A Push-Button Molecular Switch

The preparation, characterization, and switching mechanism of a unique single-station mechanically switchable hetero[2]catenane are reported. The facile synthesis utilizing a “threading-followed-by-clipping” protocol features Cu^(2+)-catalyzed Eglinton coupling as a mild and efficient route to the tetrathiafulvalene-based catenane in high yield. The resulting mechanically interlocked molecule operates as a perfect molecular switch, most readily described as a “push-button” switch, whereby two discrete and fully occupied translational states are toggled electrochemically at incredibly high rates. This mechanical switching was probed using a wide variety of experimental techniques as well as quantum-mechanical investigations. The fundamental distinctions between this single-station [2]catenane and other more traditional bi- and multistation molecular switches are significant

Dynamic Mechanically Interlocked Dendrimers: Amplification in Dendritic Dynamic Combinatorial Libraries

In the context of constructing nonclassical mechanically interlocked dendrimers by employing a convergent templation procedure, the “clipping” thermodynamic approach has been explored to introduce sterically bulky Fre´chet-type dendrons with successive generations [G0] to [G3] onto a trivalent ammonium ion core using a seven-component self-assembly via imine bond formation. Four generations of mechanically interlocked dendrimers up to a molecular weight over 8800 Da were synthesized in a one-pot reaction by simply mixing the seven components together. The dendrimers form in excellent yield (>90%). The mechanically interlocked core of the [G0]-[G2] dendrimers can be modified and transformed into kinetically stable dendrimers by reduction of the imine bonds with borane-tetrahydrofuran complex. Moreover, the dynamic nature of the thermodynamically controlled self-assembly process is employed to obtain three dynamic combinatorial libraries of dendrimers by the treatment of the dendrons [G0]-[G3] with the complementary components in one pot. The inherent modularity of the overall process should allow for the rapid and straightforward access to many other analogues of mechanically interlocked systems for which either the branched core or the dendritic periphery can be modified to suit the needs of any potential application of these molecules

Folding of a donor–acceptor polyrotaxane by using noncovalent bonding interactions

Mechanically interlocked compounds, such as bistable catenanes and bistable rotaxanes, have been used to bring about actuation in nanoelectromechanical systems (NEMS) and molecular electronic devices (MEDs). The elaboration of the structural features of such rotaxanes into macromolecular materials might allow the utilization of molecular motion to impact their bulk properties. We report here the synthesis and characterization of polymers that contain π electron-donating 1,5-dioxynaphthalene (DNP) units encircled by cyclobis(paraquat-p-phenylene) (CBPQT4+), a π electron-accepting tetracationic cyclophane, synthesized by using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The polyrotaxanes adopt a well defined “folded” secondary structure by virtue of the judicious design of two DNP-containing monomers with different binding affinities for CBPQT4+. This efficient approach to the preparation of polyrotaxanes, taken alongside the initial investigations of their chemical properties, sets the stage for the preparation of a previously undescribed class of macromolecular architectures

Template-Directed Synthesis of Mechanically Interlocked Molecular Bundles Using Dynamic Covalent Chemistry

Mixing the dipyrido[24]crown-8 derivatives carrying one or two formyl group(s) on the 4 position(s) of their pyridine ring(s) with a 3-fold symmetrical trisammonium ion template in a 3:1 ratio in CD3NO2 results in the formation of thermodynamically stable [4]pseudorotaxanes which, upon addition of a 1,3,5 trisaminobenzene cap, form mechanically interlocked molecular bundles with one and two caps, respectively, by virtue of dynamic imine bond formation

Potent Activity of the HIV-1 Maturation Inhibitor Bevirimat in SCID-hu Thy/Liv Mice

