Synthesis of monofunctional curcumin derivatives, clicked curcumin dimer, and a PAMAM dendrimer curcumin conjugate for therapeutic applications

Curcumin, the primary active ingredient in the spice turmeric, was converted to reactive monofunctional derivatives (carboxylic acid/azide/alkyne). The derivatives were employed to produce a 3 + 2 azide-alkyne "clicked" curcumin dimer and a poly(amidoamine) (PAMAM) dendrimer-curcumin conjugate. The monofunctional curcumin derivatives retain biological activity and are efficient for labeling and dissolving amyloid fibrils. The curcumin dimer selectively destroys human neurotumor cells. The synthetic methodology developed affords a general strategy for attaching curcumin to various macromolecular scaffolds.     

X-Ray Diffraction Analysis and Luminescent Study of the Structure of the Tb2(CF3COO)6(H2O)6 Dimer Obtained from Terbium(III) Carbonate

The molecular and crystal structure of the terbium(III) trifluoroacetate trihydrate dimer synthesized from terbium(III) carbonate was studied by X-ray diffraction (XRD) analysis. Luminescent data unambiguously show that the compound is one of the isomers of Tb₂(CF₃COO)₆(H₂O)₆ composition. Evidence has been found for the presence of another isomer in the terbium(III) dimer obtained from terbium(III) hydroxide.     

Differential speciation of ferriprotoporphyrin IX in the presence of free base and diprotic 4-aminoquinoline antimalarial drugs

The crystal structures of the μ-propionato dimer and π–π dimer of ferriprotoporphyrin IX (Fe(III)PPIX) have been determined by single crystal X-ray diffraction (SCD). Both species were obtained in the presence of the synthetic 4-aminoquinoline antimalarial drug, amodiaquine (AQ). The solution that afforded the μ-propionato dimer contained AQ as a free base (i.e. with both quinoline and terminal amine nitrogen atoms neutral). On the other hand, when the diprotic salt of AQ was included in the crystallization medium, the Fe(III)PPIX π–π dimer was obtained. The structure of the μ-propionato dimer, which is the discrete structural unit that constitutes haemozoin (malaria pigment), is identical to that obtained previously in presence of chloroquine free base. We suspect that the drug, via its two available basic sites, facilitates dissociation of one of the two Fe(III)PPIX propionic acid groups to yield a propionate group that is required for reciprocal coordination of the metal centre to form the centrosymmetric dimer. On the other hand, this proton transfer is not possible when the drug is present as a diprotic salt. In this case, the π–π dimer of Fe(III)PPIX is obtained. In the current study, the π–π dimer of haemin (chloro-Fe(III)PPIX) was obtained as a DMF solvate from non-aqueous aprotic solution (dimethyl formamide and chloroform), however the π–π dimer is also known to exist in aqueous solution (as aqua- or hydroxo-Fe(III)PPIX), where it is purportedly involved in the nucleation of haemozoin. We have been able to unambiguously determine the positions of all non-hydrogen atoms, as well as locate or assign all hydrogen atoms in the structure of the π–π dimer, which was not possible in the SCD structure of haemin reported by Koenig in 1965 owing to disorder in the vinyl and methyl substituents. Interestingly, no disorder in the methyl and vinyl groups is observed in the current structure. Both the π–π and μ-propionato dimers of Fe(III)PPIX are important species in the haem detoxification pathway in the malaria parasite and other blood-feeding organisms, and the structural insight gained in this study may assist target-driven design of new chemotherapeutic agents.     

