To Form Functionalized Cyclopentenes

Because of the frequent occurrence of cyclopentane subunits in bioactive compounds, the development of efficient catalytic asymmetric methods for their synthesis is an important objective. Introduced herein is a new family of chiral nucleophilic catalysts, biphenyl‐derived phosphepines, and we apply them to an enantioselective variant of a useful [4+1] annulation. A range of one‐carbon coupling partners can be employed, thereby generating cyclopentenes which bear a fully substituted stereocenter [either all‐carbon or heteroatom‐substituted (sulfur and phosphorus)]. Stereocenters at the other four positions of the cyclopentane ring can also be introduced with good stereoselectivity. An initial mechanistic study indicates that phosphine addition to the electrophilic four‐carbon coupling partner is not the turnover‐limiting step of the catalytic cycle.     

On the crystal structure of odd–even nylons: Polymorphism of nylon 5,10

The structure of nylon 5,10 has been investigated using electron microscopy and X‐ray diffraction. Nylon 5,10 shows polymorphism with two different structures related to the γ form obtained by either solution or melt crystallization. Packing differences may be attributed to a change in the hydrogen bonding system. In addition, a structure related to an α‐like phase can be found by precipitation from strong acid solutions and their mixtures with chloroform. A model with two hydrogen bonding directions is given for this form, in a similar way to that recently postulated for polyamides derived from odd diamine or odd diacid units. Temperature‐induced structural changes have also been studied for nylon 5,10 fibers. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 2383–2395, 1999     

Effects of aliphatic amines on capillary electrochromatographic performance of tricyclic antidepressants on octadecylsilica

Adding aliphatic amines to the mobile phase improves peak symmetry and efficiency in capillary electrochromatography of tricyclic antidepressants on octadecylsilica. The most hydrophobic aliphatic amine studied, dimethyloctylamine (DMOA), was the most efficient. Despite the fact that the amine additives substantially reduced the electroosmotic flow, the retention of the analytes decreased indicating a strong competitive effect of the additives. DMOA gave the largest retention decrease, and simultaneously reduced the resolution, indicating that silanophilic interaction is significant to the separation. Highest efficiencies were obtained at the lowest pH (2.8). Acetonitrile influenced both efficiency and peak symmetry, and best results were obtained at 60%.     

Playing LEGO with macromolecules: Design,synthesis, and self‐organization with metal complexes

Several synthetic strategies for the incorporation of supramolecular binding units into polymers are described. Specifically, terpyridine ligands have been introduced into polymers in such a way that they are distributed either randomly throughout the polymer backbone or at the chain end(s). Two terpyridine ligands form octahedral complexes with a variety of transition‐metal ions, each having different properties. Some general statements regarding metal complex stability are presented as well as a special case representing the selective construction of heteroleptic terpyridine complexes. This leads to a kind of LEGO system for connecting and disconnecting the polymer blocks via metal complexes. Metallo‐supramolecular block copolymers, graft copolymers, and chain‐extended polymers can be designed and prepared with the principles described. Once the design parameters have been derived, thorough control over the final material and its properties can be gained. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1413–1427, 2003     

A Long‐Living Bioengineered Neural Tissue Platform to Study Neurodegeneration

The prevalence of dementia and other neurodegenerative diseases continues to rise as age demographics in the population shift, inspiring the development of long‐term tissue culture systems with which to study chronic brain disease. Here, it is investigated whether a 3D bioengineered neural tissue model derived from human induced pluripotent stem cells (hiPSCs) can remain stable and functional for multiple years in culture. Silk‐based scaffolds are seeded with neurons and glial cells derived from hiPSCs supplied by human donors who are either healthy or have been diagnosed with Alzheimer's disease. Cell retention and markers of stress remain stable for over 2 years. Diseased samples display decreased spontaneous electrical activity and a subset displays sporadic‐like indicators of increased pathological β‐amyloid and tau markers characteristic of Alzheimer's disease with concomitant increases in oxidative stress. It can be concluded that the long‐term stability of the platform is suited to study chronic brain disease including neurodegeneration.     

