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Biomedical subjects

Kenneth N Raymond

Publications and source records attributed to Kenneth N Raymond.

At least 37 records · Page 2Linked to original sources
PubMed2005

In vivo evaluation of gadolinium hydroxypyridonate chelates: initial experience as contrast media in magnetic resonance imaging.

The effect of ligand structure on the magnetic resonance (MR) imaging and biodistribution of six gadolinium (Gd) chelates based on a hydroxypyridonate-terephthalimide (HOPO-TAM) ligand design was investigated. Modifications to the molecular structure of the Gd-HOPO-TAM chelates (hydrophilicity and aromatic group substitution) significantly influence the efficacy of imaging and biodistribution. MR imaging was performed on female mice after intravenous (iv) injection of 100 micromol of Gd/kg of body weight of the different complexes. The biodistribution results indicate that the liver uptake of the complexes is enhanced by a short poly(ethyleneoxy) (PEO) chain, while blood pool localization is facilitated by a very long PEO chain. There is a direct correlation between the blood pool localization of the complexes and the signal intensity of blood vessels in the MRI. The imaging results are consistent with in vitro NMR measurements that indicate long PEO chains increase image enhancement capabilities in the presence of serum albumin.

Animals↗
PubMed2005

The big squeeze: guest exchange in an M4L6 supramolecular host.

Guest exchange in an M4L6 supramolecular host has been evaluated to determine whether host rupture is required for guest ingress and egress. Two mechanistic models were evaluated: one requiring partial dissociation of the host structure to create a portal for guest passage and one necessitating deformation of the host structure to create a dilated aperture for guest passage without host rupture. Three related lines of inquiry support the nondissociative guest exchange mechanism. (a) Equally facile guest exchange is observed in labile ([Ga4L6]12-) and inert ([Ti4L6]8- and [Ge4L6]8-) hosts. (b) Molecular mechanics calculations demonstrate that the structural deformations required for enlargement of an M4L6 aperture in a nonrupture or nondissociative guest exchange mechanism are plausible. (c) As predicted by the calculations, CoCp*2+, a sterically demanding guest, significantly inhibits guest exchange. These results bring new insight to the application of the M4L6 supramolecular host for encapsulated reaction chemistry for which there are now several examples.

Journal Article↗
PubMed2005

Sequestered plutonium: [Pu(IV){5LIO(Me-3,2-HOPO)}2]--the first structurally characterized plutonium hydroxypyridonate complex.

The first single-crystal X-ray diffraction analysis of a hydroxypyridonate plutonium(IV) complex is presented, that of the tetradentate ligand 5LIO(Me-3,2-HOPO) with Pu(IV). The [Pu(IV){5LIO(Me-3,2-HOPO)}(2)] complex crystallizes in the space group Pna2(1) with the asymmetric unit cell containing two unique eight-coordinate plutonium complexes and one perchlorate anion. According to shape measure analysis, the geometry of both Pu centers is closest to a bicapped trigonal prism (C(2v) symmetry, for Pu 1: S(C(2v))=13.48 degrees , S(D(4d))=15.43 degrees , S(D(4d))=16.10 degrees ). The average bond length for the Pu--O(phenolic) is 2.31(4) A, whereas the Pu--O(amide) distances are slightly longer, averaging 2.40(2) A. The preparative chemistry of this compound and the implications of the structure are discussed.

Journal Article↗
PubMed2005

Incorporation of hydroxypyridinone ligands into self-assembled monolayers on mesoporous supports for selective actinide sequestration.

In this study, three isomers of hydroxypyridinones (1,2-HOPO, 3,2-HOPO, and 3,4-HOPO) were attached to self-assembled monolayers on mesoporous silica (SAMMS). The HOPO-SAMMS materials have superior solid adsorbents properties: they do not suffer from solvent swelling; their rigid, open pore structure allows rapid sorption kinetics; their extremely high surface area enables the installation of high functional density; and being silica-based, they are compatible with vitrification into a final vitreous waste form. Kinetics, equilibrium, and selectivity of the adsorptions of actinide on the HOPO-SAMMS at various pH values and in the presence of other metal cations, anions, and competing ligands are reported. Rapid sequestration of U(VI), Np(V), and Pu(IV) was observed. Very little competition from transition metal cations and common species was observed.

Adsorption↗
PubMed2005

Dendrimeric gadolinium chelate with fast water exchange and high relaxivity at high magnetic field strength.

