Deprotonated Amide Nitrogen Atoms Research Articles

Synthesis, characterization and reactivity of a Mn(III)–hydroxido complex as a biomimetic model for lipoxygenase

Manganese hydroxido (Mn–OH) complexes supported by a tripodal N,N′,N″-[nitrilotris(ethane-2,1-diyl)]tris(P,P-diphenylphosphinic amido) ([poat]3−) ligand have been synthesized and characterized by spectroscopic techniques including UV–vis and electron paramagnetic resonance (EPR) spectroscopies. X-ray diffraction (XRD) methods were used to confirm the solid-state molecular structures of {Na2[MnIIpoat(OH)]}2 and {Na[MnIIIpoat(OH)]}2 as clusters that are linked by the electrostatic interactions between the sodium counterions and the oxygen atom of the ligated hydroxido unit and the phosphinic (P=O) amide groups of [poat]3−. Both clusters feature two independent monoanionic fragments in which each contains a trigonal bipyramidal Mn center that is comprised of three equatorial deprotonated amide nitrogen atoms, an apical tertiary amine, and an axial hydroxido ligand. XRD analyses of {Na[MnIIIpoat(OH)]}2 also showed an intramolecular hydrogen bonding interaction between the MnIII–OH unit and P=O group of [poat]3−. Crystalline {Na[MnIIIpoat(OH)]}2 remains as clusters with Na+---O interactions in solution and is unreactive toward external substrates. However, conductivity studies indicated that [MnIIIpoat(OH)]− generated in situ is monomeric and reactivity studies found that it is capable of cleaving C-H bonds, illustrating the importance of solution-phase speciation and its direct effect on chemical reactivity.Synopsis: Manganese–hydroxido complexes were synthesized to study the influence of H-bonds in the secondary coordination sphere and their effects on the oxidative cleavage of substrates containing C-H bonds.

Copper (II) binding properties of an octapeptide fragment from the R3 region of tau protein: A combined potentiometric, spectroscopic and mass spectrometric study

The copper(II) complexes of a peptide fragment of the R3 domain of tau protein (tau(326–333) Ac-GNIHHKPG-NH2) and its mutants (Ac-GNGHHKPG-NH2, Ac-GNIHHKAG-NH2, Ac-GNGAHKPG-NH2 and Ac-GNGHAKPG-NH2) have been studied by potentiometric and spectroscopic (UV–Vis, CD) methods. ESR spectroscopy and mass spectrometry were also used to prove the coordination mode of the mononuclear complexes and the formation of dinuclear species, respectively. It has been demonstrated that the (326–333) fragment of tau protein is a versatile and effective ligand for copper(II) coordination. The versatility of copper(II) binding is related to the presence of two adjacent histidyl residues in the sequence, which results in the coexistence of mononuclear, bis(ligand) and dinuclear complexes at different metal to ligand ratios. The 1:1 mononuclear complexes are, however, the dominant species with all peptides and the imidazole-N and one to three deprotonated amide nitrogen atoms towards the N-terminal side of the histidyl residue have been suggested as metal binding sites. This binding mode allows the formation of coordination isomers because any of the two histidine moieties can be the primary anchoring site. It is evident from the CD spectroscopic measurements that the isomers are present in almost equal concentration. The copper(II) binding affinity of the native fragment of tau protein is comparable to that of a similar 2-histidine fragment of amyloid-β mutant, Ac-SGAEGHHQK-NH2 but the comparison with an independent histidyl residue (H32) from the N-terminal region of the protein reveals the predominance of H32 over the histidines in the R3 domain.

Heteroatom‐Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity

Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal‐ion transport. The study presented herein investigated the metal chelation of non‐natural heteroatom‐interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the CuII complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI‐lissoclinamide 5 the calculations suggest that the CuII ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti‐cancer properties demonstrated that the biological activity of HI‐lissoclinamide 5 against T24 bladder cells was eleven‐fold lower as compared to natural lissoclinamide 5. Addition of a CuII salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity.

