Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres

The natural stilbenoid dehydro-δ-viniferin, containing a benzofuran core, has been recently identified as a promising antimicrobial agent. To define the structural elements relevant to its activity, we modified the styryl moiety, appended at C5 of the benzofuran ring. In this paper, we report the construction of stilbenoid-derived 2,3-diaryl-5-substituted benzofurans, which allowed us to prepare a focused collection of dehydro-δ-viniferin analogues. The antimicrobial activity of the synthesized compounds was evaluated against S. aureus ATCC29213. The simplified analogue 5,5′-(2-(4-hydroxyphenyl)benzofuran-3,5-diyl)bis(benzene-1,3-diol), obtained in three steps from 4-bromo-2-iodophenol (63% overall yield), emerged as a promising candidate for further investigation (MIC = 4 µg/mL).     

Functional Characterizations of Basic Properties of Utility Representations

 Consider uncertain alternatives for which an event has two consequences (binary gambles, “gambles” for short) and over them an operation of joint receipt which need not be closed and may be non-commutative. The two structures are linked by a distributivity property called segregation and a preference order. Utility functions order nonnegative numbers to consequences and gambles. Utility representations describe how the utility of a gamble depends on the utilities of consequences and on the “weight” of the event (a number in [0,1], depending on the event). Functional characterizations give necessary and sufficient conditions, often in form of functional equations, for certain properties of representations. We first give a functional characterization of the often postulated event commutativity stating that two events can be interchanged in special composite gambles where one outcome is a consequence but the other is itself a gamble. A utility representation is separable if it is multiplicative for gambles with one consequence having 0 utility. We give three more specific characterizations of separable representations by segregation, by homogeneity and event commutativity, and by homogeneity and segregation, and show that in the last case event commutativity follows. Received 10 August 2001; in revised form 6 November 2001     

A dynamic programming algorithm for the bilevel knapsack problem

We propose an efficient dynamic programming algorithm for solving a bilevel program where the leader controls the capacity of a knapsack, and the follower solves the resulting knapsack problem. We propose new recursive rules and show how to solve the problem as a sequence of two standard knapsack problems.     

Measurement structures with archimedean ordered translation groups

The paper focuses on three problems of generalizing properties of concatenation structures (ordered structures with a monotonic operation) to ordered structures lacking any operation. (1) What is the natural generalization of the idea of Archimedeaness, of commensurability between large and small? (2) What is the natural generalization of the concept of a unit concatenation structure in which the translations (automorphisms with no fixed point) can be represented by multiplication by a constant? (3) What is the natural generalization of a ratio scale concatenation structure being distributive in a conjoint one, which has been shown to force a multiplicative representation of the latter and the product-of-powers representation of units found in physics? It is established (Theorems 5.1 and 5.2) that for homogeneous structures, the latter two questions are equivalent to it having the property that the set of all translations forms a homogeneous Archimedean ordered group. A sufficient condition for Archimedeaness of the translations is that they form a group, which is equivalent to their being 1-point unique, and the structure be Dedekind complete and order dense (Theorems 2.1 and 2.2). It is suggested that Archimedean order of the translations is, indeed, also the answer to the first question. As a lead into that conclusion, a number of results are reported in Section 3 on Archimedeaness in concatenation structures, including for positive structures sufficient conditions for several different notions of Archimedeaness to be equivalent. The results about idempotent structures are fragmentary.     

Investigation of non-covalent interactions between paramagnetic complexes and human serum albumin by electrospray mass spectrometry

Stable gadolinium(III) chelates are nowadays routinely used as contrast agents for magnetic resonance imaging (MRI). Their non-covalent binding to human serum albumin (HSA) has shown to improve their efficacy. Non-covalent interactions lead to complex formation that can be quantified by several techniques that are mostly tedious and time-consuming. In this study, electrospray ionization mass spectrometry (ESI-MS) was used to investigate the interaction between HSA and several gadolinium(III) complexes. The results were compared with those obtained in the liquid phase. Four gadolinium complexes were investigated: Gd-DTPA 1, Gd-C(4)Me-DTPA 2, Gd-EOB-DTPA 3, and MP-2269 4. Relaxometry studies show that complexes 1 and 2 have no significant affinity for HSA, while complexes 3 and 4 have increasing affinities for the protein. 1:1 and 1:2 complexes between HSA and MP-2269 were detected by ESI-MS for a twofold excess of the contrast agent, whereas a ligand/protein molar ratio of 4:1 was necessary to observe a 1:1 stoichiometry for Gd-EOB-DTPA, an observation that is in good agreement with the known weaker affinity of the contrast agent for the protein. At a fourfold molar excess, no supramolecular complex was observed for Gd-DTPA 1 and Gd-C(4)Me-DTPA 2; a tenfold molar excess was necessary to detect a 1:1 complex, confirming the very weak affinity of these contrast agents for HSA.     

Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.     

