Phase diagram of hard tetrahedra

Advancements in the synthesis of faceted nanoparticles and colloids have spurred interest in the phase behavior of polyhedral shapes. Regular tetrahedra have attracted particular attention because they prefer local symmetries that are incompatible with periodicity. Two dense phases of regular tetrahedra have been reported recently. The densest known tetrahedron packing is achieved in a crystal of triangular bipyramids (dimers) with a packing density of 4000/4671 ≈ 85.63%. In simulation a dodecagonal quasicrystal is observed; its approximant, with periodic tiling (3.4.3(2).4), can be compressed to a packing fraction of 85.03%. Here, we show that the quasicrystal approximant is more stable than the dimer crystal for packing densities below 84% using Monte Carlo computer simulations and free energy calculations. To carry out the free energy calculations, we use a variation of the Frenkel-Ladd method for anisotropic shapes and thermodynamic integration. The enhanced stability of the approximant can be attributed to a network substructure, which maximizes the free volume (and hence the wiggle room) available to the particles and facilitates correlated motion of particles, which further contributes to entropy and leads to diffusion for packing densities below 65%. The existence of a solid-solid transition between structurally distinct phases not related by symmetry breaking--the approximant and the dimer crystal--is unusual for hard particle systems.     

Synthesis of new acyclic nucleoside phosphonates (ANPs) substituted on the 1′ and/or 2′ positions

A series of 2′ functionalized acyclic nucleoside phosphonate derivatives of 1-[3′-(phosphonomethoxy)propyl]uracil (1-4) have been synthesized together with the 1′ and 2′-ethynyl derivatives of 9/1-[2′-(phosphonomethoxy)ethyl]adenine/thymine (5-7). Key intermediates leading to the latter series are (±)-[2-{diethyl(phosphonomethoxy)}-1-hydroxy]-but-3-yne (25) and (±)-diisopropyl{[2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl]oxy}methylphosphonate (30). Compounds 25 and 30 are easily obtained starting from (±)-solketal.     

Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists

The cannabinoid CB(2) receptor is known to modulate osteoclast function by poorly understood mechanisms. Here, we report that the natural biphenyl neolignan 4'-O-methylhonokiol (MH) is a CB(2) receptor-selective antiosteoclastogenic lead structure (K(i)?< 50?nM). Intriguingly, MH triggers a simultaneous G(i) inverse agonist response and a strong CB(2) receptor-dependent increase in intracellular calcium. The most active inverse agonists from a library of MH derivatives inhibited osteoclastogenesis in RANK ligand-stimulated RAW264.7 cells and primary human macrophages. Moreover, these ligands potently inhibited the osteoclastogenic action of endocannabinoids. Our data show that CB(2) receptor-mediated cAMP formation, but not intracellular calcium, is crucially involved in the regulation of osteoclastogenesis, primarily by inhibiting macrophage chemotaxis and TNF-α expression. MH is an easily accessible CB(2) receptor-selective scaffold that exhibits a novel type of functional heterogeneity.     

Lamellar crystalline self-assembly behaviour and solid lipid nanoparticles of a palmityl prodrug analogue of Capecitabine--a chemotherapy agent

An amphiphile prodrug, 5′-deoxy-5-fluoro-N⁴-(palmityloxycarbonyl) cytidine or 5′-deoxy-5-fluoro-N⁴-(hexadecanaloxycarbonyl) cytidine (5-FCPal), consisting of the same head group as the commercially available chemotherapeutic agent Capecitabine, linked to a palmityl hydrocarbon chain via a carbamate bond is reported. Thermal analysis of this prodrug indicates that it melts at ∼115 °C followed quickly by degradation beginning at ∼120 °C. The neat solid 5-FCPal amphiphile acquires a lamellar crystalline arrangement with a d-spacing of 28.6 ± 0.3 Å, indicating interdigitation of the hydrocarbon chains. Under aqueous conditions, solid 5-FCPal is non-swelling and no lyotropic liquid crystalline phase formation is observed. In order to assess the in vitro toxicity and in vivo efficacy in colloidal form, solid lipid nanoparticles (SLNs) with an average size of ∼700 nm were produced via high pressure homogenization. The in vitro toxicity of the 5-FCPal SLNs against several different cancer and normal cell types was assessed over a 48 h period, and IC₅₀ values were comparable to those observed for Capecitabine. The in vivo efficacy of the 5-FCPal SLNs was then assessed against the highly aggressive mouse 4T1 breast cancer model. To do so, the prodrug SLNs were administered orally at 3 different dosages (0.1, 0.25, 0.5 mmol/mouse/day) and compared to Capecitabine delivered at the same dosages. After 21 days of receiving the treatments, the 0.5 mmol dose of 5-FCPal exhibited the smallest average tumour volume. Since 5-FCPal is activated in a similar manner to Capecitabine via a 3 step enzymatic pathway with the final step occurring preferentially at the tumour site, formulation of the prodrug into SLNs combines the advantage of selective, localized activation with the sustained release properties of nanostructured amphiphile self-assembly and multiple payload materials thereby potentially creating a more effective anticancer agent.     