The copper(II) and zinc(II) coordination mode of HExxH and HxxEH motif in small peptides: The role of carboxylate location and hydrogen bonding network

Copper(II) and zinc(II) complexes with two hexapeptides encompassing HExxH and HxxEH motif were characterized by means of a combined experimental and theoretical approach. Parallel tempering and density functional theory (DFT) investigations show the presence of different hydrogen bonding networks between the copper(II) and zinc(II) complexes with the two peptides, suggesting a significant contribution of these non-covalent interactions to the stability constant values. The glutamate carboxylate group has a direct role in metal ion binding. The location of this amino acid along the sequence of the investigated peptides is critical to determine thermodynamic and spectroscopic features of the copper(II) complex species, whereas is less relevant in the zinc(II) complexes formation. Electrospray ionization mass spectrometry (ESI-MS) characterization of the zinc(II) complex species show that in the [ZnH−2L] two deprotonated amide nitrogen atoms are involved in the metal coordination environment, an uncommon behavior in zinc(II) complexes for multi-histidine ligands.

Nickel(II) and Palladium(II) Complexes with Chelating N-Heterocyclic Carbene Amidate Ligands: Interplay between Normal and Abnormal Coordination Modes

A series of six Ni(II) and Pd(II) complexes of two bidentate and two tetradentate N-heterocyclic carbene (NHC)/amidate ligands have been prepared. The complexes are uncharged, with square-planar coordination geometries, and the ligands are bound via the NHC groups and the deprotonated amide nitrogen atoms. Pd(II) complexes were prepared for the bidentate ligands, and in each case, two chelating bidentate ligands were bound to the metal center, yielding cis/trans geometric isomeric forms. The Pd(II) complexes of the tetradentate ligands were obtained as a series of constitutional isomeric forms that were separable by fractional crystallization. The constitutional isomers differed in the coordination mode of the NHC groups, which were bound as either “normal” (nNHC) or “abnormal” (aNHC) carbenes. Density functional theory (DFT) studies show that the energies of the isomeric forms increase in the order nNHC/nNHC < nNHC/aNHC < aNHC/aNHC and suggest that the “abnormal” NHC coordination mode occurs in kinetic r...

First report on a dinuclear Cu(II) complex based on pyridine dicarboxamido ligand having benzimidazole moieties in the amide side arms: Synthesis, structure and magnetic properties of [Cu(GBPA)]2·4H2O, GBPA = N,N′-bis(2-methylbenzimidazolyl)-pyridine-1,3-dicarboxamide

A first report on the X-ray crystal structure of a dinuclear Cu(II) complex of a pyridine dicarboxamide ligand, having benzimidazole moieties appended to the amide arms and coordinating through the deprotonated amide nitrogen atoms instead of the carbonyl oxygens, is presented. The coordination sphere around each metal ion is square planar due to coordination by the pyridine and amide nitrogens with the fourth position being occupied by N of the benzimidazole moiety of the symmetry related molecule in the dimer. The non-bonding Cu⋯Cu distance in the dimer is 3.07Å.Two water molecules in the asymmetric unit self assemble to form a water dimer through H-bonding interactions between them. These water dimers are in turn, involved in hydrogen bonding interactions with the complex molecules thereby linking the successive dinuclear entities to form a 1D tape extending along the c axis. The variable temperature magnetic susceptibility measurements data for the complex shows weak antiferromagnetic coupling between the Cu(II) ions in the dinuclear unit.