The synthesis and relaxivity properties of a new dendrimeric Gd chelate, Gd-TREN-bisHOPO-TAM-Asp-Asp2-12OH, are presented. The macromolecule demonstrates improved water solubility due to its 12 terminal hydroxyl groups and improved relaxivity due to its optimal water exchange rate and slower molecular tumbling. Unprecedented high relaxivity (r1p = 18 mM-1 s-1) is observed at high magnetic field (90 MHz), an important advance in the development of contrast agents for the next generation of MRI scanners.

Chelating Agents↗
PubMed2005

Selective molecular recognition, C-H bond activation, and catalysis in nanoscale reaction vessels.

Supramolecular chemistry represents a way to mimic enzyme reactivity by using specially designed container molecules. We have shown that a chiral self-assembled M4L6 supramolecular tetrahedron can encapsulate a variety of cationic guests with varying degrees of stereoselectivity. Reactive iridium guests can be encapsulated, and the C-H bond activation of aldehydes occurs with the host cavity controlling the ability of substrates to interact with the metal center based upon size and shape. In addition, the host container can act as a catalyst by itself. By restricting reaction space and preorganizing the substrates into reactive conformations, it accelerates the sigmatropic rearrangement of enammonium cations.

Catalysis↗
PubMed2005

Hydroxypyridinone functionalized self-assembled monolayers on nanoporous silica for sequestering lanthanide cations.

1,2-Hydroxypyridinone (1,2-HOPO) ligands were installed as self-assembled monolayers on nanoporous silica (MCM-41) to create a superior class of sorbent materials for lanthanide cations. Lanthanides were used as a model system for the radioactive, expensive, and highly hazardous actinides in preliminary screening studies. The ligand properties of the 1,2-HOPO ligand field and the extremely large surface area of MCM-41, coupled with the dense monolayer coating, contribute to the extremely high lanthanide binding capacity of the 1,2-HOPO nanoporous sorbent. At pH 4-5.9, the mass-weighted partition coefficients (Kd) for La, Nd, Eu, and Lu were 354,000, 344,000, 210,800, and 419,800, respectively. The rigid, open pore structure of the silica also allows for very rapid sorption. Being silica-based, the sorbent is compatible with vitrification processing into a final glasseous waste form, for subsequent disposition in a deep geological repository.

Cations↗
PubMed2004

Hetero-tripodal hydroxypyridonate gadolinium complexes: syntheses, relaxometric properties, water exchange dynamics, and human serum albumin binding.

The synthesis and relaxometric properties of hetero-tripodal hydroxypyridonate-terephthalamide gadolinium (Gd(3+)) chelates with differing structural features for probing human serum albumin (HSA) interactions are reported. The Gd(3+) complexes are divided into two series. The first series (3-5) features a benzyl derivative connected to the hydroxypyridonate (HOPO) moiety. The second series of complexes (6-10) has the common feature of a poly(ethylene glycol) (PEG) attached to the terephthalamide (TAM) moiety and is nonbenzylated. The water exchange of the complexes is in the fast exchange regime with rates (k(ex)) in the range 0.45-1.11 x 10(8) s(-1). The complexes have a moderate interaction with HSA with association constants (K(A)'s) in the range 0.7-8.6 x 10(3) M(-1). Protein binding results in an enhancement in proton relaxivity from 7.7-10.4 mM(-1) s(-1) (r(1p)) to 15-29 mM(-1) s(-1) (r(1p)(b)). It is concluded that the interaction of the complexes with HSA (i) is enhanced by the presence of benzyl groups, (ii) is entropically driven, and (iii) results in a lower hydration number (q).

Contrast Media↗
PubMed2004

Toward optimized high-relaxivity MRI agents: thermodynamic selectivity of hydroxypyridonate/catecholate ligands.

The thermodynamic selectivity for Gd(3+) relative to Ca(2+), Zn(2+), and Fe(3+) of two ligands of potential interest as magnetic resonance imaging (MRI) contrast agents has been determined by NMR spectroscopy and potentiometric and spectrophotometric titration. The two hexadentate ligands TREN-6-Me-3,2-HOPO (H(3)L2) and TREN-bisHOPO-TAM-EA (H(4)L3) incorporate 2,3-dihydroxypyridonate and 2,3-dihydroxyterephthalamide moieties. They were chosen to span a range of basicity while maintaining a structural motif similar to that of the parent ligand, TREN-1-Me-3,2-HOPO (H(3)L1), in order to investigate the effect of the ligand basicity on its selectivity. The 1:1 stability constants (beta(110)) at 25 degrees C and 0.1 M KCl are as follows. L2: Gd(3+), 20.3; Ca(2+), 7.4; Zn(2+), 11.9; Fe(3+), 27.9. L3: Gd(3+), 24.3; Ca(2+), 5.2; Zn(2+), 14.6; Fe(3+), 35.1. At physiological pH, the selectivity of the ligand for Gd(3+) over Ca(2+) increases with the basicity of the ligand and decreases for Gd(3+) over Fe(3+). These trends are consistent with the relative acidities of the various metal ions;- more basic ligands favor harder metals with a higher charge-to-radius ratio. The stabilities of the Zn(2+) complexes do not correlate with basicity and are thought to be more influenced by geometric factors. The selectivities of these ligands are superior to those of the octadentate poly(aminocarboxylate) ligands that are currently used as MRI contrast agents in diagnostic medicine.