Structural chemistry, monoclinic-to-orthorhombic phase transition, and CO2 adsorption behavior of the small pore scandium terephthalate, Sc2(O2CC6H4)CO2)3, and its nitro- and amino-functionalized derivatives

The crystal structure of the small pore scandium terephthalate Sc(2)(O(2)CC(6)H(4)CO(2))(3) (hereafter Sc(2)BDC(3), BDC = 1,4-benzenedicarboxylate) has been investigated as a function of temperature and of functionalization, and its performance as an adsorbent for CO(2) has been examined. The structure of Sc(2)BDC(3) has been followed in vacuo over the temperature range 140 to 523 K by high resolution synchrotron X-ray powder diffraction, revealing a phase change at 225 K from monoclinic C2/c (low temperature) to Fddd (high temperature). The orthorhombic form shows negative thermal expansivity of 2.4 × 10(-5) K(-1): Rietveld analysis shows that this results largely from a decrease in the c axis, which is caused by carboxylate group rotation. (2)H wide-line and MAS NMR of deuterated Sc(2)BDC(3) indicates reorientation of phenyl groups via π flips at temperatures above 298 K. The same framework solid has also been prepared using monofunctionalized terephthalate linkers containing -NH(2) and -NO(2) groups. The structure of Sc(2)(NH(2)-BDC)(3) has been determined by Rietveld analysis of synchrotron powder diffraction at 100 and 298 K and found to be orthorhombic at both temperatures, whereas the structure of Sc(2)(NO(2)-BDC)(3) has been determined by single crystal diffraction at 298 K and Rietveld analysis of synchrotron powder diffraction at 100, 298, 373, and 473 K and is found to be monoclinic at all temperatures. Partial ordering of functional groups is observed in each structure. CO(2) adsorption at 196 and 273 K indicates that whereas Sc(2)BDC(3) has the largest capacity, Sc(2)(NH(2)-BDC)(3) shows the highest uptake at low partial pressure because of strong -NH(2)···CO(2) interactions. Remarkably, Sc(2)(NO(2)-BDC)(3) adsorbs 2.6 mmol CO(2) g(-1) at 196 K (P/P(0) = 0.5), suggesting that the -NO(2) groups are able to rotate to allow CO(2) molecules to diffuse along the narrow channels.     

Degenerate quasicrystal of hard triangular bipyramids

We report a degenerate quasicrystal in Monte Carlo simulations of hard triangular bipyramids each composed of two regular tetrahedra sharing a single face. The dodecagonal quasicrystal is similar to that recently reported for hard tetrahedra [Haji-Akbari et al., Nature (London) 462, 773 (2009)] but degenerate in the pairing of tetrahedra, and self-assembles at packing fractions above 54%. This notion of degeneracy differs from the degeneracy of a quasiperiodic random tiling arising through phason flips. Free energy calculations show that a triclinic crystal is preferred at high packing fractions.     

The Host-Guest Chemistry of Proflavine with Cucurbit[6,7,8]urils

The binding of the polyaromatic guest, 3,6-diaminoacridine (Proflavine) to cucurbit[n]uril (CB[n]) where n = 6, 7 and 8 has been studied by fluorescence spectrophotometry and binding constants determined using a least squares fitting method. Titration of CB[8] into a solution of Proflavine results in a 95% decrease in fluorescence up to a CB[8] to Proflavine ratio of 2:1. From the induced fluorescence spectra a binding constant of 1.9 × 10⁷ M^? 1 was determined. When Proflavine is titrated into a solution of CB[8] a similar binding constant is calculated (1.3 × 10⁷ M^? 1). Titration of CB[6] into a solution of Proflavine yields a decrease in fluorescence of 18–20%, but no binding is observed beyond what is seen within experimental error. Finally, titration of CB[7] into a solution of Proflavine results in an increase in fluorescence (32%) and a blue-shift of the emission wavelength from 509 nm to 485 nm. From the induced fluorescence spectra a binding constant of 1.65 × 10⁷ M^? 1 was determined. From ¹H NMR it appears that the decrease in fluorescence for Proflavine with CB[6] and CB[8] is due to collisional quenching, whereas the increase in fluorescence with CB[7] may be due to rotational restriction.     

Aromatic interaction profile to understand the molecular basis of raltegravir resistance

Integrase (IN) is the enzyme of human immunodeficiency virus (HIV) which inserts the viral DNA (vDNA) into the host genome for successful viral replication leading to the infection. However, the chemical basis of HIV IN catalysis is speculative due to lack of complete co-crystal structure. Using the recently published prototype foamy virus IN crystal structure, we developed a model structure of HIV IN showing interaction of vDNA, the metal (Mg²⁺) cofactor, and raltegravir (RLT) in the active site. Molecular docking and dynamics simulations studies showed that RLT uses it core central ring with diketo motif for Mg²⁺ chelation and bridge interaction with DDE motif. The triple arene interactions mediated by RLT with neighboring molecular motifs (Y143, cytosine, and adenine) is maintained during long simulation in wild type (WT). The fluorobenzyl and oxadiazole moieties of RLT forms aromatic stacking with cytosine base (head stacking) aromatic side chain of Y143 (tail stacking), respectively, while central ring further establishes aromatic stacking with distorted adenine base of vDNA (central stacking). The novel triple stacking systems were further explored to understand the molecular basis of drug resistance by molecular simulation. The in silico mutation (N155H, Q148H, and Q148H + G140S) and simulation studies elucidated the structural mechanism of resistance to RLT. The simulation studies provided the molecular basis for interdependency observed for the primary and secondary (Q148H and G140S) mutations and also explained the mechanism of viral fitness regain. Our study reveals that triple stacking and its consequence in terms of VdW energetic profile acts as a critical point to understand the drug-resistance. Here, we demonstrate that the root mean square deviation of centroid system (aromatic stacking) can be used as a major determinant of RLT binding toward the fold resistance. This is first kind of report, which discloses a strategy to explore the molecular level of drug resistance profile using aromatic interactions.