Probing the Copper(II) Binding Features of Angiogenin. Similarities and Differences between a N-Terminus Peptide Fragment and the Recombinant Human Protein

The angiogenin protein (hAng) is a potent angiogenic factor and its cellular activities may be affected by copper ions even if it is yet unknown how this metal ion is able to produce this effect. Among the different regions of hAng potentially able to bind copper ions, the N-terminal domain appears to be an ideal candidate. Copper(II) complexes of the peptide fragments encompassing the amino acid residues 4-17 of hAng protein were characterized by potentiometric, UV-vis, CD, and EPR spectroscopic methods. The results show that these fragments have an unusual copper(II) binding ability. At physiological pH, the prevailing complex species formed by the peptide encompassing the protein sequence 4-17 is [CuHL], in which the metal ion is bound to two imidazole and two deprotonated amide nitrogen atoms disposed in a planar equatorial arrangement. Preliminary spectroscopic (UV-vis, CD, and EPR) data obtained on the copper(II) complexes formed by the whole recombinant hAng protein, show a great similarity with those obtained for the N-terminal peptide fragments. These findings indicate that within the N-terminal domain there is one of the preferred copper(II) ions anchoring site of the whole recombinant hAng protein.

Capreomycin — A polypeptide antitubercular antibiotic with unusual binding properties toward copper(II)

Capreomycin is an important therapeutic agent having intriguing and diverse molecular features. Its polypeptidic structure rich in nitrogen donors makes the drug a promising chelating agent for a number of transition metal ions, especially for copper(II). The results of the model investigational studies suggest that capreomycin anchors Cu 2+ ion with an amino function of the α,β-diaminopropionic acid residue at pH around 5. At physiological pH copper(II) ion is coordinated by two deprotonated amide nitrogen atoms of the α,β-diaminopropionic acid, the serine residue as well as the amino function deriving from the β-lysine. Above that pH value we observe a rearrangement within the coordination sphere leading to movement of Cu 2+ to the center of the peptide ring with concurrent coordination of four nitrogen donors. Spin–lattice relaxation enhancements and potentiometric measurements clearly indicate that deprotonated amide nitrogen atom from the β-ureidodehydroalanine moiety is the fourth donor atom.

Structural and NMR Studies of the Hexameric Copper(I) Complex with N‐n‐butyl‐N′‐ethoxycarbonyl‐thioureate

AbstractThe copper sulfide mineral flotation collector, N‐n‐butyl‐N′‐ethoxycarbonyl‐thiourea (H2bectu), and the 1:1 hexameric copper(I) thioureate complex, [Cu(Hbectu)]6, have been characterized by single crystal X‐ray diffraction. H2bectu crystallizes in the triclinic space group $\rm P{\bar 1}$ with a = 5.2754(4), b = 9.0042(7), c = 12.6030(9) Å, α = 80.528(6), β = 90.173(6), γ = 76.472(7)°. An intramolecular N‐H···O hydrogen bond between the thioamide proton and carbonyl oxygen forms a planar six‐membered ring in the central core of the molecule with C=O, C=S and C‐N bond lengths in accord with those reported for other N‐alkyl/aryl‐N′‐acyl‐thiourea compounds. [Cu(Hbectu)]6 crystallizes in the monoclinic space group C2/c with a = 23.269(5), b = 13.243(4), c = 23.037(7) Å, β = 91.81(2)° as discrete hexameric clusters disposed about a crystallographic centre of symmetry with a Cu6S6 core consisting of two Cu3S3 chair‐shaped rings linked by coordination of the deprotonated amide nitrogen atom to a copper atom in the adjacent ring. The six ligands assemble as a paddlewheel structure with the ethoxy and n‐butyl substituents packing in an alternating head to tail arrangement. Temperature dependent solution 1H NMR spectroscopic studies show that the hexameric structure of the complex is maintained in solution.

New Copper(II)/Cyclic Tetrapeptide System That Easily Oxidizes to Copper(III) under Atmospheric Oxygen

A 13-membered ring cyclic tetrapeptide was synthesized by the solid-phase peptide synthesis method, and its copper(II) coordination properties were analyzed by optical spectroscopy, mass spectrometry, and electrochemistry. All collected data strongly support the presence, at alkaline pH, of a stable peptide/copper(III) complex that is formed in solution by atmospheric dioxygen oxidation. On the basis of previous studies on cyclic peptide/copper systems, we suggest that the copper(III) ion is at the center of the ligand's cavity being coordinated to four deprotonated amide nitrogen atoms. This donor set would greatly lower the redox potential for the CuIII/CuII couple, thus allowing easy oxidation of the coordinated copper(II) by atmospheric oxygen.

