A 5,7-Dimethoxyflavone/Hydroxypropyl-β-Cyclodextrin Inclusion Complex with Anti-Butyrylcholinesterase Activity

This study aimed to improve the water solubility of 5,7-dimethoxyflavone (5,7-DMF) isolated from Kaempferia parviflora by complexation with 2-hydroxypropyl-β-cyclodextrin (HPβ-CD). The phase solubility profile of 5,7-DMF in the presence of HPβ-CD was classified as A_L-type and indicated a 1:1 mole ratio. Differential scanning colorimetry, X-ray diffraction, NMR and SEM analyses supported the formation of a 5,7-DMF/HPβ-CD inclusion complex involving the A ring of 5,7-DMF inside the HPβ-CD cavity. This is the first example of CD inclusion with the A ring of non-hydroxyl flavones. The stability and binding constants of the complexes were determined using the phase solubility and UV-vis absorption spectroscopy, respectively. The water solubility of 5,7-DMF was increased 361.8-fold by complexation with HPβ-CD and overcame the precipitation problem observed in aqueous buffers, such as during in vitro anti-butyrylcholinesterase activity assays. The 1:1 mole ratio of the 5,7-DMF/HPβ-CD complex showed a 2.7-fold higher butyrylcholinesterase inhibitory activity (in terms of the IC₅₀ value) compared to the non-complexed compound.     

Anti-Leishmanial activity of homo- and heteroleptic bismuth(III) carboxylates

Bismuth(III) complexes of NSAIDs (Non-Steroidal Anti Inflammatory Drugs) and substituted benzoic acids (o-methoxybenzoic acid, m-methoxybenzoic acid, o-nitrobenzoic acid, 3,5-diacetamidobenzoic acid, and 5-[(R/S)-2,3-dihydroxypropyl carbamoyl]-2-pyridine carboxylic acid) have been synthesised and fully characterised. Two new bis-carboxylato bismuth complexes have been characterised by single crystal X-ray diffraction, namely [PhBi(o-MeOC₆H₄CO₂)₂(bipy)]·0.5EtOH (bipy = 2,2'-bipyridine) and [PhBi(C₉H₁₁N₂O₃CO₂)₂(H₂O)]·6H₂O. All compounds were tested against the parasite Leishmania major promastigotes for their anti-Leishmanial activity and were further assessed for their toxicity to mammalian cells. The NSAID free acids and their bismuth derivatives show negligible anti-Leishmanial activity at concentrations 1.95 to 250 μg/mL against the promastigotes of L. major whereas in the case of mammalian cells only bismuth complexes of naproxen and mefenamic acid have significant effect at concentration ≥ 250 μg/mL. The bismuth(III) complexes of substituted benzoic acids show significant anti-Leishmanial activity against the promastigotes of L. major V121 at very low concentrations while their respective free carboxylic acids show no effective activity. However, the bismuth compounds inhibit the growth of the mammalian cells at all concentrations studied (1.95 to 500 μg/mL) following 48 h incubation. The comparatively low toxicity of BiCl₃ and Bi(NO₃)₃, suggests that overall toxicity of bismuth complexes towards the parasite is both ligand and metal dependent.     

Indole alkaloids as systematic markers of the Apocynaceae

Indole alkaloids can be characterized by skeletal specialization (S), determined upon consideration of their relative position on a biogenetic map and the number of their naturally occurring substitutional derivatives, as well as by oxidation level (O). The mean (S) and (O) for contained alkaloids of a given plant taxon are taken to represent evolutionary advancement parameters, respectively EA_s and EA_o.A correlation of these EA_s/EA_o values for tribes of the Apocynaceae-Plumerioideae reveals a chemical gradient, given by gradually increasing EA_s and EA_o values, to link Carisseae-Alstonieae-Rauvolfieae-Tabernaemontaneae.     

