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PubMed2005

Anomalous electrophoretic behavior of a very acidic protein: ribonuclease U2.

Ribonuclease U2 is a low-molecular-weight acidic protein with three disulfide bridges. This protein displays an anomalous electrophoretic behavior on standard SDS-PAGE. The electrophoretic mobility of the nonreduced protein roughly corresponds to its molecular mass while the migration of the reduced protein would be in accordance with the expected molecular mass of the protein dimer. This study reveals that the protein does not bind SDS under the SDS-PAGE conditions, its electrophoretic mobility being only determined by its electrostatic charge and hydrodynamic properties. In addition, the nonreduced protein cannot be blotted to a membrane. Unfolding of the protein upon reduction of its disulfide bridges enables electrotransference to membranes due to a restricted diffusion along the electrophoresis gel.

Amino Acid Sequence↗
PubMed1996

Synthesis and evaluation of inhibitors of bacterial D-alanine:D-alanine ligases.

BACKGROUND: D-Alanine:D-alanine ligase is essential for bacterial cell wall synthesis, assembling one of the subunits used for peptidoglycan crosslinking. The resulting aminoacyl-D-Ala-D-Ala strand is the Achilles' heel of vancomycin-susceptible bacteria; binding of vancomycin to this sequence interferes with crosslinking and blocks cell-wall synthesis. A mutant enzyme (VanA) from vancomycin-resistant Enterococcus faecium has been found to incorporate alpha-hydroxy acids at the terminal site instead of D-Ala; the resulting depsipeptides do not bind vancomycin, yet function in the crosslinking reaction. To investigate the binding specificity of these ligases, we examined their inhibition by a series of substrate analogs. RESULTS: Phosphinate and phosphonate dipeptide analogs (which, after phosphorylation by the enzyme, mimic intermediates in the ligation reaction) were prepared and evaluated as reversible inhibitors of the wild-type ligases DdlA and DdlB from Escherichia coli and of the mutant enzyme VanA. Ki values were calculated for the first stage of inhibitor binding according to a mechanism in which inhibitor competes with D-Ala for both substrate binding sites. DdlA is potently inhibited by phosphinates but not by phosphonates, while DdlB and VanA show little discrimination; both series of compounds inhibit DdlB strongly and VanA weakly. CONCLUSIONS: VanA has greatly reduced affinity for all the ligands studied. The relative affinities of the inhibitors in the reversible binding step are not, however, consistent with the substrate specificities of the enzymes. We propose a mechanism in which proton transfer from the attacking nucleophile to the departing phosphate occurs directly, without intervention of the enzyme.

Bacteria↗
PubMed1999

Translocation of the catalytic domain of diphtheria toxin across planar phospholipid bilayers by its own T domain.

The T domain of diphtheria toxin is known to participate in the pH-dependent translocation of the catalytic C domain of the toxin across the endosomal membrane, but how it does so, and whether cellular proteins are also required for this process, remain unknown. Here, we report results showing that the T domain alone is capable of translocating the entire C domain across model, planar phospholipid bilayers in the absence of other proteins. The T domain therefore contains the entire molecular machinery for mediating transfer of the catalytic domain of diphtheria toxin across membranes.

Amino Acid Sequence↗
PubMed2003

Rapid measurement of total plasma homocysteine by HPLC.

BACKGROUND: Determination of plasma homocysteine has gained increasing interest during the past few years. Several HPLC methods for determination of homocysteine are available. Based on these methods, we developed a new HPLC assay for rapid and sensitive measurement of total plasma homocysteine. METHODS: As a reducing reagent tris-(2-carboxylethyl)-phosphine is used, ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulfonate serves as the derivatization agent. Separation is performed by reversed-phase HPLC using a precolumn and a 55-mm RP(18) cartridge; mobile phase: 0.1 mol/l KH(2)PO(4) with 5% methanol, adjusted to pH 2.7 with ortho-phosphoric acid, flow-rate 1.1 ml/min. RESULTS: Homocysteine is clearly separated from other thiols, the retention time being 2.2 min, total analysis time is 6 min. Tests for linearity, recovery and precision are satisfactory, as well as the comparison with a commercial available assay method. Detection limit of the method is 0.5 micro mol/l, it could be further enhanced for measurements of even lower homocysteine concentrations in, e.g., cell culture supernatants. CONCLUSIONS: The described method is well suited for analysis of thiols in blood specimens. It is more convenient and more rapid than methods described earlier.