Dimerization of the keto tautomer of acetohydroxamic acid-infrared matrix isolation and theoretical study

Dimerization of the keto tautomer of acetohydroxamic acid has been studied using FTIR matrix isolation spectroscopy and DFT(B3LYP)/6-31+G(d,p) calculations. Analysis of CH3CONHOH/Ar matrix spectra indicates formation of two dimers in which two intramolecular CO...HON bonds within two interacting acetohydroxamic acid molecules are retained. A chain dimer I is stabilized by the intermolecular CO...HN hydrogen bond, whereas the cyclic dimer II is stabilized by two intermolecular NH...O(H)N bonds. Twelve vibrations were identified for dimer I and six vibrations for dimer II; the observed frequency shifts show a good agreement with the calculated ones for the structures I and II. Both dimers have comparable binding energies (DeltaE(ZPE)(CP)I, II=-7.02, -6.34 kcal mol-1) being less stable than calculated structures III and IV (DeltaE(ZPE)(CP)III, IV=-9.50, -8.87 kcal mol-1) in which one or two intramolecular hydrogen bonds are disrupted. In the most stable 10-membered cyclic dimer III, two intermolecular CO...HON hydrogen bonds are formed at expense of intramolecular hydrogen bonds of the same type. The formation of the less stable (AHA)2 dimers in the studied matrixes indicates that the formation of (AHA)2 is kinetically and not thermodynamically controlled.     

Oxidation state dependence of the geometry, electronic structure, and magnetic coupling in mixed oxo- and carboxylato-bridged manganese dimers

Approximate density functional theory has been used to investigate changes in the geometry and electronic structure of the mixed oxo- and carboxylato-bridged dimers [Mn(2)(mu-O)(2)(O(2)CH)(NH(3))(6)](n+)and [Mn(2)(mu-O)(O(2)CH)(2)(NH(3))(6)](n+)in the Mn(IV)Mn(IV), Mn(III)Mn(IV), and Mn(III)Mn(III) oxidation states. The magnetic coupling in the dimer is profoundly affected by changes in both the bridging ligands and Mn oxidation state. In particular, change in the bridging structure has a dramatic effect on the nature of the Jahn-Teller distortion observed for the Mn(III) centers in the III/III and III/IV dimers. The principal magnetic interactions in [Mn(2)(mu-O)(2)(O(2)CH)(NH(3))(6)](n+)() involve the J(xz/xz)and J(yz/yz) pathways but due to the tilt of the Mn(2)O(2) core, they are less efficient than in the planar di-mu-oxo structure and, consequently, the calculated exchange coupling constants are generally smaller. In both the III/III and III/IV dimers, the Mn(III) centers are high-spin, and the Jahn-Teller effect gives rise to axially elongated Mn(III) geometries with the distortion axis along the Mn-O(c) bonds. In the III/IV dimer, the tilt of the Mn(2)O(2) core enhances the crossed exchange J(x)()()2(-)(y)()()2(/)(z)()()2 pathway relative to the planar di-mu-oxo counterpart, leading to significant delocalization of the odd electron. Since this delocalization pathway partially converts the Mn(IV) ion into low-spin Mn(III), the magnetic exchange in the ground state can be considered to arise from two interacting spin ladders, one is the result of coupling between Mn(IV) (S = 3/2) and high-spin Mn(III) (S = 2), the other is the result of coupling between Mn(IV) (S = 3/2) and low-spin Mn(III) (S = 1). In [Mn(2)(mu-O)(O(2)CH)(2)(NH(3))(6)](n+)(), both the III/III dimer and the lowest energy structure for the III/IV dimer involve high-spin Mn(III), but the Jahn-Teller axis is now orientated along the Mn-oxo bond, giving rise to axially compressed Mn(III) geometries with long Mn-O(c) equatorial bonds. In the IV/IV dimer, the ferromagnetic crossed exchange J(yz)()(/)(z)()()2 pathway partially cancels J(yz/yz) and, as a consequence, the antiferromagnetic J(xz/xz) pathway dominates the magnetic coupling. In the III/III dimer, the J(yz/yz) pathway is minimized due to the smaller Mn-O-Mn angle, and since the ferromagnetic J(yz)()(/)(z)()()2 pathway largely negates J(xz/xz), relatively weak overall antiferromagnetic coupling results. In the III/IV dimer, the structures involving high-spin and low-spin Mn(III) are almost degenerate. In the high-spin case, the odd electron is localized on the Mn(III) center, and the resulting antiferromagnetic coupling is similar to that found for the IV/IV dimer. In the alternative low-spin structure, the odd electron is significantly delocalized due to the crossed J(yz)()(/)(z)()()2 pathway, and cancellation between ferromagnetic and antiferromagnetic pathways leads to overall weak magnetic coupling. The delocalization partially converts the Mn(IV) ion into high-spin Mn(III), and consequently, the spin ladders arising from coupling of Mn(IV) (S = 3/2) with high-spin (S = 2) and low-spin (S = 1) Mn(III) are configurationally mixed. Thus, in principle, the ground-state magnetic coupling in the mixed-valence dimer will involve contributions from three spin-ladders, two associated with the delocalized low-spin structure and the third arising from the localized high-spin structure.     