The complexation chemistry of cyclohexaamyloses: Adducts with 1-adamantanecarboxylic acid and anion

A study is reported of complexation reactions of cyclohexaamylose (Cy) with 1-adamantanecarboxylic acid and its anion using conductometry, pH potentiometry, and ¹³C nmr spectrometry. Binary and ternary (2 mol Cy/mol substrate) complexes are detected with both the acid and anion, and standard entropies and enthalpies of complexation are determined from the temperature dependences of the formation constants for all except the very weak ternary complex with the anion. Both the ¹³C nmr results and the entropy of complexation confirm the earlier suggestion that the anion in binary complexation is structured with the adamantanyl group in proximity to, but not penetrating, the Cy cavity. However, a negative ΔS^o for formation of this complex is reported which casts doubt on an earlier proposal that the adamantyl binary complex binding mode involves an “apolar” mechanism accompanied by loss of solvated water molecules. Values are also reported for pK_a, ΔH^o, and ΔS^o for the aqueous dissociation of 1-adamantanecarboxylic acid.     

Electronic transitions and heterogeneity of the bacteriophytochrome Pr absorption band: An angle balanced polarization resolved femtosecond VIS pump–IR probe study

Photoisomerization of biliverdin (BV) chromophore triggers the photoresponse in native Agp1 bacteriophytochrome. We discuss heterogeneity in phytochrome Pr form to account for the shape of the absorption profile. We investigated different regions of the absorption profile by angle balanced polarization resolved femtosecond VIS pump–IR probe spectroscopy. We studied the Pr form of Agp1 with its natural chromophore and with a sterically locked 18Et-BV (locked Agp1). We followed the dynamics and orientations of the carbonyl stretching vibrations of ring D and ring A in their ground and electronically excited states. Photoisomerization of ring D is reflected by strong signals of the ring D carbonyl vibration. In contrast, orientational data on ring A show no rotation of ring A upon photoexcitation. Orientational data allow excluding a ZZZasa geometry and corroborates a nontwisted ZZZssa geometry of the chromophore. We found no proof for heterogeneity but identified a new, to our knowledge, electronic transition in the absorption profile at 644 nm (S₀→S₂). Excitation of the S₀→S₂ transition will introduce a more complex photodynamics compared with S₀→S₁ transition. Our approach provides fundamental information on disentanglement of absorption profiles, identification of chromophore structures, and determination of molecular groups involved in the photoisomerization process of photoreceptors.     

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility,Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin, randomly methylated β-cyclodextrin, and methyl β-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-βCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEβCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an A_P-type system. Aqueous solubility of SN-38 was enhanced by about 30–1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEβCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEβCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEβCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.     

Physicochemical Characterization of Berberine Chloride: A Perspective in the Development of a Solution Dosage Form for Oral Delivery

The objective of the present research was to evaluate the physicochemical characteristics of berberine chloride and to assess the complexation of drug with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a first step towards solution dosage form development. The parameters such as log P value were determined experimentally and compared with predicted values. The pH-dependent aqueous solubility and stability were investigated following standard protocols at 25°C and 37°C. Drug solubility enhancement was attempted utilizing both surfactants and cyclodextrins (CDs), and the drug/CD complexation was studied employing various techniques such as differential scanning calorimetry, Fourier transform infrared, nuclear magnetic resonance, and scanning electron microscopy. The experimental log P value suggested that the compound is fairly hydrophilic. Berberine chloride was found to be very stable up to 6 months at all pH and temperature conditions tested. Aqueous solubility of the drug was temperature dependent and exhibited highest solubility of 4.05 ± 0.09 mM in phosphate buffer (pH 7.0) at 25°C, demonstrating the effect of buffer salts on drug solubility. Decreased drug solubility was observed with increasing concentrations of ionic surfactants such as sodium lauryl sulfate and cetyl trimethyl ammonium bromide. Phase solubility studies demonstrated the formation of berberine chloride–HPβCD inclusion complex with 1:1 stoichiometry, and the aqueous solubility of the drug improved almost 4.5-fold in the presence of 20% HPβCD. The complexation efficiency values indicated that the drug has at least threefold greater affinity for hydroxypropyl-β-CD compared to randomly methylated-β-CD. The characterization techniques confirmed inclusion complex formation between berberine chloride and HPβCD and demonstrated the feasibility of developing an oral solution dosage form of the drug.KEY WORDS: berberine chloride, complexation, cyclodextrin, solubility, surfactants     