Chromatography, High Pressure Liquid↗
PubMed2003

In vitro splicing of erythropoietin by the Mycobacterium tuberculosis RecA intein without substituting amino acids at the splice junctions.

Protein splicing is a self-catalyzed process involving the excision of an intervening polypeptide sequence, the intein, and joining of the flanking polypeptide sequences, the extein, by a peptide bond. We have studied the in vitro splicing of erythropoietin (EPO) using a truncated form of the Mycobacterium tuberculosis RecA mini-intein in which the homing endonuclease domain was replaced with a hexahistidine sequence (His-tag). The intein was inserted adjacent to cysteine residues to assure that the spliced product had the natural amino acid sequence. When expressed in Escherichia coli, intein-containing EPO was found entirely as inclusion bodies but could be refolded in soluble form in the presence of 0.5 M arginine. Protein splicing of the refolded protein could be induced with a reducing agent such as DTT or tris(2-carboxyethyl)phosphine and led to the formation of EPO and mini-intein along with some cleavage products. Protein splicing mediated by the RecA intein requires the presence of a cysteine residue adjacent to the intein insertion site. We compared the efficiencies of protein splicing adjacent to three of the four cysteine residues of EPO (Cys29, Cys33 and Cys161) and found that insertion of intein adjacent to Cys29 allowed far more efficient protein splicing than insertion adjacent to Cys33 or Cys161. For ease of purification, our experiments involved a His-tagged EPO fusion protein and a His-tagged intein and the spliced products (25 kDa EPO and 24 kDa mini-intein) were identified by Western blotting using anti-EPO and anti-His-tag antibodies and by mass spectroscopy. The optimal splicing yield at Cys29 (40%) occurred at pH 7.0 after refolding at 4 degrees C and splicing for 18 h at 25 degrees C in the presence of 1 mM DTT.

Amino Acid Sequence↗
PubMed1998

Palladium(0)-Catalyzed Allylation of Highly Acidic and Nonnucleophilic Anilines. The Origin of Stereochemical Scrambling When Using Allylic Carbonates.

Acidic anilines such as diphenylamine, phenothiazine, and nitroanilines are efficiently allylated under palladium catalysis using allyl carbonates as allylating reagents. A stereochemical study of the reactions of ethyl cis-5-methyl-2-cyclohexenylcarbonate with 4-nitro- and 2,4-dinitroaniline was performed. Bidentate phosphines as stabilizing ligands gave clean retention of configuration whereas triphenylphosphine permitted cis-trans isomerization of the allylic carbonate, the allylation reactions occurring under Curtin-Hammet preequilibrium conditions.

Journal Article↗
PubMed1996

Ligand Substitution Reactions at the Nickel of [Mo(3)NiS(4)(H(2)O)(10)](4+) with Two Water Soluble Phosphines, CO, Br(-), I(-), and NCS(-) and the Inertness of the 1,4,7-Triazacyclononane (L) Complex [Mo(3)(NiL)S(4)(H(2)O)(9)](4+).

Comparisons (25 degrees C) are made of substitution reactions, X replacing H(2)O, at the tetrahedral Ni of the heterometallic sulfido cuboidal cluster [Mo(3)NiS(4)(H(2)O)(10)](4+), I = 2.00 M (LiClO(4)). Stopped-flow formation rate constants (k(f)/M(-)(1) s(-)(1)) for six X reagents, including two water soluble air-stable phosphines, 1,3,5-triaza-7-phosphaadamantane PTA (119) and tris(3-sulfonatophenyl)phosphine TPPTS(3)(-) (58), and CO (0.66), Br(-) (14.6), I(-) (32.3), and NCS(-) (44) are reported alongside the previous value for Cl(-) (9.4). A dependence on [H(+)] is observed with PTA, which gives an unreactive form confirmed by NMR as N-protonated PTA (acid dissociation constant K(a) = 0.61 M), but in no other cases with [H(+)] in the range 0.30-2.00 M. The narrow spread of rate constants for all but the CO reaction is consistent with an I(d) dissociative interchange mechanism. In addition NMR studies with H(2)(17)O enriched solvent are too slow for direct determination of the water-exchange rate constant indicating a value <10(3) s(-)(1). Equilibrium constants/M(-)(1) for 1:1 complexing with the different X groups at the Ni are obtained for PTA (2040) and TPPTS(3)(-) (8900) by direct spectrophotometry and from kinetic studies (k(f)/k(b)) for Cl(-) (97), Br(-) (150), NCS(-) (690), and CO (5150). No NCS(-) substitution at the Ni is observed in the case of the heterometallic cube [Mo(3)Ni(L)S(4)(H(2)O)(9)](4+), with tridentate 1,4,7-triazacyclononane(L) coordinated to the Ni. Substitution of NCS(-) for H(2)O, at the Mo's of [Mo(3)NiS(4)(H(2)O)(10)](4+) and [Mo(3)(NiL)S(4)(H(2)O)(9)](4+) are much slower secondary processes, with k(f) = 2.7 x 10(-)(4) M(-)(1) s(-)(1) and 0.94 x 10(-)(4) M(-)(1) s(-)(1) respectively. No substitution of H(2)O by TPPTS(3)(-) or CO is observed over approximately 1h at either metal on [Mo(3)FeS(4)(H(2)O)(10)](4+), on [Mo(4)S(4)(H(2)O)(12)](5+) or [Mo(3)S(4)(H(2)O)(9)](4+).