Investigation of chiral recognition mechanism on chicken alpha(1)-acid glycoprotein using separation system

Chicken alpha1-acid glycoprotein (alpha1-AGP) consists of 183 amino acid residues and has only one Trp residue at the 26 position. In this study, the Trp26 residue was modified with 2-nitrophenylsulfenyl chloride and chiral separation of neutral, acidic and basic compounds was examined on chicken alpha1-AGP and Trp-modified chicken alpha1-AGP columns. Chiral separation of propranolol, alprenolol and oxprenolol was lost on the Trp-modified chicken alpha1-AGP column, while chlorpheniramine, ketoprofen and benzoin were still enantioseparated on the Trp-modified chicken alpha1-AGP column despite of lower enantioselectivity than that on the chicken alpha1-AGP column. These results suggest that the Trp26 residue could be responsible for chiral recognition of these compounds. Competition studies using N,N-dimethyl-n-octylamine (DMOA) as a competitor indicated that propranolol, alprenolol and oxprenolol competed with DMOA on a single binding site near the Trp26 region and that further bindings of chlorpheniramine, ketoprofen and benzoin occurred at the secondary binding site in a non-competitive fashion with DMOA.     

C?H Functionalization/Asymmetric Michael Addition Cascade Enabled by Relay Catalysis: Metal Carbenoid Used for C?C Bond Formation

A combination of either ruthenium(II) or rhodium(II) complexes and quinine‐derived squaramide enables 3‐diazooxindoles, indoles, and nitroalkenes to undergo highly efficient asymmetric three‐component reactions, thus affording optically active 3,3′‐bis(indole)s through a consecutive C C bond‐forming sequence, which turned out to be applicable to the facile total synthesis of (−)‐folicanthine.     

CH Functionalization/Asymmetric Michael Addition Cascade Enabled by Relay Catalysis: Metal Carbenoid Used for CC Bond Formation

A combination of either ruthenium(II) or rhodium(II) complexes and quinine‐derived squaramide enables 3‐diazooxindoles, indoles, and nitroalkenes to undergo highly efficient asymmetric three‐component reactions, thus affording optically active 3,3′‐bis(indole)s through a consecutive C? C bond‐forming sequence, which turned out to be applicable to the facile total synthesis of (?)‐folicanthine.     

A Consistent Determination of the Dimerization Constants of the Self‐Association of 2,2‐Dimethyl‐3‐ethyl‐3‐pentanol in Carbon Tetrachloride from its Infrared Spectral Data

Two equations of linear type (Eqs. 10 and 17 in the text) have been derived to analyze the IR data to determine the dimerization constant consistently. Equation 10 is to be used to fit the integrated absorbances of the monomer band to obtain the molar monomer absorptivity, ?_m, and dimerization constant, K; Eq. 17 is to be used to fit the integrated absorbances of the dimer bands to obtain the molar dimer absorptivity, ?_d, and dimerization constant, K. Thus the same dimerization constant can be independently determined either from the monomer band or from the dimer band. The discrepancy between the two determined values provides an assessment of the consistency of determination. The monomer‐dimer self‐association of 2,2‐dimethyl‐3‐ethyl‐3‐pentanol in the solvent of carbon tetrachloride was chosen to demonstrate the utility of these two equations.     

Eine neuartige Methode zur Analyse kombinatorischer Substanzbibliotheken mittels paramagnetischer Reporter

A Novel Method to Identify Chemical Compounds of Combinatorial Libraries by the Use of Paramagnetic Tags An EPR method to identify non‐destructively chemical compounds bound to a single solid‐phase‐synthesis bead for combinatorial chemistry applications is discribed. During synthesis chemical inert paramagnetic substances can be attached in small amounts to a solid‐phase‐synthesis resin for tagging of organic compounds or even reaction steps. The identification of single members of a combinatorial library in short time and high sensitivity can be carried out by using an EPR‐spectrometer.