Time-resolved keto-enol tautomerization of the medicinal pigment curcumin.

Curcumin is a medicinal agent that exhibits anti-cancer and anti-Alzheimer's disease properties. It has a keto-enol moiety that gives rise to many of its chemical properties including metal complexation and acid-base equilibria. A previous study has shown that keto-enol tautomerization at this moiety is implicated in the anti-Alzheimer's disease effect of curcumin, highlighting the importance of this process. In this study, tautomerization of curcumin in methanol, acetone and acetonitrile was investigated using time-resolved 1H nuclear magnetic resonance spectroscopy. Curcumin undergoes hydrogen-deuterium exchange with the solvents and the proton resonance peak corresponding to the hydrogen at the α-carbon position (Cα) decays as a function of time, signifying deuteration at this position. Because tautomerization is the rate limiting step in the deuteration of curcumin at the Cα position, the rate of tautomerization is inferred from the rate of deuteration. The rate constant of tautomerization of curcumin shows a temperature dependence and analysis using the Arrhenius equation revealed activation energies (Ea) of tautomerization of (80.1 ± 5.9), (64.1 ± 1.0) and (68.3 ± 5.5) kJ mol-1 in methanol, D2O/acetone and D2O/acetonitrile, respectively. Insight into the role of water in tautomerization of curcumin was further offered by density functional theory studies. The transition state of tautomerization was optimized in the presence of water molecules. The results show a hydrogen-bonded solvent bridge between the diketo moiety and Cα of curcumin. The Ea of tautomerization of curcumin shows a strong dependence on the number of water molecules in the solvent bridge, indicating the critical role played by the solvent bridge in catalyzing tautomerization of curcumin.

Preparation of a poly(acrylic acid) based hydrogel with fast adsorption rate and high adsorption capacity for the removal of cationic dyes.

A biocompatible Dex-MA/PAA hydrogel was prepared through copolymerization of glycidyl methacrylate substituted dextran (Dex-MA) with acrylic acid (AA), which was applied as the adsorbent to remove cationic dyes from aqueous solutions. Dex-MA/PAA hydrogel presented a fast adsorption rate and the removal efficiency of Methylene Blue (MB) and Crystal Violet (CV) reached 93.9% and 86.4%, respectively within one minute at an initial concentration of 50 mg L-1. The adsorption equilibrium data fitted the Sips isotherm model well with high adsorption capacities of 1994 mg g-1 for MB and 2390 mg g-1 for CV. Besides, dye adsorption occurred efficiently over the pH range 3-10 and the temperature range 20-60 °C. Moreover, the removal efficiencies for MB and CV were still >95% even after five adsorption/desorption cycles which indicates the robust nature of the Dex-MA/PAA hydrogel and its potential as an eco-friendly adsorbent for water treatment.

Molecular tweezers with a rotationally restricted linker and freely rotating porphyrin moieties.

The effect of the degree of conformational rigidity and/or flexibility on preorganisation in artificial molecular receptors continues to be actively explored by supramolecular chemists. This work describes a bis-porphyrin architecture, linked via a rigid polycyclic backbone, in which a sterically bulky 2,3,5,6-tetramethylphenyl diimide core restricts rotation to afford two non-interconvertible tweezer conformations; syn- and anti-. After separation, the host-guest chemistry of each conformation was studied independently. The difference in host geometry allows only the syn-conformation to form a strong 1 : 1 bis-porphyrin complex with the diamino ligand 1,4-diazabicyclo[2.2.2]octane (DABCO) (K11 = 1.25 × 108 M-1), with the anti-conformation adopting a 2 : 2 sandwich complex with DABCO (K22 = 5.57 × 1017 M-3).

ß-Cyclodextrin- and adamantyl-substituted poly(acrylate) self-assembling aqueous networks designed for controlled complexation and release of small molecules.