Journal Article↗
PubMed2004

Enantioselective total synthesis of erogorgiaene: applications of asymmetric Cu-catalyzed conjugate additions of alkylzincs to acyclic enones.

The first enantioselective synthesis of erogorgiaene (1), an inhibitor of mycobacterium tuberculosis, is disclosed. The total synthesis highlights the utility of asymmetric conjugate additions (ACA) of alkylzincs to acyclic alpha,beta-unsaturated ketones catalyzed by peptidic phosphine ligands and (CuOTf)(2).C(6)H(6). Moreover, several critical attributes of this catalytic C-C bond-forming reaction are illustrated in the context of the total synthesis; these include the significance of various structural features of the amino acid-based chiral ligands and the chiral ligand's effectiveness in reactions involving achiral and chiral substrates. In addition, the total synthesis showcases some of the special properties of nonphosphine Ru complex 3 as a highly effective catalyst for olefin cross-metathesis.

Alkenes↗
PubMed2003

Human acid sphingomyelinase.

Human acid sphingomyelinase (haSMase, EC 3.1.4.12) catalyzes the lysosomal degradation of sphingomyelin to ceramide and phosphorylcholine. An inherited haSMase deficiency leads to Niemann-Pick disease, a severe sphingolipid storage disorder. The enzyme was purified and cloned over 10 years ago. Since then, only a few structural properties of haSMase have been elucidated. For understanding of its complex functions including its role in certain signaling and apoptosis events, complete structural information about the enzyme is necessary. Here, the identification of the disulfide bond pattern of haSMase is reported for the first time. Functional recombinant enzyme expressed in SF21 cells using the baculovirus expression system was purified and digested by trypsin. MALDI-MS analysis of the resulting peptides revealed the four disulfide bonds Cys120-Cys131, Cys385-Cys431, Cys584-Cys588 and Cys594-Cys607. Two additional disulfide bonds (Cys221-Cys226 and Cys227-Cys250) which were not directly accessible by tryptic cleavage, were identified by a combination of a method of partial reduction and MALDI-PSD analysis. In the sphingolipid activator protein (SAP)-homologous N-terminal domain of haSMase, one disulfide bond was assigned as Cys120-Cys131. The existence of two additional disulfide bridges in this region was proved, as was expected for the known disulfide bond pattern of SAP-type domains. These results support the hypothesis that haSMase possesses an intramolecular SAP-type activator domain as predicted by sequence comparison [Ponting, C.P. (1994) Protein Sci., 3, 359-361]. An additional analysis of haSMase isolated from human placenta shows that the recombinant and the native human protein possess an identical disulfide structure.

Amino Acid Sequence↗
PubMed1999

Developing a chiral toolbox for asymmetric catalytic reactions.