Electrochemical behavior of S,S-bridged adducts of square planar metalladithiolene complexes [M(S2C2Ph2)2](M=Ni, Pd, and Pt)

The electrochemical behavior of the S,S^′-bridged adducts of square planar metalladithiolene complexes was investigated by using cyclic voltammetry and electrochemical spectroscopies (visible, near-IR, and ESR). The norbornene-bridged S,S^′-adduct [Ni(S₂C₂Ph₂)₂(C₇H₈)] (2a; C₇H₈=norbornene) formed by [Ni(S₂C₂Ph₂)₂] (1a) and quadricyclane (Q) was dissociated by an electrochemical reduction, and anion 1a⁻ and norbornadiene (NBD) were formed. Q was isomerized to NBD in the overall reaction. The o-xylyl-bridged S,S^′-adduct [Ni(S₂C₂Ph₂)₂(CH₂)₂(C₆H₄)] (3a; (CH₂)₂(C₆H₄)=o-xylyl) was also dissociated by an electrochemical reduction, and this reaction gave the o-xylyl radical (o-quinodimethane). The reduction of complex 3a in the presence of excess o-xylylene dibromide underwent the catalytic formation of o-quinodimethane. The butylene-bridged S,S^′-adduct [Ni(S₂C₂Ph₂)₂(CH₂)₄] (4a; (CH₂)₄=butylene) was stable on an electrochemical reduction. The lifetimes of reduced species of these adducts 2a-4a were influenced by the stability of the eliminated group (stability: NBD > o-xylyl radical (o-quinodimethane) > butylene radical). Therefore, the reduced species are stable in the sequence 4a⁻ > 3a⁻ > 2a⁻. Although the palladium complex [Pd(S₂C₂Ph₂)₂] (1b) was easier to reduce than the nickel complex 1a or the platinum complex [Pt(S₂C₂Ph₂)₂] (1c), their S,S^′-adducts were easier to reduce in the order of Ni adduct > Pd adduct > Pt adduct.     

Synthesis,structure and magnetic properties of the binuclear chromium(III) complex di-μ-hydroxobis [(1,4,7,10-tetraazacyclododecane)chromium(III)] dithionate tetrahydrate, [(cyclen)CrOH]2(S206)2·4H2O

The dark blue dimeric complex di-μ-hydroxo- bis [(1,4,7,10-tetraazacyclododecane)chromium(III)] dithionate tetrahydrate, [Cr(C₈H₂₀N₄)OH]₂(S₂O₆)₂· 4H₂O or [Cr(cyclen)OH]₂(S₂O₆)₂·4H₂O, has been synthesized. The crystal structure of the complex has been determined from threeodimensional counter X-ray data. The complex crystallizes in space group P2₁/n of the monoclinic system with two dimeric formula units in a cell of dimensions a = 8.837(5), b = 14.472(8), c= 13.943(6) Å andβ=95.83(4)^o. The structure has been refined by full-matrix least- squares methods to a final value of the weighted R-factor of 0.059 on the basis of 1774 independent intensities. The geometry of the cyclen macrocycle is unsymmetrical, the observed conformations being λδδλ and its enantiomer. The strained ligand conformation leads to significant deviations from octahedral geometry at the chromium centers, and to a bridged geometry in which the CrOCr angle ø and the Cr···Cr separation of 104.1(1)^o and 3.086(2) Å are the largest observed in dimers of this kind. The magnetic susceptibility of the complex indicates antiferromagnetic coupling, with the ground state singlet lying 21.56(6) cm⁻¹ below the lowest lying triplet state. The structural parameters have been used to calculate the triplet energy by means of the Glerup- Hodgson- Pedersen (GHP) model, and the calculated value of 22.3 cme⁻¹ is very similar to the observed value.     