Three aqueous self-assembling poly(acrylate) networks have been designed to gain insight into the factors controlling the complexation and release of small molecules within them. These networks are formed between 8.8% 6A-(2-aminoethyl)amino-6A-deoxy-6A-ß-cyclodextrin, ß-CDen, randomly substituted poly(acrylate), PAAß-CDen, and one of the 3.3% 1-(2-aminoethyl)amidoadamantyl, ADen, 3.0% 1-(6-aminohexyl)amidoadamantyl, ADhn, or 2.9% 1-(12-aminododecyl)amidoadamantyl, ADddn, randomly substituted poly(acrylate)s, PAAADen, PAAADhn and PAAADddn, respectively, such that the ratio of ß-CDen to adamantyl substituents is ca. 3:1. The variation of the characteristics of the complexation of the dyes methyl red, methyl orange and ethyl orange in these three networks and by ß-cyclodextrin, ß-CD, and PAAß-CDen alone provides insight into the factors affecting dye complexation. The rates of release of the dyes through a dialysis membrane from the three aqueous networks show a high dependence on host-guest complexation between the ß-CDen substituents and the dyes as well as the structure and the viscosity of the network as shown by ITC, 1H NMR and UV-vis spectroscopy, and rheological studies. Such networks potentially form a basis for the design of controlled drug release systems.

Excited-state dynamics of the medicinal pigment curcumin in a hydrogel.

Curcumin is a yellow polyphenol with multiple medicinal effects. These effects, however, are limited due to its poor aqueous stability and solubility. A hydrogel of 3% octadecyl randomly substituted polyacrylate (PAAC18) has been shown to provide high aqueous stability for curcumin under physiological conditions, offering a route for photodynamic therapy. In this study, the excited-state photophysics of curcumin in the PAAC18 hydrogel is investigated using a combination of femtosecond transient absorption and fluorescence upconversion spectroscopy. The transient absorption results reveal a multiexponential decay in the excited-state kinetics with fast (1 ps & 15 ps) and slow (110 ps & ≈5 ns) components. The fast decay component exhibits a deuterium isotope effect with D2O in the hydrogel, indicating that the 15 ps decay component is attributable to excited-state intramolecular hydrogen atom transfer of curcumin in the PAAC18 hydrogel. In addition, solvent reorganisation of excited-state curcumin is investigated using multiwavelength femtosecond fluorescence upconversion spectroscopy. The results show that the dominant solvation response (τ = 0.08 ps) is a fast inertial motion owing to the presence of bulk-like water in the vicinity of the hydrophobic octadecyl substituents of the PAAC18 hydrogel. The results also show an additional response with longer time constants of 1 and 6 ps, which is attributable to translational diffusion of confined water molecules in the three-dimensional, cross-linking network of the octadecyl substituents of PAAC18. Overall, we show that excited-state intramolecular hydrogen atom transfer and solvent reorganisation are major photophysical events for curcumin in the PAAC18 hydrogel.

Supramolecular polymer assembly in aqueous solution arising from cyclodextrin host-guest complexation.

The employment of cyclodextrin host-guest complexation to construct supramolecular assemblies with an emphasis on polymer networks is reviewed. The main driving force for this supramolecular assembly is host-guest complexation between cyclodextrin hosts and guest groups either of which may be discrete molecular species or substituents on a polymer backbone. The effects of such complexation on properties at the molecular and macroscopic levels are discussed. It is shown that cyclodextrin complexation may be used to design functional polymer materials with tailorable properties, especially for photo-, pH-, thermo- and redox-responsiveness and self-healing.

A Cyclodextrin-Based Photoresponsive Molecular Gate that Functions Independently of Either Solvent or Potentially Competitive Guests.

The photoinduced interconversion between cinnamido-substituted cyclodextrins constitutes a gating switch through which the substituent moves to open or block access to the cyclodextrin cavity. Most unusually for a cyclodextrin-based device, the operation of this gate is solvent-independent and unaffected by potentially competitive guests. It occurs in MeOH and DMSO, as well as in water. This contrasts with other cyclodextrin inclusion phenomena that are usually driven by hydrophobic effects and limited to aqueous media.

Femtosecond transient absorption spectroscopy of the medicinal agent curcumin in diamide linked γ-cyclodextrin dimers.