Tetrapodal amidoxime ligands I. Coordination isomerism due to self-complementary dimerization of a pyramidal cobalt(III) coordination module

A bis-μ-amidoximato-bridged cobalt(III) dimer obtained with a new tetrapodal ligand possesses interesting structural parameters as a consequence of intramolecular hydrogen bonding intentionally built into the complex. Its synthesis and properties are described. The new ligand type combines attributes of two previously described ligand classes: It binds a metal ion in a tetrapodal pentadentate fashion and forms a pseudomacrocycle through hydrogen bonds, characteristic of chelating oxime ligands. Coordination isomerism, which is a consequence of dimer formation, has been analyzed by means of X-ray crystallography and carbon-13 nuclear magnetic resonance spectroscopy.     

ABSORPTION AND FLUORESCENCE SPECTROSCOPIC STUDIES ON DIMERIZATION OF CHLOROALUMINUM (III) PHTHALOCYANINE TETRASULFONATE IN AQUEOUS ALCOHOLIC SOLUTIONS

Dimerization of chloroaluminum (III) phthalocyanine tetrasulfonates (AIPCS) has been observed in different aqueous alcoholic solvents at room temperature by absorption and fluorescence spectroscopic methods. Both absorption and fluorescence spectral bands of the dimer are red shifted by ca 550 cm^-1 from the monomer Q bands in the corresponding spectra, suggesting that the interaction energy between the two monomer subunits is very weak. The fluorescence lifetime of the dimer is longer ( ca 9.5 ns) than that of the monomer ( ca 7–8 ns). These spectral behaviors of AIPCS dimer contrast with those of transition-metallaloid phthalocyanine dimers, which usually have a nonfluorescent face-to-face stacking conformation. The dimer fluorescence is interpreted to be due to the fact that the lowest excited singlet state of the dimer is lower in energy than a charge-resonance state, based on the excitoncoupling theory applied to the face-to-face slipping conformation. The dimerization constant determined spectrometrically decreases with an increase of water content in the aqueous alcoholic solution. Propanol and ethanol have been observed to be more effective than methanol in promoting dimerization. These results indicate that a specific interaction of water with AIPCS plays an important role in the inhibition of dimerization of AIPCS.     

Photophysical studies on binding of curcumin to bovine serum albumins

The excited-state photophysical properties of curcumin in the presence of bovine serum albumin (BSA) have been studied. The absorption and fluorescence changes in curcumin on binding to BSA have been followed at varying concentrations of either curcumin or BSA to determine the binding constant, which has been found to be approximately 10(4) to 10(5) M(-1). Stopped-flow kinetics studies suggested at least two distinct kinetic steps for the binding of curcumin to BSA. The photophysical properties of the singlet-excited state of the curcumin-BSA complex have also been studied. Whereas the absorption spectrum of curcumin is redshifted, the fluorescence spectrum of curcumin was blueshifted in the presence of BSA. The fluorescence quantum yield of curcumin on complexing with BSA was approximately 0.05. Steady-state fluorescence anisotropy studies showed a significant increase in the anisotropy value of 0.37 in BSA-bound curcumin. The fluorescence decay of the curcumin-BSA complex followed a biexponential decay with fluorescence lifetimes of 413 ps (33%) and 120 ps (67%). On the basis of these complementary results, it has been concluded that curcumin shows very high binding to BSA, probably at the hydrophobic cavities inside the protein.     