Calcium↗
PubMed2004

Time gating improves sensitivity in energy transfer assays with terbium chelate/dark quencher oligonucleotide probes.

Lanthanides are attractive as biolabels because their long luminescence decay rates allow time-gated detection, which separates background scattering and fluorescence from the lanthanide emission. A stable and highly luminescent terbium complex based on a tetraisophthalamide (TIAM) chelate is paired with a polyaromatic-azo dark quencher (referred to as a Black Hole Quencher or BHQ) to prepare a series of 5'TIAM(Tb)/3'BHQ dual-labeled oligonucleotide probes with no secondary structure. Luminescence quenching efficiency within terbium/BHQ probes is very dependent on the terbium-BHQ distance. In an intact probe, the average terbium-BHQ distance is short, and Tb --> BHQ energy transfer is efficient, decreasing both the terbium emission intensity and lifetime. Upon hybridization or nuclease digestion, which spatially separate the Tb and BHQ moieties, the Tb luminescence intensity and lifetime increase. As a result, time-gated detection increases the emission intensity ratio of the unquenched probe/quenched probe due to the shorter lifetime of the quenched species. A 40-mer probe that has a 3-fold increase in steady-state luminescence upon digestion has a 50-fold increase when gated detection is used. This study demonstrates that time gating with lanthanide/dark quencher probes in energy transfer assays is an effective means of improving sensitivity.

Amides↗
PubMed2004

Large cooperativity in the removal of iron from transferrin at physiological temperature and chloride ion concentration.

Iron removal from serum transferrin by various chelators has been studied by gel electrophoresis, which allows direct quantitation of all four forms of transferrin (diferric, C-monoferric, N-monoferric, and apotransferrin). Large cooperativity between the two lobes of serum transferrin is found for iron removal by several different chelators near physiological conditions (pH 7.4, 37 degrees C, 150 mM NaCl, 20 mM NaHCO(3)). This cooperativity is manifested in a dramatic decrease in the rate of iron removal from the N-monoferric transferrin as compared with iron removal from the other forms of ferric transferrin. Cooperativity is diminished as the pH is decreased; it is also very sensitive to changes in chloride ion concentration, with a maximum cooperativity at 150 mM NaCl. A mechanism is proposed that requires closure of the C-lobe before iron removal from the N-lobe can be effected; the "open" conformation of the C-lobe blocks a kinetically significant anion-binding site of the N-lobe, preventing its opening. Physiological implications of this cooperativity are discussed.

Anions↗
PubMed2004

Characterization of 2,3-dihydroxyterephthalamides as M(IV) chelators.

The ligand N,N'-diethyl-2,3-dihydroxyterephthalamide (ETAM) has been characterized as a chelator for Zr(IV), Ce(IV), and Th(IV). The K(+) salts of the complexes [Zr(ETAM)(4)](4)(-), [Ce(ETAM)(4)](4)(-), and [Th(ETAM)(4)](4)(-) were prepared in a MeOH solution containing H(2)ETAM, the corresponding M(acac)(4), and 4 equiv of KOH. Single-crystal X-ray diffraction analyses are reported for K(4)[Zr(ETAM)(4)] (C2/c, Z = 8, a = 27.576(3) A, b = 29.345(3) A, c = 15.266(2) A, alpha = 90 degrees, beta = 118.688(4) degrees, gamma = 90 degrees ), [Me(3)BnN](4)[Th(ETAM)(4)] (P, Z = 2, a = 13.7570(3) A, b = 13.9293(3) A, c = 26.9124(6) A, alpha = 99.941(1) degrees, beta = 94.972(1) degrees, gamma = 103.160(1) degrees ), and the dimeric (NMe(4))(4)[Th(ETAM)(3)MeOH](2) (P2(1)/c, Z = 4, a = 18.2603(9) A, b = 18.5002(9) A, c = 19.675(1) A, beta = 117.298(1) degrees ). Solution thermodynamic studies were used to determine formation constants (log K(f) and esd) for Th(IV)-ETAM log K(110) =17.47(1), log K(120) = 13.23(1), log K(130) = 8.28(3), log K(140) = 6.57(6), and log beta(140) = 45.54(5). These results support the hypothesis that the terephthalamides are high-affinity chelators for the actinide(IV) ions and thus promising ligands for use in nuclear waste remediation.