Curcumin is a biologically active polyphenol and a yellow pigment extracted from turmeric. Our previous study has shown effective encapsulation of curcumin using diamide linked γ-cyclodextrin dimers, namely 66γCD2su and 66γCD2ur, through cooperative 1:1 host-guest complexation. In this study, the excited-state dynamics of curcumin complexed with either 66γCD2su or 66γCD2ur in water are investigated using femtosecond transient absorption spectroscopy. Both 66γCD2su-curcumin and 66γCD2ur-curcumin complexes in water show only an excited-state absorption (ESA) band at 530 nm without any stimulated emission (SE) signals, indicating non-radiative decays as the major relaxation pathways. The ESA dynamics of 66γCD2su-curcumin are similar to those of 66γCD2ur-curcumin, consisting of a rapid growth component and three decay components. The growth component, which has a time constant of 0.25-0.41 ps, is assigned to solvent reorganization. The relatively fast decay components with time constants of 9.3-21.8 ps show significant deuterium isotope effect, consistent with the presence of excited-state intramolecular hydrogen atom transfer (ESIHT) of curcumin. The small-amplitude and slow decay components may be attributed to the dynamics of complexed curcumin and molecular motions due to flexibility of 66γCD2su and 66γCD2ur. In addition, transient absorption anisotropy measurements reveal slow rotational motions of 66γCD2su-curcumin and 66γCD2ur-curcumin complexes. The overall results show that complexation in 66γCD2su and 66γCD2ur has pronounced effects on the photophysics of curcumin.

The capture and stabilization of curcumin using hydrophobically modified polyacrylate aggregates and hydrogels.

Hydrophobically modified polyacrylates are shown to suppress the degradation of the medicinal pigment curcumin under physiological conditions. In aqueous solution, the 3% octadecyl randomly substituted polyacrylate, PAAC18, forms micelle-like aggregates at a concentration of <1 wt % and a hydrogel at >1 wt %. Under both conditions, PAAC18 shows a remarkable ability to suppress the degradation of curcumin at pH 7.4 and 37 °C such that its degradation half-life is increased by 1600-2000-fold. The suppression of degradation is attributed to hydrophobic interactions between curcumin and the octadecyl substituents of PAAC18 within the micelle-like aggregates and the hydrogel, as indicated by 2D NOESY (1)H NMR spectroscopy. UV-visible absorption titration results are consistent with the interaction of curcumin with five octadecyl substituents on average, which appears to substantially exclude water and greatly decrease the curcumin degradation rate. Dynamic light scattering and zeta potential measurements show the average hydrodynamic diameters of the PAAC18 aggregates to be 0.86-1.15 µm with a negative surface charge. In contrast to the octadecyl substitution, the 3% dodecyl randomly substituted polyacrylate, PAAC12, shows a negligible effect on slowing the degradation of curcumin, consistent with the dodecyl substituents being insufficiently long to capture curcumin in a adequately hydrophobic environment. These observations indicate the potential for PAAC18 to act as a model drug delivery system.

Diamide linked γ-cyclodextrin dimers as molecular-scale delivery systems for the medicinal pigment curcumin to prostate cancer cells.

Diamide linked γ-cyclodextrin (γ-CD) dimers are proposed as molecular-scale delivery agents for the anticancer agent curcumin. N,N'-Bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)succinamide (66γCD2su) and N,N'-bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)urea (66γCD2ur) markedly suppress the degradation of curcumin by forming a strong 1:1 cooperative binding complexes. The results presented in this study describe the potential efficacy of 66γCD2su and 66γCD2ur for intracellular curcumin delivery to cancer cells. Cellular viability assays demonstrated a dose-dependent antiproliferative effect of curcumin in human prostate cancer (PC-3) cells that was preserved by the curcumin-66γCD2su complex. In contrast, delivery of curcumin by 66γCD2ur significantly delayed the antiproliferative effect. We observed similar patterns of gene regulation in PC-3 cells for curcumin complexed with either 66γCD2su or 66γCD2ur in comparison to curcumin alone, although curcumin delivered by either 66γCD2su or 66γCD2ur induces a slightly higher up-regulation of heme oxygenase-1. Highlighting their nontoxic nature, neither 66γCD2su nor 66γCD2ur carriers alone had any measurable effect on cell proliferation or candidate gene expression in PC-3 cells. Finally, confocal fluorescence imaging and uptake studies were used to demonstrate the intracellular delivery of curcumin by 66γCD2su and 66γCD2ur. Overall, these results demonstrate effective intracellular delivery and action of curcumin when complexed with 66γCD2su and 66γCD2ur, providing further evidence of their potential applications to deliver curcumin effectively in cancer and other treatment settings.