During the last several decades, chemists have made major progress in discovering man-made catalysts to perform challenging asymmetric transformations. The research in our group addresses fundamental and practical problems in this field by developing a diverse set of chiral ligands that combine with transition metals to form highly enantioselective catalysts. Families of tridentate ligands have been developed for the enantioselective hydrogenation of unfunctionalized substrates. In addition, we have developed several new bidentate phosphine ligands for asymmetric catalysis. The common feature of these ligands are that they contain rigid aromatic backbones or ring structures which restrict conformational flexibility of the ligands. Several asymmetric reactions have been studied: asymmetric hydrogenation of functionalized substrates such as N-acylaminoacrylic acids, enamides and enol acetates; asymmetric hydrogenation of simple ketones, and imines; and asymmetric carbon-carbon bond forming reactions. In addition, we have designed and synthesized several novel chiral monophosphines for asymmetric catalytic reactions. Transition metal complexes with these monophosphines have also been developed for asymmetric transformations.

Catalysis↗
PubMed1999

Human selenium-dependent thioredoxin reductase from HeLa cells: properties of forms with differing heparin affinities.

The TrxRl form of thioredoxin reductase (TrxR) was the major form of the enzyme isolated from HeLa cells grown in a fermentor at 35 degrees C under controlled aeration conditions favorable to growth, nominally 30% of saturation of dissolved oxygen or 8 ml of oxygen in a liter of medium. This TrxR1 form was not retained on a heparin affinity matrix, it contained one selenium per subunit, was highly active catalytically, and showed strong cross-reactivity with anti-rat liver TrxR1 polyclonal antibodies. At higher aeration, 50% of saturation of dissolved oxygen or 12 ml of oxygen in a liter of medium, HeLa cell growth was slower and additional TrxR forms that bound to heparin were present in purified enzyme preparations. A minor component, TrxR2, the mitochondrial form of TrxR, was detected in the heparin-bound enzyme fraction. One enzyme form that contained less selenium (ca. 0.5 Se per TrxR subunit) was only about 50% as active with thioredoxin or 5,5'dithiobis(2-nitrobenzoic acid) as substrate. Cross-reactivity of this form with anti-rat liver TrxR1 polyclonal antibodies was very weak. The isoelectric point of the low Se enzyme, 5.85, was higher than that, 5.2-5.4, of normal Se content enzyme. Affinity of purified fully active TrxR1 to heparin could be induced by reduction with NADPH or tris-(2-carboxyethyl)phosphine (TCEP). Under anaerobic conditions there was complete retention of Se indicating that an enzyme conformation change effected by reduction was involved. The TCEP-reduced enzyme form was very oxygen labile and upon exposure to air both the Se content and catalytic activity decreased by about 50%. Addition of millimolar concentrations of NADPH or NADP(+) to the TCEP-reduced enzyme gave full protection from oxygen inactivation. TrxR1 exhibited weak peroxidase activity with H(2)O(2) as substrate in the presence of an NADPH-generating system but this activity was unstable. Specific alkylation of the selenocysteine residue of TrxR1 which completely inhibits the NADPH-dependent reduction of disulfides also destroyed peroxidase activity.

Amino Acid Sequence↗
PubMed2003

The remarkable reactivity of high oxidation state ruthenium and osmium polypyridyl complexes.