Synthesis, structure and magnetic properties of carboxylate-bridged polynuclear copper(II)–lanthanide(III) rings: [Ln(H 2O) 5(CuL) 2][CuL] · 8H 2O (Ln = La, Ce)

Reaction of Na[CuL] (H 3L = the Schiff base derived from 5-bromosalicylaldehyde and glycylglycine) with Ln(NO 3) 3 leads to the formation of the title complexes [Ln(H 2O) 5(CuL) 2][CuL] · 8H 2O (Ln = La ( 1) and Ce ( 2)), which contain ring-like hexanuclear [Ln 2(H 2O) 10(CuL) 4] 2+ cations. The Ln(III) cations in 1 and 2 are coordinated by five water molecules, one carbonyl oxygen and three carboxylic oxygen atoms, and the copper(II) cations are coordinated by one phenolic oxygen, one carboxylate oxygen atom, one deprotonated amide nitrogen atom and one imino nitrogen atom. Complex 1 exhibits a ferromagnetic interaction and 2 exhibits an antiferromagnetic interaction in the solid state.

Synthesis, characterization, and X-ray crystal structures of cyclam derivatives. 5. Copper(II) binding studies of a pyridine-strapped 5,12-dioxocyclam-based macrobicycle.

The copper(II) binding properties of the macrobicyclic diamide 1,9,12,18,22-pentaazatricyclo[7.6.6.1(3,7)]docosa-3,5,7(22)-triene-13,19-dione (L1) have been fully investigated by spectroscopic (IR, UV-vis, EPR, MALDI-TOF MS), X-ray diffraction, potentiometric, electrochemical, and spectroelectrochemical methods. This constrained receptor possesses a hemispherical cavity created by cross-bridging the 1 and 8 positions of trans-dioxocyclam (1,4,8,11-tetraazacyclotetradecane-5,12-dione, L2) with a 2,6-pyridyl strap. Treatment of L1 with a copper salt in methanol produces a red complex of [Cu(L1H(-1))]+ formula in which the copper atom is embedded in a 13-membered ring and coordinated by both amines as well as the pyridine and one deprotonated amide nitrogen atoms. Infrared spectroscopy provides evidence for protonation of the carbonyl oxygen atom belonging to the copper-bound amide of [Cu(L1H(-1))]+ under strongly acidic conditions. The resulting conversion of the amidate into an iminol group highlights the inert character of the corresponding complexes, which do not dissociate at low pH values. In contrast, both secondary amides of L1 deprotonate in the presence of a weak base, thus affording a blue pentacoordinated [Cu(L1H(-2))] compound where the copper atom sits in the center of the 14-membered dioxocyclam fragment. In aqueous solution, both complexes undergo a pH-driven (pK(a) = 8.73(2)) molecular reorganization, which is reminiscent of a glider motion. The copper(II) cation switches rapidly and reversibly from a four-coordinate flattened tetrahedral arrangement of the donor atoms in the red species to a five-coordinate environment in the blue species, which is intermediate between a square pyramid and a trigonal bipyramid. Conversion of the red to the blue form was also demonstrated to occur upon reduction of [Cu(L1H(-1))]+ by cyclic voltammetry (E(pc) = -0.64 V/SCE in CH(3)CN).

Interplay of terminal amino group and coordinating side chains in directing regioselective cleavage of natural peptides and proteins with palladium(II) complexes.