Lanthanide(III) complexes of a mono(methylphosphonate) analogue of H4dota: the influence of protonation of the phosphonate moiety on the TSAP/SAP isomer ratio and the water exchange rate

A monophosphonate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-4,7,10-tris(carboxymethyl)-1-methylphosphonic acid (H5do3aP), and its complexes with lanthanides were synthesized. Multinuclear NMR studies reveal that, in aqueous solution, lanthanide(III) complexes of the ligand exhibit structures analogous to those of H4dota complexes. Thus, the central ion is nine-coordinate, surrounded by four nitrogen atoms, three acetate and one phosphonate oxygen atoms, and one water molecule in an apical position. For complexes of H5do3aP with Ln(III) ions in the middle of the series, the abundance of the desired twisted square-antiprismatic (TSAP) isomer is higher than for the corresponding H4dota complexes. The TSAP/square-antiprismatic (SAP) isomer ratio is highly sensitive to protonation of the phosphonate group: a higher abundance of the TSAP isomer was found in acidic solutions. The microscopic protonation constants of the TSAP isomers are higher than those of the SAP isomers. The presence of one water molecule in the first coordination sphere of the complexes in the pH region studied (pH 2.5-7.0) is confirmed by 17O NMR spectroscopy. The results of a simultaneous fit of variable-temperature 17O NMR relaxation data and 1H NMRD profiles show that the residence time of water (tauM) in the Gd(III) complex is much smaller than for [Gd(dota)(H2O)]-. The exchange rate appears to be dependent on the pH of the solution. The values of tauM are 37, 40, and 14 ns at pH 2.5, 4.7, and 7.0, respectively. These observations can be explained by an extensive second-sphere hydrogen-bonding network that varies with the state of protonation of the phosphonate moiety. Upon protonation of the complex, the second-sphere hydration probably becomes more ordered, which may result in a decrease in penetrability and an increase in tauM. The relaxivity of the Gd(III) complex is almost independent of the pH and is equal to 4.7 s(-1) mM(-1) (20 MHz, pH 7 and 37 degrees C). The solid-state structure was determined for the Nd(III) complex. It crystallizes as the TSAP isomer and the unit cell contains two independent molecules of the complex with different Nd-O(water) bond lengths of 2.499 and 2.591 A.     

Lanthanide(III) complexes of novel mixed carboxylic-phosphorus acid derivatives of diethylenetriamine: a step towards more efficient MRI contrast agents

Three novel phosphorus-containing analogues of H(5)DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L1, H5L2, H5L3). These compounds have a -CH2-P(O)(OH)-R function (R = OH, Ph, CH2NBn2) attached to the central nitrogen atom of the diethylenetriamine backbone. An NMR study reveals that these ligands bind to lanthanide(III) ions in an octadentate fashion through the three nitrogen atoms, a P-O oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitrogen atom and the phosphorus atom upon coordination. All lanthanide complexes studied have one coordinated water molecule. The residence times (tau(M)298) of the coordinated water molecules in the gadolinium(III) complexes of H6L1 and H5L2 are 88 and 92 ns, respectively, which are close to the optimum. This is particularly important upon covalent and noncovalent attachment of these Gd(3+) chelates to polymers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water molecules in the second coordination sphere of the Gd(3+) ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The complex [Gd(L3)(H2O)](2-) shows strong binding ability to HSA, and the adduct has a relaxivity comparable to MS-325 (40 s(-1) mM(-1) at 40 MHz, 37 degrees C) even though it has a less favourable tau(M) value (685 ns). Transmetallation experiments with Zn(2+) indicate that the complexes have a kinetic stability that is comparable to-or better than-those of [Gd(dtpa)(H2O)](2-) and [Gd(dtpa-bma)(H2O)].     

Lanthanide chelates containing pyridine units with potential application as contrast agents in magnetic resonance imaging

A new pyridine-containing ligand, N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H(4)L), has been designed for the complexation of lanthanide ions. (1)H and (13)C NMR studies in D(2)O solutions show octadentate binding of the ligand to the Ln(III) ions through the nitrogen atoms of two amine groups, the oxygen atoms of four carboxylates, and the two nitrogen atoms of the pyridine rings. Luminescence measurements demonstrate that both Eu(III) and Tb(III) complexes are nine-coordinate, whereby a water molecule completes the Ln(III) coordination sphere. Ligand L can sensitize both the Eu(III) and Tb(III) luminescence; however, the quantum yields of the Eu(III)- and Tb(III)-centered luminescence remain modest. This is explained in terms of energy differences between the singlet and triplet states on the one hand, and between the 0-phonon transition of the triplet state and the excited metal ion states on the other. The anionic [Ln(L)(H2O)]- complexes (Ln=La, Pr, and Gd) were also characterized by theoretical calculations both in vacuo and in aqueous solution (PCM model) at the HF level by means of the 3-21G* basis set for the ligand atoms and a 46+4 f(n) effective core potential for the lanthanides. The structures obtained from these theoretical calculations are in very good agreement with the experimental solution structures, as demonstrated by paramagnetic NMR measurements (lanthanide-induced shifts and relaxation-rate enhancements). Data sets obtained from variable-temperature (17)O NMR at 7.05 T and variable-temperature (1)H nuclear magnetic relaxation dispersion (NMRD) on the Gd(III) complex were fitted simultaneously to give insight into the parameters that govern the water (1)H relaxivity. The water exchange rate (k(298)(ex)=5.0 x 10(6) s(-1)) is slightly faster than in [Gd(dota)(H2O)]- (DOTA=1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). Fast rotation limits the relaxivity under the usual MRI conditions.