A biomimetic approach to artificial photosynthesis: Ru(II)-polypyridine photo-sensitisers linked to tyrosine and manganese electron donors

The paper describes recent advances towards the construction of functional mimics of the oxygen evolving complex in photosystem II (PSII) that are coupled to photoinduced charge separation. Some key principles of PSII and artificial systems for light-induced charge accumulation are discussed. Systems are described where biomimetic electron donors--manganese complexes and tyrosine--have been linked to a Ru(II)-polypyridine photosensitiser. Oxidation of the donors by intramolecular electron transfer from the photo-oxidised Ru(III) complex has been studied using optical flash photolysis and EPR experiments. A step-wise electron transfer Mn(III,III)-->tyrosine Ru(III) has been demonstrated, in analogy to the reaction on the donor side of PSII. Electron transfer from the tyrosine to Ru(III) was coupled to tyrosine deprotonation. This resulted in a large reorganisation energy and thus a slow reaction rate, unless the tyrosine was hydrogen bonded or already deprotonated. A comparison with analogous reactions in PSII is made. Finally, light-induced oxidation of a manganese dimer linked to a Ru(II)-photosensitiser has been observed. Preliminary results suggest the possibility of photo-oxidising manganese dimers in several steps, which is an important advancement towards water oxidation.     

Ab initio calculations of structures and interaction energies of toluene dimers including CCSD(T) level electron correlation correction

The intermolecular interaction energy of the toluene dimer has been calculated with the ARS-F model (a model chemistry for the evaluation of intermolecular interaction energy between ARomatic Systems using Feller's method), which was formerly called as the AIMI model III. The CCSD(T) (coupled cluster calculations with single and double substitutions with noniterative triple excitations) interaction energy at the basis set limit has been estimated from the second-order Moller-Plesset perturbation interaction energy at the basis set limit obtained by Feller's method and the CCSD(T) correction term obtained using a medium-size basis set. The cross (C(2)) dimer has the largest (most negative) interaction energy (-4.08 kcal/mol). The antiparallel (C(2h)) and parallel (C(S)) dimers (-3.77 and -3.41 kcal/mol, respectively) are slightly less stable. The dispersion interaction is found to be the major source of attraction in the toluene dimer. The dispersion interaction mainly determines the relative stability of the stacked three dimers. The electrostatic interaction of the stacked three dimers is repulsive. Although the T-shaped and slipped-parallel benzene dimers are nearly isoenergetic, the stacked toluene dimers are substantially more stable than the T-shaped toluene dimer (-2.62 kcal/mol). The large dispersion interaction in the stacked toluene dimers is the cause of their enhanced stability.     

Exploring the localized-to-delocalized boundary in mixed-valence systems using infrared spectroelectrochemistry

Infrared spectroelectrochemistry has been used to explore the vibrational properties of a pyrazine-bridged osmium-polypyridine dimer as a function of its formally metal-centered oxidation states (i.e., Os(II)Os(II), Os(II)Os(III), and Os(III)Os(III)). The infrared spectrum of the "mixed-valent" species is particularly interesting and exhibits features consistent with both electronic localization and delocalization on the vibrational time scale, as revealed by the presence of both (i) a highly active totally symmetric mode from the bridging pyrazine ligand (nu(8a)), and (ii) total coalescence of at least four modes from peripheral bipyridine ligands. The nature and origin of the observed peaks were confirmed by analysis of the shifts in vibrational frequencies accompanying deuteration of pyrazine and also by comparison of the data for the dimeric complexes with those for the parent monomers.     