Amides↗
PubMed2004

Gadolinium(III) 1,2-hydroxypyridonate-based complexes: toward MRI contrast agents of high relaxivity.

Prospective gadolinium(III) MRI contrast agent precursors [Gd-TREN-1,2-HOPO] (1) [TREN-1,2-HOPO = tris[(1-hydroxy-2-oxo-1,2-dihydropyridine-6-carboxamido)ethyl]amine] and [Gd-TREN-bis(Me-3,2-HOPO)-1,2-HOPO] (2) have been synthesized and characterized by relaxometric measurements. The water proton relaxivity values of 1 and 2 (20 MHz and 25 degrees C) are 9.5 and 9.3 mM(-)(1)s(-)(1), respectively, suggesting the presence of two coordinated water molecules. The molecular structure of [1.DMF](2) was obtained and reveals a similar eight-coordinate geometry to [Gd-TREN-Me-3,2-HOPO.2H(2)O] ([3.2H(2)O]). A shape analysis of the coordination polyhedron of 1 reveals that this geometry is best described as a bicapped trigonal prism, poised to accommodate an additional donor atom to give a tricapped trigonal prismatic intermediate. This geometry supports the model that formation of a tris-aquo intermediate for 1 enables fast and associative water exchange.

Chelating Agents↗
PubMed2004

Enantioselective guest binding and dynamic resolution of cationic ruthenium complexes by a chiral metal-ligand assembly.

A supramolecular metal-ligand assembly encapsulates a variety of cationic half-sandwich ruthenium complexes. Due to the chirality of both host and guest, chiral recognition is observed with diastereomeric excesses up to 70%. The chiral cavity can be used to carry out a dynamic resolution of the rapidly equilibrating enantiomers of the chiral organometallic guest.

Journal Article↗
PubMed2004

Encapsulation of cationic ruthenium complexes into a chiral self-assembled cage.

A chiral supramolecular assembly encapsulates the two cationic ruthenium sandwich complexes [CpRu(eta(6)-C(6)H(6))](+) and [CpRu(p-cymene)](+). The host-guest complexes K(11)[CpRu(eta(6)-C(6)H(6)) subset Ga(4)L(6)] (2) and K(11)[CpRu(p-cymene) subset Ga(4)L(6)] (3) were characterized by one- and two-dimensional NMR techniques as well as by electrospray mass spectrometry. Encapsulation of the prochiral complex [CpRu(p-cymene)](+) by the chiral host renders enantiotopic protons diastereotopic as evidenced by (1)H NMR spectroscopy.

Cations↗
PubMed2003

A highly stable gadolinium complex with a fast, associative mechanism of water exchange.

The stability and water exchange dynamics of gadolinium (GdIII) complexes are critical characteristics that determine their effectiveness as contrast agents for magnetic resonance imaging (MRI). A new heteropodal GdIII chelate, [Gd-TREN-bis(6-Me-HOPO)-(TAM-TRI)(H2O)2] (Gd-2), is presented which is based on a hydroxypyridinate (HOPO)-terephthalamide (TAM) ligand design. Thermodynamic equilibrium constants for the acid-base properties and the GdIII complexation strength of TREN-bis(6-Me-HOPO)-(TAM-TRI) (2) were measured by potentiometric and spectrophotometric titration techniques, respectively. The pGd of 2 is 20.6 (pH 7.4, 25 degrees C, I = 0.1 M), indicating that Gd-2 is of more than sufficient thermodynamic stability for in vivo MRI applications. The water exchange rate of Gd-2 (kex = 5.3(+/-0.6) x 107 s-1) was determined by variable temperature 17O NMR and is in the fast exchange regime - ideal for MRI. Variable pressure 17O NMR was used to determine the volume of activation (DeltaV) of Gd-2. DeltaV for Gd-2 is -5 cm3 mol-1, indicative of an interchange associative (Ia) water exchange mechanism. The results reported herein are important as they provide insight into the factors influencing high stability and fast water exchange in the HOPO series of complexes, potentially future clinical contrast agents.

Contrast Media↗