Femtosecond transient absorption spectroscopy of copper(II)-curcumin complexes.

Ligand-metal interaction between curcumin and Cu(II) in methanol and sodium dodecyl sulfate (SDS) micelles was investigated using fluorescence spectroscopy and transient absorption spectroscopy. The Cu(II) ion exhibits a high efficiency in quenching the fluorescence of curcumin. By quantifying fluorescence quenching as a function of Cu(II) concentration, the complexation constants, K(1) and K(2), for the formation of the 1 : 1 and 1 : 2 Cu(II)-curcumin complexes, [Cu(II)-Cur](+) and [Cu(II)-Cur(2)], have been determined. In methanol, K(1) and K(2) are (1.33 ± 0.47) × 10(8) M(-1) and (6.79 ± 1.77) × 10(5) M(-1), respectively, whereas those in SDS micelles are (9.90 ± 1.68) × 10(5) M(-1) and (1.70 ± 0.48) × 10(6) M(-1), respectively. The transient absorption spectra of curcumin and the Cu(II)-curcumin complexes from 520 nm to 700 nm show a combination of stimulated emission and excited state absorption (ESA). However, the transient absorption signal at 500 nm corresponds to ESA exclusively. For curcumin, the ESA kinetics exhibit two rising components with time constants of 0.9 ps and 8.2 ps in methanol, and 0.5 ps and 2.5 ps in SDS micelles, which are consistent with solvation dynamics of excited state curcumin in these media. In addition, the ESA kinetics show a decay component with a time constant of 125 ps in methanol and 64 ps in SDS micelles, reflecting the excited state intramolecular hydrogen atom transfer of curcumin in these media. The ESA kinetics of the Cu(II)-curcumin complexes exhibit a sharp rise and a fast decay with a time constant of approximately 1 ps in both media due to the strong interaction between Cu(II) and curcumin.

Options for change in the Australian energy profile.

Climate change is occurring largely as a result of increasing CO(2) emissions whose reduction requires greater efficiency in energy production and use and diversification of energy sources away from fossil fuels. These issues were central to the United Nation climate change discussions in Durban in December 2011 where it was agreed that a legally binding agreement to decrease greenhouse gas emissions should be reached by 2015. In the interim, nations were left with the agreement reached at the analogous 2009 Copenhagen and 2010 Cancun meetings that atmospheric CO(2) levels should be constrained to limit the global temperature rise to 2 °C. However, the route to this objective was largely left to individual nations to decide. It is within this context that options for reduction in the 95 % fossil fuel dependency and high CO(2) emissivity of the Australian energy profile using current technologies are considered. It is shown that electricity generation in particular presents significant options for changing to a less fossil fuel dependent and CO(2) emissive energy profile.

Cooperative binding and stabilization of the medicinal pigment curcumin by diamide linked γ-cyclodextrin dimers: a spectroscopic characterization.

Diamide linked γ-cyclodextrin (γ-CD) dimers are used to capture curcumin and suppress its decomposition in water. In this study, succinamide and urea linked γ-CD dimers joined through the C6(A) carbon on each γ-CD are used. The γ-CD dimers, 66γCD(2)su and 66γCD(2)ur, show a remarkable ability to suppress the decomposition of curcumin and extend its half-life from less than 30 min to greater than 16 h. The 1:1 association of curcumin with 66γCD(2)su and 66γCD(2)ur has high stability constants of 8.7 × 10(6) M(-1) and 2.0 × 10(6) M(-1), respectively. In addition, 2D (1)H NOESY NMR results show specific hydrogen interactions in the association of curcumin with 66γCD(2)su and 66γCD(2)ur, consistent with the cooperative binding of curcumin by both γ-CD annuli of 66γCD(2)su and 66γCD(2)ur. The interactions between curcumin in the linked γ-CD dimers and surfactant micelles were studied using fluorescence spectroscopy. While linked γ-CD dimer-bound curcumin has a negligible fluorescence quantum yield, a significant increase in fluorescence intensity (Φ(fl) > 2%) in the presence of micelles suggests that curcumin is delivered to the micelle. The overall results indicate that the diamide linked γ-CD dimers are highly promising systems for curcumin delivery in vivo due to effective curcumin stabilization.