Palladium(II) ions anchored to side chains of histidine and methionine residues in peptides and proteins in weakly acidic aqueous solutions promote hydrolytic cleavage of proximate amide bonds in the backbone. In this study, we determine how attachment of Pd(II) ions to histidine and methionine anchors and also to the terminal amino group in six natural peptides (chains A and B of insulin, segment 11-14 of angiotensinogen, pentagastrin, angiotensin II, and segment 3-8 of angiotensin II) and two proteins (ubiquitin and cytochrome c) affects regioselectivity and rate of backbone cleavage. These Pd(II)-promoted reactions follow a clear pattern of regioselectivity, directed by the anchoring side chains. When the Pd(II) reagent is nonspecifically anchored to the terminal amino group, the ligating site that is present in almost all proteins, the cleavage is fortunately absent. When the reagent is anchored to a residue in positions 1, 2, or 3, cleavage is absent, because the terminal amino group and deprotonated amide nitrogen atom(s) interposed between it and the anchor "lock" the Pd(II) ion in hydrolytically inactive chelate complexes. When the reagent is anchored to residues in positions beyond 3, the second amide bond upstream from the anchor is regioselectively cleaved in all cases when the anchor was "isolated," that is, flanked by noncoordinating side chains. Segment 3-8 of angiotensin II undergoes additional cleavage, which we explain by determining the rate constants for the cleavage, identifying the rate-limiting displacement of ethylenediamine ligand from the Pd(II) ion, and detecting several intermediates. Experiments with cytochrome c demonstrate that the number of cleavage sites can be controlled by adjusting the mole ratio of the Pd(II) reagent to the substrate. Our inorganic peptidases are useful for biochemical applications because their regioselectivity and reactivity set them apart from proteolytic enzymes and organic chemical reagents.

Metal–ligand interactions in benzodioxotetraaza-macrocyclic metal chelates

Reactions of ethylenediaminetetraacetic (edta) dianhydride with o-phenylenediamine (od) and 9,10-diaminophenanthrene (phn) gave (edtaod)H 2 and (edtaphn)H 2, respectively, in which a chelating edta unit and an aromatic diamine unit are linked by two amide bonds. The complexation of these new 12-membered macrocycles with transition metal ions was studied by X-ray crystallography, potentiometric titrations, UV–Vis absorption spectroscopy and fluorescence spectroscopy. The absorption spectra are sensitively changed by metal complexation. The spectral changes are the most significant for the Cu 2+ complexes, and are well correlated with the species distribution diagram. The X-ray study of the Cu 2+ complex, [Cu(edtaod)] 0, has shown that a square plane is formed around the central metal ion by an amide oxygen atom, a carboxylate oxygen atom and an amino nitrogen atom from a ligand molecule and a carboxylate oxygen atom from the adjacent chelate molecule. The amide nitrogen atoms in [Cu(edtaod)] 0 are readily deprotonated and result in the formation of [Cu(edtaodH −1)] − and [Cu(edtaodH −2)] 2− in neutral and basic media. The coordination of deprotonated amide nitrogen atoms to a Cu 2+ ion leads to a strong metal–ligand interaction, which causes an intense charge-transfer band in [Cu(edtaodH −1)] −, new UV absorption bands in [Cu(edtaodH −2)] 2− and the effective quenching of emission in the Cu 2+ complex of (edtaphn)H 2.

Potentiometric and spectroscopic studies of reactions of histidine with 13-membered amide-based macrocyclic Cu 2+ chelates

The Cu 2+ complex of a 13-membered macrocycle, 2,9-dioxo-1,4,7,10-tetraaza-4,7-cyclotridecanediacetic acid (abbreviated as LH 2), formed histidine adducts in which a histidine molecule occupied a secondary coordination site of the macrocyclic Cu 2+ chelate. The formation of these adducts was observed as a change in the d–d band of the macrocyclic Cu 2+ chelate in the presence of histidine at different pH values. The compositions of the species were determined by potentiometric titration, and the formation constants were obtained as: log[CuL(hdH)]/[CuL][hdH]=2.8(0.2) and log[Cu(LH −2)(hdH)]/[Cu(LH −2)][hdH]=2.6(0.4) (hd=histidinate(−1) ion; LH −2=L with deprotonated amide nitrogen atoms). These adducts are formed by the coordination of the imidazole ring nitrogen atom to the central metal ion, and are stabilized by an interaction (such as hydrogen bond formation) between the pendant arms of the macrocyclic chelate and the substrate.