Magnetic circular dichroism studies on monomeric and dimeric iron—sulfur complexes

Magnetic Circular dichroism (MCD) spectra were obtained for bis(o-xylyl-dithiolato)ferrate(III) ([Fe(S₂-o-xylyl)₂]⁻) and bis[o-xylyl-dithiolato-μ₂-sulfidoferrate(III)] ([Fe₂S^*₂(S₂-o-xylyl)₂]²⁻) ions. The MCD magnitude of the dimeric [Fe₂S^*₂(S₂-o-xylyl)₂]²⁻ ion was found to be only one half of that for the monomeric [Fe(S₂-o-xylyl)₂]⁻ ion. The difference in MCD magnitudes was attributed to the change in the thermal populations of ground state sublevels derived from the magnetic exchange interaction.     

Silver(I) derivatives with new functionalised acylpyrazolonates

Silver(I) acylpyrazolonate derivatives of formula [Ag(Q)(R₃P)]₂ and [Ag(Q)(R₃P)₂], (QH=1-phenyl-3-methyl-4-R′(CO)-pyrazol-5-one; Q^OH, R′=furane; Q^SH, R′=thiophene; R=Ph, Cy, o-tol), have been synthesised and characterised, both in the solid state and in solution. The derivatives [Ag(Q)(R₃P)]₂ contain dinuclear AgO₂NP units with the acylpyrazolonate coordinating in a bridging O,O′-Q-N fashion. The [Ag(Q)(R₃P)₂] are tetrahedral species, with the distortion from ideal geometry increasing with the bulk of the phosphine. The [Ag(Q)(R₃P)₂] derivatives are fluxional in chloroform solution when R₃P is sterically hindered (R=Cy or o-tol), dissociating partially to the [Ag(Q)(R₃P)] fragment and free R₃P. [Ag(Q^S)(Ph₃P)]₂ reacts with 1-methyl-2-mercaptoimidazole (Hmimt) affording the compound [Ag(Hmimt)(Ph₃P)(Q^S)] and [Ag(Q^O)(Ph₃P)]₂ reacts with 1-methyl-imidazole (Meim) affording the compound [Ag(Meim)(Ph₃P)(Q^O)], whereas [Ag(Q^S)(Ph₃P)]₂ reacts with 1,10-phenanthroline (phen), affording the compound [Ag(phen)(Ph₃P)](Q^S). Finally [Ag(Q^S)(Ph₃P)₂] reacts with phen producing the ionic species [Ag(phen)(Ph₃P)₂](Q^S).     

Electronic transitions and heterogeneity of the bacteriophytochrome Pr?absorption band: An angle balanced polarization resolved femtosecond VIS pump–IR probe study

Photoisomerization of biliverdin (BV) chromophore triggers the photoresponse in native Agp1 bacteriophytochrome. We discuss heterogeneity in phytochrome Pr form to account for the shape of the absorption profile. We investigated different regions of the absorption profile by angle balanced polarization resolved femtosecond VIS pump–IR probe spectroscopy. We studied the Pr form of Agp1 with its natural chromophore and with a sterically locked 18Et-BV (locked Agp1). We followed the dynamics and orientations of the carbonyl stretching vibrations of ring D and ring A in their ground and electronically excited states. Photoisomerization of ring D is reflected by strong signals of the ring D carbonyl vibration. In contrast, orientational data on ring A show no rotation of ring A upon photoexcitation. Orientational data allow excluding a ZZZasa geometry and corroborates a nontwisted ZZZssa geometry of the chromophore. We found no proof for heterogeneity but identified a new, to our knowledge, electronic transition in the absorption profile at 644 nm (S₀→S₂). Excitation of the S₀→S₂ transition will introduce a more complex photodynamics compared with S₀→S₁ transition. Our approach provides fundamental information on disentanglement of absorption profiles, identification of chromophore structures, and determination of molecular groups involved in the photoisomerization process of photoreceptors.     