A Panchromatic Cyclometalated Iridium Dye Based on 2-Thienyl-Perimidine

Though 2-arylperimidines have never been used in iridium(III) chemistry, the present study on structural, electronic and optical properties of N-unsubstituted and N-methylated 2-(2-thienyl)perimidines, supported by DFT/TDDFT calculations, has shown that these ligands are promising candidates for construction of light-harvesting iridium(III) complexes. In contrast to N-H perimidine, the N-methylated ligand gave the expected cyclometalated μ-chloro-bridged iridium(III) dimer which was readily converted to a cationic heteroleptic complex with 4,4′-dicarboxy-2,2′-bipyridine. The resulting iridium(III) dye exhibited panchromatic absorption up to 1000 nm and was tested in a dye-sensitized solar cell.     

Resonance raman evidence for μ-oxo linkage in ferriporphyrins

The UV-Visible absorption and resonance Raman spectra of the μ-oxo iron(III) deuteroporphyrin dimethyl ester has been studied and compared to the data obtained from the well known μ-oxo iron(III) tetraphenylporphyrin. The symmetric Fe-O-Fe stretching vibration is tentatively assigned to the 414 cm-1 line; but in contrast with the tetraphenylporphyrin dimer, no resonance enhancement is observed with excitation in the α,β region. The influence of the Fe-O-Fe angle on a charge transfer transition involving the μ-oxo linkage in the visible region is discussed.     

A simple RP-HPLC method for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate, in rat plasma and the application to pharmacokinetic study

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of curcumin and its prodrug, curcumin didecanoate (CurDD), in rat plasma. The analytes were extracted by ethyl acetate following the addition of sodium dodecyl sulfate, and separated on a reverse-phase C(18) column using a gradient mobile phase system of acetonitrile-tetrahydrofuran-water containing 0.1% formic acid. Detection by UV absorption at 425 nm gave a lower limit of quantitation (LLOQ) of 5 and 10 ng/mL for curcumin and CurDD in 50 μL of plasma, respectively. Intra- and inter-day precisions of quality control samples except those at LLOQ were within 15% for curcumin and CurDD, respectively, and the accuracies for both compounds were between 93.9 and 108%. The method was successfully applied to determine plasma concentration-time curves of curcumin and CurDD in rats following intravenous (i.v.) administration of curcumin or CurDD at doses of 1 mg/kg (calculated as curcumin). The results suggested that i.v. dosed CurDD provided sustained plasma levels of curcumin.     

Reversible switching between linear and ring polystyrenes bearing porphyrin end groups

A route to macrocyclic polymers based on a new unimolecular ring-closure process has been investigated. It involves the direct end-to-end coupling of an α,ω-bis[chloroiron(III) meso-tetraphenylporphyrin] telechelic linear polystyrene synthesized by living polymerization followed by chain-end functionalization. The corresponding macrocyclic polystyrene was obtained readily and selectively by intramolecular condensation of the α,ω-bis[chloroiron(III) meso-tetraphenylporphyrin] polymer ends in the presence of a base to yield a diiron(III)-μ-oxobis(porphyrin) dimer as ring-closing unit. Addition of dilute HCl was shown to rapidly reconvert the diiron(III)-μ-oxobis(porphyrin) unit into the initial bis[chloroiron(III) porphyrin], demonstrating the selectivity and complete reversibility of the cyclization process. The synthesis and detailed structural characterization of the α,ω-homodifunctional precursor and the corresponding macrocyclic polystyrene along with an analysis of the porphyrin dimerization reaction using NMR spectroscopy and size-exclusion chromatography coupled with a diode array detector are presented.     

Synthesis and coordination chemistry of organoiridium complexes supported by an anionic tridentate ligand

Treatment of deprotonated N-(dimethylaminoethyl)-2-diphenylphosphinoaniline with bis(cyclooctene)iridium chloride dimer affords a thermally stable iridium(I) olefin complex. Infrared analysis of the corresponding monocarbonyl iridium(I) compound indicates a relatively electron rich metal center. Reaction of the iridium(I) cyclooctene complex with iodomethane effects oxidation of the metal yielding a five-coordinate iridium(III) methyl iodide complex which reversibly coordinates tetrahydrofuran. X-ray crystallography confirms coordination of ether to the iridium(III) methyl iodide complex and NMR spectroscopic experiments establish an equilibrium constant of 1.66(9) M for tetrahydrofuran binding. A five-coordinate iridium(III) dimethyl complex has also been prepared and characterized by X-ray diffraction. Hydrogenolysis of the dialkyl species permits identification of a short-lived classical iridium(III) dihydride complex.     