There is a remarkable redox chemistry of higher oxidation state M(IV)-M(VI) polypyridyl complexes of Ru and Os. They are accessible by proton loss and formation of oxo or nitrido ligands, examples being cis-[RuIV(bpy)2(py)(O)]2+ (RuIV=O2+, bpy=2,2'-bipyridine, and py=pyridine) and trans-[OsVI(tpy)(Cl)2(N)]+ (tpy=2,2':6',2' '-terpyridine). Metal-oxo or metal-nitrido multiple bonding stabilizes the higher oxidation states and greatly influences reactivity. O-atom transfer, hydride transfer, epoxidation, C-H insertion, and proton-coupled electron-transfer mechanisms have been identified in the oxidation of organics by RuIV=O2+. The Ru-O multiple bond inhibits electron transfer and promotes complex mechanisms. Both O atoms can be used for O-atom transfer by trans-[RuVI(tpy)(O)2(S)]2+ (S=CH3CN or H2O). Four-electron, four-proton oxidation of cis,cis-[(bpy)2(H2O)RuIII-O-RuIII(H2O)(bpy)2]4+ occurs to give cis,cis-[(bpy)2(O)RuV-O-RuV(O)(bpy)2]4+ which rapidly evolves O2. Oxidation of NH3 in trans-[OsII(tpy)(Cl)2(NH3)] gives trans-[OsVI(tpy)(Cl)2(N)]+ through a series of one-electron intermediates. It and related nitrido complexes undergo formal N- transfer analogous to O-atom transfer by RuIV=O2+. With secondary amines, the products are the hydrazido complexes, cis- and trans-[OsV(L3)(Cl)2(NNR2)]+ (L3=tpy or tpm and NR2-=morpholide, piperidide, or diethylamide). Reactions with aryl thiols and secondary phosphines give the analogous adducts cis- and trans-[OsIV(tpy)(Cl)2(NS(H)(C6H4Me))]+ and fac-[OsIV(Tp)(Cl)2(NP(H)(Et2))]. In dry CH3CN, all have an extensive multiple oxidation state chemistry based on couples from Os(VI/V) to Os(III/II). In acidic solution, the OsIV adducts are protonated, e.g., trans-[OsIV(tpy)(Cl)2(N(H)N(CH2)4O)]+, and undergo proton-coupled electron transfer to quinone to give OsV, e.g., trans-[OsV(tpy)(Cl)2(NN(CH2)4O)]+ and hydroquinone. These reactions occur with giant H/D kinetic isotope effects of up to 421 based on O-H, N-H, S-H, or P-H bonds. Reaction with azide ion has provided the first example of the terminal N4(2-) ligand in mer-[OsIV(bpy)(Cl)3(NalphaNbetaNgammaNdelta)]-. With CN-, the adduct mer-[OsIV(bpy)(Cl)3(NCN)]- has an extensive, reversible redox chemistry and undergoes NCN(2-) transfer to PPh3 and olefins. Coordination to Os also promotes ligand-based reactivity. The sulfoximido complex trans-[OsIV(tpy)(Cl)2(NS(O)-p-C6H4Me)] undergoes loss of O2 with added acid and O-atom transfer to trans-stilbene and PPh3. There is a reversible two-electron/two-proton, ligand-based acetonitrilo/imino couple in cis-[OsIV(tpy)(NCCH3)(Cl)(p-NSC6H4Me)]+. It undergoes reversible reactions with aldehydes and ketones to give the corresponding alcohols.

Ammonia↗
PubMedDate not supplied

2-Hydroxypropyl-dithio-2'-isobutyric acid (HPDI) as a multipurpose peptide-resin linker for SPPS.

A new type of bifunctional handle for solid-phase peptide synthesis is described that contains both a disulfide and an ester group. Several peptides up to 22 residues long were assembled. Our results demonstrate the stability of this bifunctional handle in the repetitive steps of the Fmoc/tBu protocol and in the corresponding side-chain deprotection conditions. New ways of peptide release were investigated. Cyanolysis in mild conditions led to a C-terminal free-form peptide by a concerted mechanism involving the two groups of the handle. Furthermore, reduction of the disulfide bond, performed with tris-carboxyethyl phosphine, quantitatively releases beta-mercaptoester peptides suitable for biochemical applications (e.g., coupling to protein carriers). Another promising route for peptide release was found: beta-mercaptoester peptides gave, in slightly basic conditions, the C-terminal free-form peptide in good yields and purities. Finally, classical ester cleavage performed with OH or NH3 led to C-terminal free-form or amide peptides, respectively.

Amino Acid Sequence↗
PubMed2005

Density functional investigation of the Mitsunobu reaction.

In this article we performed an extensive density functional [BP86/6-311++G(3df,3pd) level] investigation of the hypersurface of the Mitsunobu reaction. Reaction of a phosphine with a dialkyl azodicarboxylate (first step in the Mitsunobu conversion) leads to either a five-membered oxadiazaphosphole ring (more stable) or a betaine. The subsequent formation of two stable intermediates, a dialkoxyphosphorane and an acyloxyalkoxyphosphorane, constitutes the second step in the mechanism. These intermediates are in equilibrium with each other (under exchange of alkoxy and acyloxy ligands), and both can undergo an acid-induced decomposition to yield the alkoxy- and/or acyloxyphosphonium salts. The alkoxyphosphonium salt generates the desired ester via a SN2 mechanism (inversion product). Alternatively, the phosphorus atom in a mixed acyloxyalkoxyphosphorane species can easily undergo Berry pseudorotation. A subsequent intramolecular substitution leads to the final ester via a retention mechanism. The hypersurface is much more complicated than previously assumed, and the Mitsunobu reaction is fundamentally capable of running under either inversion or retention. The possibility of selective stereocontrol is discussed. Side reactions include the formation of a degradation product and an anhydride.