Electronic spectra and structures of Cu2+ and Ni2+ complexes with dioxotetraazacycloalkanediacetates and their diester derivatives

Functionalized macrocyclic ligands, dioxotetraazacycloalkanediacetic acid, with different ring sizes and their diester derivatives were synthesized, and their Cu2+ and Ni2+ chelates were characterized by electronic absorption spectra in solution. A single-crystal X-ray analysis of nickel(II) 2,9-dioxo-1,4,7,10-tetraaza-4,7-cyclotetradecandiacetate pentahydrate showed that the central metal ion had an octahedral coordination with two amine nitrogen atoms, two car☐ylate oxygen atoms and an amide oxygen atom from a ligand molecule and an oxygen atom from a water molecule: the metal complex crystallized in the monoclinic space group P21/n with a = 9.040(1), b = 13.539(1), c = 18.168(2)Å, β = 101.895(2)° and Z = 4. Electronic spectra showed that all the complexes studied had similar structures in acidic solutions. In alkaline solutions, some metal chelates had a distorted planar structure in which two deprotonated amide nitrogen atoms and two amine nitrogen atoms were coordinated to the central metal ion. The tendency of deprotonation of amide groups is dependent on the ring size of the ligand, the nature of the central metal ion and the ability of the pendant arm to coordinate with the central metal ion.

Coordination of histamine and imidazole with macrocyclic Zn 2+, Cd 2+ and Cu 2+ chelates of dioxotetraazacycloalkanediacetates

Coordination of histamine and imidazole with macrocyclic Cu 2+, Zn 2+ and Cd 2+ chelates has been studied by 1H NMR and electronic spectroscopy: the macrocyclic ligands studied are 2,9-dioxo-1,4,7,10-tetraaza-4,7-cyclododecanediacetic acid, abbreviated as (12edtaen)H 2, and 2,9-dioxo-1,4,7,10-tetraaza-4,7-cyclotridecanediacetic acid, (13edtapn)H 2. A molecule of histamine or imidazole takes the place of a water molecule in [M(12edtaen)(H 2O)] 0 and [M(13edtapn)(H 2O)] 0. The formation constants of [ZnL(hsH +)] + (hsH +: histaminium ion) are of the same order of magnitude as the corresponding [CdL(hsH +)] +, although the electron donation of hsH + in the Zn 2+ complexes is less significant than that in the Cd 2+ complexes. The Cu 2+ chelate with the 13-membered macrocycle forms [Cu(13edtapnH −2)] 2−, in which deprotonated amide nitrogen atoms are coordinated. In a reaction between this metal chelate and hsH +, one of the vacant coordination sites of the Cu 2+ chelate is occupied by an hsH + molecule and [Cu(13edtapnH −2)(hsH +)] − is formed. Such a complexation reaction does not occur with imidazole. The complexation of hsH + occurs with two binding sites of each component: the central metal ion towards the hsH + ring nitrogen, and a pendant carboxymethyl group in the macrocyclic ligand towards the pendant arm of hsH +.

Dicarboxylate diamide dimercaptide (N2S2) technetium-99m complexes: synthesis and biological evaluation as potential renal radiopharmaceuticals.