Cobalt(III) Chaperone Complexes of Curcumin: Photoreduction,Cellular Accumulation and Light‐Selective Toxicity towards Tumour Cells

Light‐activated prodrugs offer the potential for highly selective tumour targeting. However, the application of many photoactivated chemotherapeutics is limited by a requirement for oxygen, or for short activation wavelengths that can damage surrounding tissue. Herein, we present a series of cobalt(III)‐curcumin prodrugs that can be activated by visible light under both oxygenated and hypoxic conditions. Furthermore, the photoproduct can be controlled by the activation wavelength: green light yields free curcumin, whereas blue light induces photolysis of curcumin to a phototoxic product. Confocal fluorescence microscopy and phototocytotoxicity studies in DLD‐1 and MCF‐7 tumour cells demonstrated that the cobalt(III) prodrugs are nontoxic in the dark but accumulate in significant concentrations in the cell membrane. When cells were treated with light for 15 min, the cytotoxicity of the cobalt complexes increased by up to 20‐fold, whereas free curcumin exhibited only a two‐fold increase in cytotoxicity. The nature of the ancillary ligand and cobalt reduction potential were found to strongly influence the stability and biological activity of the series.     

The synthesis and properties of iridium(III)-cored dendrimers with carbazole peripherally functionalized beta-diketonato dendrons

A simple convergent synthetic approach has been developed for the synthesis of iridium(III)-cored dendrimers with carbazole peripherally functionalized beta-diketonato dendrons. The zeroth- to third-generation green-emitting dendrimers were synthesized by reacting the corresponding beta-diketonato dendrons with iridium(III) dimer under mild conditions with good yields, respectively. This approach proved to be modular, and could be used to prepare blue-green-emitting and red-emitting dendrimers with the same beta-diketonato dendrons only by using different cyclometallating ligands. The resulting dendritic ligands and iridium(III)-cored dendrimers were well characterized. Their photoluminescent properties both in solution and in the solid state were tested. It was found that all the dendrimers retained the photophysical properties of the corresponding small analogues with high emission quantum yields (0.06-0.30). Preliminary results indicated that these dendrimers functionalized carbazole units exhibited distinct light-harvesting potential, resulting in a strong intense emission from the iridium core of the dendrimers.     

Spectrometric study on the interaction of dodecyltrimethylammonium bromide with curcumin

The interaction between dodecyltrimethylammonium bromide (DTAB) and curcumin has been studied in pH 5.0 sodium phosphate buffer using absorption and fluorescence measurements. With increasing DTAB concentration (C(DTAB)) from 0 to 20 mM, the absorption peak of curcumin at 430 nm, corresponding to the conjugated structure of curcumin, first weakens gradually into a shoulder but increases back into one peak with much higher absorption intensity. On the contrary, as C(DTAB) increases, the initial small absorption shoulder of curcumin at 355 nm, corresponding to the feruloyl unit of curcumin, first increases gradually into a clear peak but decreases back into one shoulder until almost disappeared finally. By remaining at nearly the same wavelength, the fluorescence of curcumin first decreases at C(DTAB) lower than 5 mM and then increases gradually up to C(DTAB) = 10 mM, which is followed by sharp increases of fluorescence intensity with marked blue-shifts at higher C(DTAB). The values of anisotropy and microviscosity of curcumin obtained from the fluorescence polarization technique also showed pronounced changes at different surfactant concentrations. The interaction mechanisms of DTAB with curcumin have been presented at low, intermediate, and high surfactant concentrations, which is relating to interaction forces, surfactant aggregations, as well as structural alterations of curcumin.