Azo Compounds↗
PubMed2003

Surface modification of poly(lactic acid) nanoparticles by covalent attachment of thiol groups by means of three methods.

The aim of the present work was to find a suitable method for the introduction of thiol functions on the surface of poly(DL-lactic acid) (PLA) nanoparticles. Three different approaches were investigated. The modification of the surface involves the activation of PLA carboxylic acid groups followed by the attack of a nucleophile such as cysteine (method #1) or cystamine (method #2 and #3) that provide thiol functions via an amide bond. For the conjugation with cystamine, a second reaction step is required to expose the sulfhydryl function of cystamine that is otherwise protected in a disulfide bond. 1,4-Dithio-DL-threitol (DTT) (method #2) or Tris(2-carboxyethyl)-phosphine hydrochloride (method #3) were evaluated for their ability to reduce this linkage. Method #1 allowed a maximum of 8.5+/-2.8 mmol of thiol functions per mol of PLA to be attached on the surface of the nanoparticles. Method #2 allowed the introduction of a greater number of thiol functions (up to 190+/-15 mmol per mol of PLA). However, this latter method has a major drawback: DTT interacts strongly with the nanoparticle matrix during the reduction step. Method #3 has the advantage over method #2 in that it allowed a significant number of thiol functions to be covalently bound to the particles (up to 107.6+/-0.6 mmol per mol of PLA) without the problem of undesired interaction between DTT and the nanoparticle matrix. The introduction of thiol groups onto the surface of PLA nanoparticles is possible with all three suggested methods. The method #3 provides a straight forward approach for the substitution of carboxylic acid groups with a high number of activated sulfhydryl at the surface of PLA nanoparticles.

Lactic Acid↗
PubMed2005

Enzyme inhibitors as chemical tools to study enzyme catalysis: rational design, synthesis, and applications.

Carefully designed molecules that are intimately related to the reaction mechanism of enzymes are often highly selective and potent inhibitors that serve as extremely useful chemical probes for understanding the reaction mechanism and structure of enzymes. This article describes the design, synthesis, and applications of specific inhibitors of two mechanistically distinct groups of enzymes, ATP-dependent amide ligases and Ser- and Thr-hydrolases. Our strategy is based on the premise that stable analogues of the transition state (transition-state analogues) are highly potent inhibitors that serve as good mechanistic probes, and that a key structure of a good inhibitor of one enzyme is also utilized for the inhibitors of other enzymes that share the same chemistry in their catalyzed reactions, irrespective of the degree of structural similarity and evolutionary link between the enzymes. According to these principles, we designed and synthesized a series of phosphinate- and sulfoximine-based transition-state analogue inhibitors of glutathione synthetase, gamma-glutamylcysteine synthetase and asparagine synthetase. For the second group of enzymes, we synthesized a gamma-monofluorophosphono glutamate analogue for mechanism-based affinity labeling of gamma-glutamyltranspeptidase and fluorescent phosphonic acid esters for the active-site titration of lipase. These inhibitors were used successfully as ligands for detailed kinetic analyses, X-ray crystallography, and mass analysis of the enzymes to identify the key amino acid residues responsible for catalysis and substrate recognition in the transition state.

Animals↗
PubMed1987

Synthesis, characterization and evaluation of 99Tc/99mTc DIARS and DMPE complexes containing pentadecanoic acid.

The synthesis and purification of two new ligands, 15-[bis(3,4-dimethyl arsino)phenyl] pentadecanoic acid (FA-DIARS) and [bis(16,17-dimethyl phosphino)] heptadecanoic acid (FA-DMPE) and the preparation of their corresponding 99Tc/99mTc complexes of the general formula [Tc(III)L2Cl2]+, wherein L is FA-DIARS or FA-DMPE are reported. After careful purification by preparative HPLC, the 99Tc complexes were characterized by spectroscopy, while the 99mTc complexes were used to determine the biodistribution in mice. The results of the organ distribution studies indicated a relatively high uptake in heart (5-7% dose/g). The complexes were, however, found to be very slowly cleared from the blood, probably due to strong binding to serum proteins. Further, the heart to liver and heart to lung ratios were unfavourable. Attempts to improve the efficacy by synthesizing complexes containing one fatty acid per molecule are also described.

Animals↗