Tailoring Polymeric Hydrogels through Cyclodextrin Host-Guest Complexation.

A close correllation between molecular-level interactions and macroscopic characteristics of polymer networks exists. The characteristics of the polymeric hydrogels assembled from ß-cyclodextrin (ß-CD) and adamantyl (AD) substituted poly(acrylate)s can be tailored through selective host-guest complexation between ß-CD and AD substituents and their tethers. Dominantly, steric effects and competitive intra- and intermolecular host-guest complexation are found to control poly(acrylate) isomeric inter-strand linkage in polymer network formation. This understanding of the factors involved in polymeric hydrogel formation points the way towards the construction of increasingly sophisticated biocompatible materials.

The foundation of a light driven molecular muscle based on stilbene and alpha-cyclodextrin.

The rotaxane 3(E,E) serves as the basis of a light driven molecular muscle, where reversible photoisomerisation of the stilbene units causes the cyclodextrins to move off and on the stilbene units, contracting and extending the distance between the blocking groups.

Complexation behavior of alpha-, beta-, and gamma-cyclodextrin in modulating and constructing polymer networks.

A systematic study of the host-guest complexation by alpha-, beta-, and gamma-cyclodextrin (CD) in either the free state or as substituents of poly(acrylic acid) (PAA) with the hydrophobic n-octadecyl groups, C18, substituted onto PAA (HMPAA) and its effect on polymer aggregation and network formation is reported. Free alpha-CD, beta-CD, and gamma-CD mask hydrophobic associations between the C18 substituent of HMPAA in aqueous solution and form host-guest complexes with a 1:1 or CD:C18 substituent stoichiometry at 0.5 wt % polymer concentration. For alpha-CD this host-guest stoichiometry changes to 2:1 or 2alpha-CD:C18 at > or =1 wt % polymer concentrations but not for beta-CD and gamma-CD. Shear-thickening occurs when gamma-CD complexes C18 HMPAA substituents. Upon addition of sodium dodecyl sulfate, SDS (SDS:CD = 1:1), the hydrophobic associations between C18 diminished by alpha-CD masking were fully restored, were only partly restored in the case of beta-CD, and not restored for gamma-CD. When alpha- and beta-CD substituted PAA (alpha-CDPAA and beta-CDPAA) were mixed with HMPAA polymer, networks formed. As for free beta-CD, the beta-CD substituents of beta-CDPAA also formed 1:1 or beta-CD:C18 stoichiometry host-guest complexes with the C18 substituents of HMPAA. The alpha-CD substituents of alpha-CDPAA also formed 1:1 or alpha-CD:C18 stoichiometry host-guest complexes with some indication of the formation of 2:1 or 2alpha-CD:C18 stoichiometry host-guest complexes at polymer concentrations > or =1 wt %. The polymer networks formed by beta-CDPAA with HMPAA are less viscous than those formed by alpha-CDPAA, for which shear-thickening occurs at polymer concentrations > or =2 wt %. It is evident that the difference in CD annular size and its match with the C18 of HMPAA control the diversity of the interactions of alpha-CD, beta-CD, gamma-CD, alpha-CDPAA, and beta-CDPAA with HMPAA.

Synthesis of alpha-cyclodextrin [2]-rotaxanes using chlorotriazine capping reagents.

Ten alpha-cyclodextrin [2]-rotaxanes have been prepared with alkane-, stilbene- and azobenzene-based axles, capped through nucleophilic substitution of either 2-chloro-4,6-dimethoxy-1,3,5-triazine or 2,4-dichloro-6-methoxy-1,3,5-triazine in aqueous solution, followed by further substitution of the remaining triazinyl chlorine in some cases when the latter capping reagent was used. In one case the rotaxane is a [c(2)]-daisy chain obtained by double-capping the corresponding hermaphroditic cyclic dimer. One of the rotaxane azobenzene derivatives was shown to undergo photochemically-induced reversible interconversion between its trans- and cis-isomers, causing the cyclodextrin to move back and forth along the axle, and therefore behave as a molecular shuttle. The methodology is therefore shown to constitute a general and versatile approach for the construction of supramolecular species as the basis of photochemical molecular devices.