Novel diamide dimercaptide (N2S2) ligands 4, 5, and 8 have been synthesized and evaluated as potential renal radiopharmaceuticals. The target compounds were prepared in modest overall yields of 22%, 19%, and 20%, respectively, using readily available starting materials. Following in situ deprotection, 99mTc complexes of high radiochemical purity were obtained in excellent yield and were found to be stable for up to 6 h. The 99Tc complex of ligand 8 was isolated as the AsPh4 salt. The X-ray crystallographic data for [99TcO(8)]AsPh4 (space group P2(1)/n: Z = 4, a = 9.342(3) A; b = 18.594(5) A; c = 18.417(7) A; beta, deg = 90.61(3); V, A3 = 3199.1(20)) show that the Tc is bound to both thiolate sulfur atoms and to two deprotonated amide nitrogen atoms. The coordination geometry about the Tc is square-pyramidal with an -yl oxygen atom in the apical position. The Tc-N bond distances (2.002(12) and 1.984(12) A), the Tc-S bond distances (2.300(5) and 2.286(5) A), and the Tc-O bond distance (1.667(11) A) are in good agreement with bond lengths reported for similar complexes. The carboxylate groups are not bonded to the Tc atom in the solid state, nor in CDCl3 solution, as evidenced by X-ray crystal data and solution NMR data, respectively. In the solid state, [99TcO(8)]AsPh4 is monoanionic, therefore, at physiological pH, [99mTcO(8)] is presumably trianionic. Biodistribution studies performed in rats with the 99mTc complexes revealed slow blood clearance and high muscle uptake for these agents. Modest hepatobiliary excretion was observed, and low quantities of the complexes were found in the heart, lungs, and spleen after 1 h. The urinary excretion of the 99mTc complexes of ligands 4, 5, and 8 was found to be slow when compared to the excretion of [131I]OIH in rats (22%, 22%, and 32% vs 85-86%, respectively). Protein binding of 99mTc complexes of ligands 4, 5, and 8 in both rat and monkey plasma was found to be similar to MAG3. While the synthetic schemes reported here supply facile routes to novel N2S2 ligands, biodistribution studies of the 99mTc complexes performed on rats revealed slow renal excretion rates, accompanied by slow blood clearance and high uptake in muscle tissue. Preliminary planar imaging studies in monkeys also revealed slow renal excretion for these agents. The 99mTc complexes evaluated here are poor candidates as renal radiopharmaceuticals.

Sulphonamide nitrogen-containing, nitrogen-protected amino acids interacting with the Cd2+ion. A cadmium-113 nuclear magnetic resonance and potentiometric study. X-Ray diffraction of [Cd(ts-β-alaO)2(H2O4)

α-Alanine and β-alanine, N-protected by a tosyl (toluene-p-sulphonyl) group, bind Cd2+ acting initially as a simple carboxylate at low pH, and, at increasing pH, as N,O-bidentate ligands, through the carboxylic oxygen and the deprotonated amide nitrogen atoms. In the latter case they give rise to five- and six-membered ring chelate species, respectively. Cadmium-113 n.m.r. and potentiometric measurements reveal that the stability of the complexes is almost unaffected by the chelate ring size. The five-membered ring chelate species has a more deshielded chemical shift and only a slightly greater stability than the six-membered species. The crystal and molecular structures of the [Cd(ts-β-alaO)2(H2O)4](ts-β-alao =N-tosyl-β-alaninate monoanion) complex have been solved. Crystal data are: monoclinic, space group P21/c, a= 14.956 (6), b= 5.472(2), c= 16.860(7)Å, β= 107.36(3)°, Z= 2, and R= 0.039 for 1 635 reflections. The amina acid molecule binds through the unidentate carboxylate group and the structure consists of discrete units in which the Cd2+ exhibits a nearly regular octahedral geometry.

Cytotoxic activity of cyclic peptides of marine origin and their derivatives: importance of oxazoline functions

Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal‐ion transport. The study presented herein investigated the metal chelation of non‐natural heteroatom‐interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the CuII complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI‐lissoclinamide 5 the calculations suggest that the CuII ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti‐cancer properties demonstrated that the biological activity of HI‐lissoclinamide 5 against T24 bladder cells was eleven‐fold lower as compared to natural lissoclinamide 5. Addition of a CuII salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity.