Amino Acid Chelates Research Articles

Bifunctional chelates with mixed aromatic and aliphatic amine donors for labeling of biomolecules with the {Tc(CO) 3} + and {Re(CO) 3} + cores

A series of tridentate ligands consisting of mixed aromatic and aliphatic amine derivatives of single amino acid chelates and phenylpiperazine have been developed, and their reactions with [NEt 4] 2[ReBr 3(CO) 3] have been investigated. The compounds [Re(CO) 3{(NC 5H 4CH 2)NCH 3(C 2H 4)NHCH 3}]Br ( 4), [Re(CO) 3{(NC 5H 4CH 2)NCH 3(C 2H 4)NCH 3(CH 2) x COOC 2H 5}]Br ( x = 1, 5; x = 4, 6) [Re(CO) 3{(NC 5H 4CH 2)NH(C 2H 4)N(CH 3) 2}]Br ( 7), [Re(CO) 3{(NC 5H 4CH 2)N(CH 2COOC 2H 5)(C 2H 4)N(CH 3) 2}]Br ( 8) and [Re(CO) 3(NC 5H 4CH 2)(C 2H 4NH 2)N(CH 2) 3–CH 3Ophenpip]Br ( 9) (phenpip: phenylpiperazine, –C 6H 4–(CH 2CH 2) 2N–) were prepared and characterized by elemental analysis, NMR, IR, HSMS and X-ray crystallography. All complexes exhibit fac-{Re(CO) 3N 3} coordination geometry in the cationic molecular unit. Crystal data for C 13H 17BrN 3O 3Re ( 4): orthorhombic, Pbca, a = 13.4510(8) Å, b = 10.5728(6) Å, c = 22.5378(13) Å, V = 3205.2(3) Å 3, Z = 8; C 17H 23BrN 3O 5Re ( 5): orthorhombic, Pcca, a = 16.5907(7) Å, b = 14.8387(6) Å, c = 16.7075(7) Å, V = 4113.1(3) Å 3, Z = 8; C 13H 25BrN 3O 7Re ( 7 · 4H 2O): monoclinic, P2 1/ n, a = 14.0698(17) Å, b = 9.6760(12) Å, c = 15.6099 (19) Å, β = 114.930(2)°, V = 1927.1(4) Å 3, Z = 4; C 17H 23BrN 3O 5Re ( 8): monoclinic, P2 1/ n, a = 7.5312(5) Å, b = 16.0366(10) Å, c = 16.8741(10) Å, β = 98.9990(10)°, V = 2012.9(2) Å 3, Z = 4.

Straightforward Approach to Iminoxazines and Azetidinimines via 1,4-Additions of Chelated Enolates toward Nitroalkenes

[reaction: see text] Chelated amino acid ester enolates undergo 1,4-addition toward nitroalkenes in a highly stereoselective fashion. Trapping the nitronates formed in the addition step with chloroformates or acyl chlorides gives rise to highly reactive intermediates that directly undergo cyclization. Depending on the N-protecting group (PG) used, iminoxazines or azetidinimines are formed in a simple one-pot protocol.

Efficient 1,5‐Chirality Transfer in Palladium‐Catalyzed Allylic Alkylations of Chelated Amino Acid Ester Enolates

Neither the olefin geometry nor the configuration of secondary allylic substrates in palladium-catalyzed allylic alkylations of chelated enolates has an influence on the newly formed stereogenic center of the amino acid (see scheme, TBDPS=tert-butyldiphenylsilyl, Tfa=trifluoroacetyl). This is controlled exclusively by the protecting group on the chiral center. Therefore, the choice of the protecting group on the allylic alcohol can lead to either of the diastereomeric amino acids in a highly stereoselective fashion.

Structure, stability, and ligand exchange of copper(II) complexes with oxidized glutathione

Formation constants and structures of copper(II) complexes with oxidized glutathione (L) have been determined by computer modelling of spectrophotometric and NMR relaxation measurements data over a wide range of pH (1–13) and metal and ligand concentrations in aqueous KNO 3 (1 M) at 298 K. Among 11 found complexes, four forms were characterized for the first time. Based on a comparison of thermodynamic, relaxation, and optical and EPR spectroscopy parameters the structural conclusions were made. In particular, the CuLH 2 and CuLH − complexes both contain two isomers which are similar to mono- and bis-aminoacid copper(II) complexes. In the Cu 2L and Cu 3 L 2 2 - species one of the copper atoms is bound only with the carboxylate or carbonyl groups and the others are coordinated similarly to aminoacid chelates. Along with the last, in Cu 2 LH - 2 2 - two bridging OH − groups in one isomer or two chelate rings including deprotonated peptide nitrogen and glycinyl carboxylate oxygen in another are also present. In Cu 3 L 2 H - 4 6 - the mixed variant of coordination between CuL 2− (CuN 2O 2) and Cu 2 LH - 4 4 - ( CuN 3 O ) is realized. The structures of polynuclear complexes have been optimized in density functional theory computations. Rate constants of ligand exchange reactions of Cu ( LH ) 2 4 - and CuL 2 6 - with participation of the LH 3− and L 4− forms were determined for the first time. Factors determining rates of these processes have been revealed and their proceeding by associative substitution mechanism shown.

Applications of Nonstabilized Enolates as Nucleophiles in Palladium‐Catalyzed Allylic Alkylations

AbstractFor Abstract see ChemInform Abstract in Full Text.

Iron Amino Acid Chelates

Iron amino acid chelates, such as iron glycinate chelates, have been developed to be used as food fortificants and therapeutic agents in the prevention and treatment of iron deficiency anemia. Ferrous bis-glycine chelate (FeBC), ferric tris-glycine chelate, ferric glycinate, and ferrous bis-glycinate hydrochloride are available commercially. FeBC is the most studied and used form. Iron absorption from FeBC is affected by enhancers and inhibitors of iron absorption, but to a lesser extent than ferrous sulfate. Its absorption is regulated by iron stores. FeBC is better absorbed from milk, wheat, whole maize flour, and precooked corn flour than is ferrous sulfate. Supplementation trials have demonstrated that FeBC is efficacious in treating iron deficiency anemia. Consumption of FeBC-fortified liquid milk, dairy products, wheat rolls, and multi-nutrient beverages is associated with an improvement of iron status. The main limitations to the widespread use of FeBC in national fortification programs are the cost and the potential for promoting organoleptic changes in some food matrices. Additional research is required to establish the bioavailability of FeBC in different food matrices. Other amino acid chelates should also be evaluated. Finally there is an urgent need for more rigorous efficacy trials designed to define the relative merits of amino acid chelates when compared with bioavailable iron salts such as ferrous sulfate and ferrous fumarate and to determine appropriate fortification levels

Enhancing the Absorption of Fortification Iron

Iron deficiency remains a major global health problem affecting an estimated 2 billion people. The World Health Organization ranked it as the seventh most important preventable risk for disease, disability, and death in 2002. Since an important factor in its causation is the poor bioavailability of iron in the cereal-based diets of many developing countries, SUSTAIN set up a Task Force, consisting of nutritional, medical, industry, and government experts to consider strategies for enhancing the absorption of fortification iron. This paper summarizes the findings of this Task Force. Detailed reviews of each strategy follow this overview. Highly soluble compounds of iron like ferrous sulfate are desirable food fortificants but cannot be used in many food vehicles because of sensory issues. Thus, potentially less well-absorbed forms of iron commonly are used in food fortification. The bioavailability of iron fortificants can, however, be enhanced with innovative ingredient technologies. Ascorbic acid, NaFeEDTA, ferrous bisglycinate, and dephytinization all enhance the absorption of fortification iron, but add to the overall costs of fortification. While all strategies cannot be recommended for all food fortification vehicles, individual strategies can be recommended for specific foods. For example, the addition of ascorbic acid is appropriate for dry blended foods such as infant foods and other dry products made for reconstitution that are packaged, stored, and prepared in a way that maximizes retention of this vitamin. NaFeEDTA can be recommended for fortification of fish sauce and soy sauce, whereas amino acid chelates may be more useful in milk products and beverages. With further development, dephytinization may be possible for low-cost, cereal-based complementary foods in developing countries. Encapsulation of iron salts in lipid coatings, while not an iron absorption-enhancing strategy per se, can prevent soluble forms of iron from interacting undesirably with some food vehicles and hence broaden the application of some fortificants. Research relevant to each of these strategies for enhancing the bioavailability or utility of iron food fortificants is reviewed. Individual strategies are evaluated in terms of enhancing effect and stability, organoleptic qualities, cost, and regulatory issues of interest to the nutrition community, industry, and consumers. Recommendations are made on potential usages and further research needs. Effective fortification depends on the selection of technically feasible and efficacious strategies. Once suitable strategies have been identified, cost becomes very important in selecting the best approach to implement. However it is essential to calculate cost in relation to the amount of bioavailable iron delivered. An approach to the calculation of cost using a conservative estimate of the enhancing effects of the innovative technologies discussed in the supplement is given in the final section.

Allylic alkylation versus Michael induced ring closure: chelated enolates as versatile nucleophiles.

Allylic carbonates 8 bearing an electron-withdrawing ester functionality can act as substrates for palladium-catalyzed allylic alkylations or as Michael acceptors with the option to undergo subsequent ring closure. Chelated amino acid ester enolates 1' are versatile nucleophiles for both reactions giving high yields and selectivites.

Effects of Supplemental Amino Acid‐Chelated Trace Elements on the Immune Response of Rainbow Trout Subjected to Bacterial Challenge

AbstractThis study examined whether supplemental amino acid‐chelated trace elements were effective in improving disease resistance in rainbow trout Oncorhynchus mykiss. Four semipurified diets containing trace elements from either sulfates or an amino acid chelate source were fed to the fish for 18 weeks. Subsequently, fish weighing about 20–40 g were challenged with β‐hemolytic Streptococcus sp. The cumulative mortality was less in the chelate‐supplemented groups but not significantly different from that of the sulfate groups. Antibody titer was significantly higher in the chelate‐fed fish. Lysozyme activity and total immunoglobulin content were slightly more enhanced in the chelate‐fed than in the sulfate‐fed groups. Despite the increased antibody production, no distinct improvement in disease resistance against Streptococcus sp. was achieved by supplementing rainbow trout diets with amino acid‐chelated trace elements. Further confirmatory studies focusing on the amounts of the trace elements used are needed to shed light on the influence of amino acid chelates on disease resistance.

Effect of Recognized and Unrecognized Salt on the Self-Assembly of New Thermosensitive Metal-Chelating Surfactants

New functional thermoreversible metal complexing surfactants consisting of a chelating amino acid residue grafted to the tip of a nonionic surfactant [alkyl poly(oxyethylene) CiEj] or in a branched position are studied. Nonionic surfactants are thermoreversible and exhibit a clouding phenomenon associated with phase separation of micelles. The functional molecules retain both the surface-active properties and the characteristic thermoreversible behavior. Because of the hydrophilic contribution of the chelating group (acetyl lysine), the cloud point and the area at the air-water interface are higher for functional surfactants than for nonionic precursors. These new surfactants have efficient complexing properties toward metal ions and are more efficient than the mixture of the corresponding nonionic surfactant and the acetyl lysine ligand solubilized in micelles. This reveals the synergistic effect obtained by the covalent link between the two functions. Addition of a bulky group on classical amphiphilic structures modifies markedly the packing constraints at the origin ofmicellar structures. Small-angle X-ray or neutron scattering results, modeled jointly on the absolute scale, demonstrate the influence of unrecognized lithium nitrate (LiNO3) as well as specifically recognized uranyl nitrate [UO2(NO3)2] salts on micellar structure and phase boundaries. The determination of the micellar shape variations induced by a recognized salt, that is, a decrease of the polar headgroup, allows the rationalization of uncommon synergistic effects on the cloud point variation: increase with lithium nitrate, no decrease in the presence of uranyl nitrate, and a very large decrease when these two salts are present together.

Amino acid-chelate: a better source of Zn, Mn and Cu for rainbow trout, Oncorhynchus mykiss

This study aimed to evaluate the amino acid-chelated trace elements as dietary supplement to rainbow trout. Three diets were formulated containing trace elements either from the inorganic salt (SF) or amino acid-chelate (AM). Diets 1 (SF) and 2 (AM) contained the same amount of trace elements from inorganic and amino acid-chelates, respectively. Diet 3 (AM-Hf) was added with trace elements from amino acid-chelatex at one-half of their levels in Diets 1 and 2. Each diet was fed for 15 weeks to three groups of 30 fish each, with an average weight of 1.52±0.21 g. Growth of fish was not affected by the treatment ( P>0.05). However, bone ( P<0.01) and liver ( P<0.05) Cu contents were higher in the AM than the SF group. Similarly, hematocrit level ( P<0.05) and alkaline phosphatase (ALP) activity ( P<0.01) were higher in the chelate-fed fish. Further, DNA polymerase and CuZnSOD expression in the AM group was highly upregulated ( P<0.05) compared to the SF fed fish as quantified by RT-PCR. Absorption and whole body retention of Mn and Zn from the AM were higher ( P<0.05) than the inorganic salt. Half supplementation of those fed the elements from AM was at par with the full provision from the inorganic source tested.

Bifunctional chelates with aliphatic amine donors for labeling of biomolecules with the {Tc(CO)3}+ and {Re(CO)3}+ cores: the crystal and molecular structure of [Re(CO)3{(H2NCH2CH2)2 N(CH2)4CO2Me}]Br

A general synthetic approach to the design of bis(ethylamine) derivatives of single amino acid chelates has been developed. In general, protection of diethylenetriamine as the phthalimide, followed by reaction with the appropriate bromoalkylcarboxylate and deprotection, yields the bifunctional reagents (H2NCH2CH2)2N–R–CO2H. Reaction of the bis(aminoethyl)aminovaleric acid derivative with (NEt4)2[Re(CO)3Br3] in methanol yields [Re(CO)3{(H2NCH2CH2)2N(CH2)4CO2Me}]Br (1Br), the first example of the {Re(CO)3}+ core ligated to exclusively aliphatic amine donors. Crystal data: C13H23BrN3O5Re (1Br), monoclinic P21/c, a=8.3419(5) Å, b=9.4018(6) Å, c=23.569(1) Å, β=99.165(1)°, V=1824.9(2) Å3, Z=4, Dcalc=2.065 g cm−3.

Relative Bioavailability of Novel Amino Acid Chelates of Manganese and Copper for Chicks

ABSTRACT Two experiments were conducted to estimate the relative bioavailability of two new organic chelates of Mn or Cu compared with either reagent-grade Mn sulfate monohydrate or reagentgrade Cu sulfate pentahydrate as the standards in chicks fed for 21 d. Based on either bone Mn concentration, regressed on added dietary Mn concentration, or log10 liver Cu concentration, regressed on non-zero added dietary Cu intake, and assuming a value of 100% for either reagentgrade standard, relative bioavailability values were 84 ± 3.5 and 96 ± 14%, for the Mn and Cu chelates, respectively.

A new strategy for the preparation of peptide-targeted radiopharmaceuticals based on an fmoc-lysine-derived single amino acid chelate (SAAC). automated solid-phase synthesis, NMR characterization, and in vitro screening of fMLF(SAAC)G and fMLF[(SAAC-Re(CO)3)+]G.

A tridentate single amino acid chelate (SAAC) derived from N-alpha-Fmoc-l-lysine was incorporated within a short peptide sequence using an automated peptide synthesizer. Novel derivatives of the chemotactic peptide fMLF were prepared such that the SAAC and its Re complex were selectively placed between a terminal glycine amino acid and the targeting fMLF sequence. The products, which were synthesized in parallel, were characterized by mass spectrometry and multi-NMR spectroscopy. The latter technique demonstrated that the structures of the targeting portions of the peptides are the same in the SAAC and Re-SAAC derivatives. The affinities of the reported compounds for the formyl peptide receptor were subsequently determined using flow cytometry and were found to be comparable to that of the parent peptide. The results of this work demonstrate the feasibility and numerous benefits of using the SAAC system to prepare peptide-targeted Tc(I) and Re(I) radiopharmaceuticals.

Bioavailability and tissue distribution of amino acid-chelated trace elements in rainbow trout Oncorhynchus mykiss

: Feeding trials were conducted to determine the availability of amino acid-chelated trace elements to rainbow trout. Three practical diets were supplemented with trace element mix either all from sulfates (Tr-Sf), Zn and Mn from sulfates added with Cu from amino acid chelates (Cu-Am) or a mixture of trace elements from amino acid chelates (Tr-Am). Rainbow trout weighing 1.11 g were fed the experimental diets for 15 weeks. Growth, feed gain ratio (FGR), tissue distribution, retention of the elements and plasma alkaline phosphatase (ALP) activity were compared between the treatments. Absorption of the elements was determined using larger fish of approximately 95 g fed the same experimental diets. Growth and FGR were not significantly influenced by the chemical form of the elements. The highest concentration of Cu was measured in the liver, whereas highest concentrations of Zn and Mn were in bone. Plasma ALP activity was significantly higher in the Tr-Am group. The absorption of elements from the Tr-Am diet was higher but not significantly different from the other two diets. These results suggest that trace elements from Tr-Am seem to be more available than from inorganic sources tested.

Copper Supplementation Has No Effect on Markers of DNA Damage and Liver Function in Healthy Adults (FOODCUE Project)

Background/Aims: Copper is routinely used in the laboratory to promote oxidation in vitro. However, copper concentrations are million-fold higher than physiological concentrations and, in contrast, accumulating evidence suggests that copper may have an antioxidant role in vivo. The aim of this study was to provide data on how increased intake of copper affected mononuclear leukocyte DNA damage and liver function in healthy young free-living men and women. Methods: The study design was a double-blind repeated crossover trial with treatment and intervening placebo periods, each of 6 weeks’ duration. The following supplementations were given orally in sequence: CuSO₄ at a dose of 3 mg copper/day and copper amino acid chelates at doses of 3 and 6 mg copper/day. Oxidative DNA damage was assessed using a modification of the alkaline Comet assay incorporating an endonuclease III digestion step. The assessment of liver function was by measurement of the liver enzymes, alanine aminotransferase and L-γ-glutamyltransferase. Results: There was no significant alteration in mononuclear leukocyte DNA damage or on liver function after 6 weeks of copper supplementation at two doses (3 and 6 mg/day). Conclusions: Copper supplementation (giving total copper intake at the highest level of 7 mg/day) did not induce DNA damage or adversely affect liver function in healthy adults.

Availability of supplemental amino acid-chelated trace elements in diets containing tricalcium phosphate and phytate to rainbow trout, Oncorhynchus mykiss

This study investigated the availability of amino acid-chelated trace elements to rainbow trout fed diets containing tricalcium phosphate (TCP) and phytate (PH) that are known mineral inhibitors. Six semi-purified diets were supplemented with trace elements either from the sulfate (SF, diets 1 and 2) or amino acid-chelate (AM, diets 3–6). Diets 1 (SF) and 3 (AM) contained neither TCP nor PH. Diet 4 (AMPO) included TCP while Diet 5 (AMPH) contained PH alone. Diets 2 (SF++) and 6 (AM++), on the other hand, contained both inhibitors. Rainbow trout weighing 1.6 g were fed the experimental diets three times daily to near satiation for 18 weeks. Growth, whole body mineral deposition, and enzyme activity/expression were measured after the trial. Growth of fish fed the SF++ diet was significantly lower than the rest of the groups. Whole body Cu content was significantly higher in AM groups than in SF groups with or without TCP and PH. Whole body and bone Zn contents were significantly higher in fish fed the diet containing AM alone compared to the rest. Alkaline phosphatase activity was significantly higher in fish fed the diet containing AM alone than with fish fed the SF diet with or without TCP and PH. CuZnSOD and DNA polymerase were highly expressed in the AM compared to the SF groups. The results show that availability of trace elements is significantly affected by their chemical form and that amino acid-chelates are more beneficial for rainbow trout even in the presence of TCP and PH compared to the inorganic sources tested.

Glutamic acid residues as metal ligands in the active site of Escherichia coli alkaline phosphatase

Four independent mutations were introduced to the Escherichia coli alkaline phosphatase active site, and the resulting enzymes characterized to study the effects of Glu as a metal ligand. The mutations D51E and D153E were created to study the effects of lengthening the carboxyl group by one methylene unit at the metal interaction site. The D51E enzyme had drastically reduced activity and lost one zinc per active site, demonstrating importance of the position of Asp 51. The D153E enzyme had an increased k cat in the presence of high concentrations of Mg 2+, along with a decreased Mg 2+ affinity as compared to the wild-type enzyme. The H331E and H412E enzymes were created to probe the requirement for a nitrogen-containing metal ligand at the Zn 1 site. The H331E enzyme had greatly decreased activity, and lost one zinc per active site. In the absence of high concentrations of Zn 2+, dephosphorylation occurs at an extremely reduced rate for the H412E enzyme, and like the H331E enzyme, metal affinity is reduced. Except at the 153 position, Glu is not an acceptable metal chelating amino acid at these positions in the E. coli alkaline phosphatase active site.

Applications of nonstabilized enolates as nucleophiles in palladium catalyzed allylic alkylations

Palladium catalyzed allylic alkylations are important reactions in organic synthesis. In general stabilized carbanions are used as soft C-nucleophiles. Nonstabilized enolates from ketones and esters often cause problems, and the developments and improvements made with these interesting nucleophiles are summarized in this review. With respect to ketone enolates, best results are obtained with the corresponding tin derivatives, but enoxyborates also can be used. With ketone enolates α-allylated products are obtained. In the presence of suitable chiral ligands, the optically active substitution products are obtained with high stereoselectivity. In contrast, sterically hindered ester enolates do not provide allylation products, hut give rise to cyclopropane derivatives, while with silylketene acetals as nucleophiles, or vinylepoxides as allylic substrates, the α-allylated products are obtained as well. This is also ture with more or less stabilized enolates derived from pyrazinones or azlactones, giving rise to α-alkylated amino acid derivates. Normal unsaturated amino acids can be obtained by using chelated amino acid ester enolates as nucleophiles. This enolates show a high reactivity and therefore these reactions can be carried out under very mild conditions, conditions under which the π-σ-π-isomerization of the p-allyl intermediates can he suppressed. This opens up totally new synthetic possibilities. In the presence of chiral ligands optically active amino acids are obtained.

Re(III)Cl(3)] core complexes with bifunctional single amino acid chelates.

The reactions of the Re(V) starting material [ReO(PPh(3))(2)Cl(3)] with ligands of the type XN(Y)Z [X = Y = 2-pyridylmethyl, Z = -CH(2)CO(2)Et (L(1)Et), -CH(2)CH(2)CO(2)Et (L(2)Et), -CH(2)CH(2)CH(2)CH(2)CH(NHCO(2)Bu(t))CO(2)H (L(3)H); X = 2-pyridylmethyl, Y = 2-(1-methylimidazolyl)methyl, Z = -CH(2)CO(2)Et (L(4)Et)] yielded the Re(III) trichloride complexes of the type [ReCl(3)(L(n)R)]. The complexes are mononuclear, paramagnetic species with a facial geometry of the chloride ligands. The nitrogen donors of the tridentate L(n)()R ligands complete the distorted octahedral coordination spheres of the complexes. Crystal data: [ReCl(3)(L(1)Et)] (1), monoclinic, C2/m, a = 16.088(3) A, b = 9.980(2) A, c = 12.829(2) A, beta = 91.384(3) degrees, Z = 4, D(calc) = 1.967 g/cm(-)(3); [ReCl(3)(L(4)Et)] (4), monoclinic, C2/c, a = 22.880(1) A, b = 7.4926(4) A, c = 22.560(1) A, beta = 94.186(1) degrees, Z = 8, D(calc) = 2.001 g/cm(-3).