The HIV-1 maturation inhibitor, 3-O-(3',3'-dimethylsuccinyl) betulinic acid (bevirimat, PA-457) is a promising drug candidate with 10 nM in vitro antiviral activity against multiple wild-type (WT) and drug-resistant HIV-1 isolates. Bevirimat has a novel mechanism of action, specifically inhibiting cleavage of spacer peptide 1 (SP1) from the C-terminus of capsid which results in defective core condensation.Oral administration of bevirimat to HIV-1-infected SCID-hu Thy/Liv mice reduced viral RNA by >2 log(10) and protected immature and mature T cells from virus-mediated depletion. This activity was observed at plasma concentrations that are achievable in humans after oral dosing, and bevirimat was active up to 3 days after inoculation with both WT HIV-1 and an AZT-resistant HIV-1 clinical isolate. Consistent with its mechanism of action, bevirimat caused a dose-dependent inhibition of capsid-SP1 cleavage in HIV-1-infected human thymocytes obtained from these mice. HIV-1 NL4-3 with an alanine-to-valine substitution at the N-terminus of SP1 (SP1/A1V), which is resistant to bevirimat in vitro, was also resistant to bevirimat treatment in the mice, and SP1/AIV had replication and thymocyte kinetics similar to that of WT NL4-3 with no evidence of fitness impairment in in vivo competition assays. Interestingly, protease inhibitor-resistant HIV-1 with impaired capsid-SP1 cleavage was hypersensitive to bevirimat in vitro with a 50% inhibitory concentration 140 times lower than for WT HIV-1.These results support further clinical development of this first-in-class maturation inhibitor and confirm the usefulness of the SCID-hu Thy/Liv model for evaluation of in vivo antiretroviral efficacy, drug resistance, and viral fitness

Multiproxy bioarchaeological data reveals interplay between growth, diet and population dynamics across the transition to farming in the central Mediterranean

The transition to farming brought on a series of important changes in human society, lifestyle, diet and health. The human bioarchaeology of the agricultural transition has received much attention, however, relatively few studies have directly tested the interrelationship between individual lifestyle factors and their implications for understanding life history changes among the first farmers. We investigate the interplay between skeletal growth, diet, physical activity and population size across 30,000 years in the central Mediterranean through a ‘big data’ cross-analysis of osteological data related to stature (n = 361), body mass (n = 334) and long bone biomechanics (n = 481), carbon (δ 13C) and nitrogen (δ 15N) stable isotopes (n = 1986 human, n = 475 animal) and radiocarbon dates (n = 5263). We present the observed trends on a continuous timescale in order to avoid grouping our data into assigned ‘time periods’, thus achieving greater resolution and chronological control over our analysis. The results identify important changes in human life history strategies associated with the first farmers, but also highlight the long-term nature of these trends in the millennia either side of the agricultural transition. The integration of these different data is an important step towards disentangling the complex relationship between demography, diet and health, and reconstruct life history changes within a southern European context. We believe the methodological approach adopted here has broader global implications for bioarchaeological studies of human adaptation more generally

The stability of imine-containing dynamic [2]rotaxanes to hydrolysis

Large amounts (>100 mol equivalents) of water are required to effect by hydrolysis the partial disassembly of the rings from the dumbbell components of two dynamic [2]rotaxanes. The two dynamic [2]rotaxanes are comprised of [24]crown-8 rings—each of which incorporate two imine bonds—encircling a dumbbell component composed of a dibenzylammonium ion in which each of the two benzyl substituents carries two methoxyl groups ttached to their 3- and 5-positions. A mechanism for the partial disassembly of the two dynamic [2]rotaxanes, involving the cleavage of the kinetically labile imine bonds by water molecules, is proposed. The most important experimental observation to be noted is the fact that the hydrolysis of the macrocyclic diimines, associated with the templating –CH2NH2 +CH2–centres in the middle of their dumbbells, turns out to be an uphill task to perform in the face of the molecular recognition provided by strong [N+–H ◊ ◊ ◊ O] hydrogen bonds and weaker, yet not insignificant, [C–H◊ ◊ ◊ O] interactions. The dynamic nature of the imine bond formation and hydrolysis is such that the acyclic components produced during hydrolysis of the imine bonds can be enticed to cyclise once again around the –CH2NH2 +CH2–template, affording the [2]rotaxanes. The reluctance of imine bonds, present in substantial numbers in larger molecular and extended structures, is significant when it comes to exercising dynamic chemistry in compounds where multiple imine bonds are present

Magnetoresistance of a 2-dimensional electron gas in a random magnetic field

We report magnetoresistance measurements on a two-dimensional electron gas (2DEG) made from a high mobility GaAs/AlGaAs heterostructure, where the externally applied magnetic field was expelled from regions of the semiconductor by means of superconducting lead grains randomly distributed on the surface of the sample. A theoretical explanation in excellent agreement with the experiment is given within the framework of the semiclassical Boltzmann equation.Comment: REVTEX 3.0, 11 pages, 3 Postscript figures appended. The manuscript can also be obtained from our World Wide Web server: http://roemer.fys.ku.dk/randmag.ht