Complexes with asymmetric tetraamine ligands. IV. Cobalt(III) complexes containing two chiral ligands. Structure of Λ-cis-β2-(SS)-[S-alaninato-2S, 5R, 9S-trimethyltriencobalt(III)] perchlorate hydrate

Complexes of cobalt(III) with two optically active ligands have been prepared and characterized. One of the ligands was an amino acid (S-alanine or S-isoleucine) and the other was a methyl-substituted derivative of triethylenetetramine (trien), either 2S,5R,9S-Me₃trien or 2S,5S,9S-Me₃trien. The amino acid complexes were prepared from the cis-α or cis-β dichloro complexes of Co(III) with the appropriate trien derivative. The crystal and molecular structure of one of these complexes, with S-alanine and 2S,5R, 9S-Me₃trien, is reported.Since the cobalt(III) complex contains two chiral ligands of known absolute configuration, the overall configuration of the complex could be assigned unambiguously as the Λ isomer. Although one of the three chelate rings of the chiral tetraamine deviates from ideal symmetric skew geometry, all three methyl groups are in equatorial positions. Both secondary nitrogen atoms have S configuration, and the methyl group on the central chelate ring of the tetraamine is adjacent to the ‘flat’ rather than the ‘apical’ secondary N. The alanine anion is coordinated with its nitrogen trans to a secondary nitrogen and its oxygen trans to a primary nitrogen of the tetraamine, to give the β₂ geometric isomer. Both perchlorate anions are disordered.Crystallographic data for the title complex are as follows: C₁₂H₃₀O₁₁N₅Cl₂Co, M_r=550.23, tetragonal, P4₃2₁2, Z=8, a=9.166(5), c=53.51(4) Å, V=4495.4 ų, D_m=1.63(1), D_c=1.657 g cm⁻³, CuKα, λ=1.54178 Å, μ(CuKα)=90.89 cm⁻¹, F(000)=2288, room temperature, final R=[Σ(6F_o| −|F_c|)/Σ|F_o|]=O.089 for 2620 unique, observed reflections.     

Synthesis and stereochemistry of new cobalt azo-nitroso complexes

Synthesis and characterization of new cobalt-substituted phenylazo 2,4-dinitrosoresorcinol complexes have been carried out. The analytical data depict the formation of complex compounds with the stoichiometry 2:3 (o-COOH, m-NO₂) and 1:2 (o-Cl, o-CH₃, m-Cl, m-CH₃). All the complexes are of low spin in octahedral and square planar or distorted tetrahedral environments. The octahedral ⇄ tetrahedral equilibria are evident. The complexes in the presence of basic compounds gave some addition products. The electronic transitions and the ligand field parameters are assigned and calculated. The complex formation occurred through the azo group and the phenolic oxygen atom in most complexes. In the o-carboxy ligand, the COO⁻, NN and the oximic groups participate through complexation.     

Hydroxymethylnitrofurazone:Dimethyl-β-cyclodextrin Inclusion Complex: A Physical–Chemistry Characterization

Hydroxymethylnitrofurazone (NFOH) is active against Trypanosoma cruzi; however, its low solubility and high toxicity precludes its current use in treatment of parasitosis. Cyclodextrin can be used as a drug carrier system, as it is able to form inclusion (host–guest) complexes with a wide variety of organic (guest) molecules. Several reports have shown the interesting use of modified β-cyclodextrins in pharmaceutical formulation, to improve the bioavailability of drugs and to decrease their toxicity. The aim of this work was to characterize inclusion complexes formed between NFOH and dimethyl-β-cyclodextrin (DM-β-CD) by complexation/release kinetics and solubility isotherm experiments using ultraviolet (UV)-visible spectrophotometry and by the measurement of the dynamics information obtained from T ₁ relaxation times and diffusion (DOSY) experiments using nuclear magnetic resonance (NMR) spectroscopy. The complex was prepared at different NFOH and DM-β-CD molar ratios. The UV-visible measurements were recorded in a spectrophotometer, and NMR experiments were recorded at 20°C on a NMR spectrometer (Varian Inova) operating at 500 MHz. Longitudinal relaxation times were obtained by the conventional inversion-recovery method and the DOSY experiments were carried out using the BPPSTE sequence. The kinetics of complexation revealed that 30 h is enough for stabilization of the NFOH absorbance in presence of cyclodextrin. Solubility isotherm studies show a favorable complexation and increase in solubility when NFOH interacts with cyclodextrin. The analysis of the NMR-derived diffusion coefficients and T ₁ relaxation times shows that in the presence of DM-β-CD, NFOH decreases its mobility in solution, indicating that this antichagasic compound interacts with the cyclodextrin cavity. The release kinetics assays showed that NFOH changes its release profile when in the presence of cyclodextrin due to complexation. This study was focused on the physicochemical characterization of drug-delivery formulations that may serve as potentially new therapeutic options for the treatment of Chagas’ disease.     

Electrochemical reduction of rhenium(V) dithiocarbamate complexes trans-Re2O3(S2CNR2)4 in nonaqueous media

The electrochemistry for the reduction of tetrakis(dialkyl- and diphenyldithiocarbamato)-μ-oxodioxodirhenium complexes trans-Re₂O₃(S₂CNR₂)₄ (R = methyl, ethyl, propyl, butyl and phenyl) was investigated in seven nonaqueous solvents. The complexes underwent a reversible reduction involving one- electron at a platinum electrode to [Re₂O₃(S₂CNR₂)₄]⁻, which decomposed with the cleavage of the μ-oxo bridge to form ReO(S₂CNR₂)₂, R₂CNS₂⁻ and other rhenium complexes. The redox potential E^o′ of [Re₂O₃(S₂CNR₂)₄]^0/− couples and the stability of the reduction product [Re₂O₃(S₂CNR₂)₄]⁻ depend on the R group. The E^o′ are appreciably solvent-dependent. The difference in E^o′ with solvents could be interpreted in terms of the solubility parameters.     

NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect – why do we keep using it?

The carboxylic acid group (–COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.     

Elevated Ratio of Urinary Metabolites of Thromboxane and Prostacyclin Is Associated with Adverse Cardiovascular Events in ADAPT

Results from prevention trials, including the Alzheimer''s Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B₂ (Tx-M) to 2′3-donor–6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F₂-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F₂-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F₂-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.     

Aggregation of cyclodextrins as an important factor to determine their complexation behavior

Here, we report a study on the complexation behavior of carotenoids with cyclodextrins (CDs) using solubility experiments and molecular-modelling methods. Carotenoids are an important group of naturally occurring dyes found in vegetables and fruits. Their antioxidant property has initiated investigations on their possible use as drugs. However, carotenoids are lipophilic molecules with very little inherent aqueous solubility. Cyclodextrin complexation has been widely used in order to increase the potential applications of hydrophobic compounds. Thus, the aim of our investigation was to design carotenoids with enhanced water solubility by cyclodextrin complexation. Molecular modelling of carotenoid-cyclodextrin complexes with a 1 : 1 stoichiometry successfully explained the experimentally observed capability of beta-cyclodextrins (beta-CDs) to form complexes with carotenoids as opposed to alpha-cyclodextrins (alpha-CDs) and gamma-cyclodextrins (gamma-CDs). Furthermore, molecular-dynamics calculations revealed that the aggregation properties of CD derivatives significantly influence their complexation behavior. Our docking calculations showed that RAMEB (random methylated beta-CD) is the beta-CD derivative that possesses the lowest tendency to aggregate. Solubility experiments yielded the same results, namely, RAMEB complexes possess the best water solubility. Our results showed that complexation of a ligand not buried inside of the CD cavity is dependent on two factors: i) the geometry of the inclusion part of the complex; ii) the self-aggregation property of the CD itself. The lower affinity the CDs possess for self-aggregation, the more likely are they involved in interactions with carotenoids. These results suggest that self-aggregation of CDs should be considered as an important parameter determining complexation in general.     

Part 3: Design and synthesis of proline-derived α2δ ligands

A potent series of substituted (2S,4S)-benzylproline α₂δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.