Molecular fibers and wires in solid-state and solution self-assemblies of cyclodextrin [2]rotaxanes.

Cyclodextrin [2]rotaxanes have been prepared by coupling dimethylanilines with dicarboxylic acids using DMT-MM, in aqueous solutions of alpha-cyclodextrin, and the example illustrated shows unusual fluorescence emission and other spectroscopic behavior characteristic of the formation of molecular wires in solution, similar to the fibers observed in the solid state.

Synthesis and characterization of water-operative cationic and anionic metal-ion activated molecular receptors for aromatic anions.

Two new, octadentate, water-soluble, macrocyclic ligands, 1,4,7,10-tetrakis((2S)-(-)-2-hydroxy-3-[3'-(N,N,N-trimethylammonium)-phenoxy]-propyl)-1,4,7,10-tetraazacyclododecane tetratriflate, ((S)-tmappc12 triflate, L1 triflate) and 1,4,7,10-tetrakis((2S)-(-)-2-hydroxy-3-[2'-sulfo-4'-methylphenoxy]-propyl)-1,4,7,10-tetraazacyclododecane, ((S)-sthmppc12, L2H4) have been prepared with a view to using them to study anion sequestration in aqueous solution. Their pKa and metal-ion binding constant values with a range of alkaline earth, transition, and post-transition metals are reported. The eight-coordinate, water-soluble Cd(II) complexes of (L1)4+ and (L2)4-, [CdL1](CF3SO3)6 and (NH4)2-[CdL2], the former cationic and the latter anionic, have both been shown to be capable of acting as anion receptors in aqueous solution. The binding constant values (log(K/M-1) given in parentheses) for binding by the cationic receptor to a range of aromatic anions in water are p-nitrophenolate (1.7), p-formylphenolate (2.1), p-nitrobenzoate (3.0), p-aminobenzoate (4.5), p-dimethylaminobenzoate (>4.5), D- and L-tryptophanate (1.6, 2.2), phenoxyacetate (2.1), and acetate (2.3). With the anionic receptor, nonzero binding constants were only measurable for p-nitrobenzoate (approximately 0.4), p-aminobenzoate (2.0), and p-dimethylaminobenzoate (1.8). By reference to the X-ray determined structures of related, but water-insoluble inclusion complexes, anion retention is thought to occur within a hydrophobic cavity, with four convergent hydroxy groups at its base, which develops in (L1)4+ and (L2)4- through the juxtapositioning of aromatic rings that occurs as a consequence of octadentate coordination.

Harnessing the energy of molecular recognition in a nanomachine having a photochemical on/off switch.

6A-Deoxy-6A-(N-methyl-3-phenylpropionamido)-beta-cyclodextrin operates as a molecular machine, where the amide group serves as a torsion bar to harness the work output resulting from extraction of 1-adamantanol and consequent complexation of the aryl substituent by the cyclodextrin, when the latter behave as the piston and cylinder, respectively, of a molecular pump. At 25 degrees C, the complexation changes the ratio of the amide (Z)- and (E)-isomers from 2.4:1 to 25:1, on which basis the work performed on the amide bond is calculated to be 1.4 kcal mol-1. trans-6A-Deoxy-6A-(N-methylcinnamido)-beta-cyclodextrin and the cis isomer function as a more advanced version of the machine, with the alkene moiety serving as a photochemical on/off switch. Irradiation at 300 nm converts the trans cinnamide to the cis isomer, while the reverse process occurs at 254 nm. With the cis isomer there is little interaction of the phenyl group with the cyclodextrin cavity, so in that mode the machine is turned off. By contrast, complexation of the aryl substituent by the cyclodextrin occurs with the trans cinnamide and changes the ratio of the amide (Z)- and (E)-isomers from 2.6:1 to 100:1. Consequently, in this mode the machine is turned on, and the work harnessed by the amide bond is 2.1 kcal mol-1.