Novel chiral "calixsalen" macrocycle and chiral robson-type macrocyclic complexes.

A family of novel chiral "calixsalen" Schiff base macrocycles R,R-H(3)L4, R,R-H(3)L5, containing three chiral diamino moieties were synthesized by an efficient self-assembly and characterized by (1)H and (13)C NMR, mass spectrometry, and X-ray diffraction. The systematic synthesis, structure, and coordination properties of the [2 + 2] and [3 + 3] Robson-type Schiff base macrocyclic mono-, di-, tri-, and tetranuclear metal complexes were explored.

In vivo evaluation of copper-64-labeled monooxo-tetraazamacrocyclic ligands.

Copper-64 (T(1/2)=12.7 h; beta(+): 0.653 MeV, 17.4%; beta(-): 0.578 MeV, 39%) has applications in positron emission tomography (PET) imaging and radiotherapy, and is conveniently produced on a biomedical cyclotron. Tetraazamacrocyclic ligands are the most widely used bifunctional chelators (BFCs) for attaching copper radionuclides to antibodies and peptides due to their relatively high kinetic stability. In this paper, we evaluated three monooxo-tetraazamacrocyclic ligands with different ring sizes and oxo group positions. H1 [1,4,7,10-tetraazacyclotridecan-11-one], H2 [1,4,8,11-tetraazacyclotetradecan-5-one] and H3 [1,4,7,10-tetraazacyclotridecan-2-one] were radiolabeled with (64)Cu in high radiochemical yields under mild conditions. The three (64)Cu-labeled complexes are all +1 charged, as determined by their electrophoretic mobility. While they demonstrated >95% stability in rat serum out to 24 h, both biodistribution and microPET imaging studies revealed high uptake and long retention of the compounds in major clearance organs (e.g., blood, liver and kidney), which suggests that (64)Cu dissociated from the complexes in vivo. Of the three complexes, (64)Cu-2(+), which has a cyclam backbone (1,4,8,11-tetraazacyclotetradecane), exhibited the lowest nontarget organ accumulation. The data from these studies may invalidate the candidacy of the monooxo-tetraazamacrocyclics as BFCs for copper radiopharmaceuticals. However, the data presented here suggest that neutral or negatively charged Cu(II) complexes of tetraazamacrocyclic ligands with a cyclam backbone (tetradecane) are optimal for copper radiopharmaceutical applications.

Direct observation of enantioselective synergism at trimetallic centers.

[structure: see text] [structure: see text] New oligomeric chiral macrocyclic ligands have been synthesized using an efficient self-assembly method. High enantioselective cooperativity in the catalytic asymmetric aldol reactions was directly observed using the conceptually novel chiral multinuclear complex catalysts.

A systematic evaluation of molecular recognition phenomena. 4. Selective binding of dicarboxylic acids to hexaazamacrocyclic ligands based on molecular flexibility.

The host-guest interaction between four hexaaza macrocyclic ligands (3,6,9,17,20,23-hexaazatricyclo[23.3.1.1]triaconta-1(29),11,13,15 (30),25(27)-hexaene (Bd), 3,6,9,16,19,22-hexaazatricyclo[22.2.2.2]triaconta-1(27),11(30),12,14(29),24(28),25-hexaene (P2), 3,7,11,19,23,27-hexaazatricyclo[27.3.1.1]tetratriaconta-1(33),13, 15,17(34),29,31-hexaene (Bn), 3,7,11,18,22,26-hexaazatricyclo[26.2.2.2]tetratriaconta-1(31),13(34),14,16(33),28(32),29-hexaene (P3)) and two dicarboxylic acids (oxalic acid, H2Ox; oxydiacetic acid, H2Od) have been investigated using potentiometric equilibrium methods. Ternary complexes are formed in aqueous solution as a result of hydrogen bond formation and Coulombic interactions between the host and the guest. In the [(H6P2)(Ox)]4+ complex those bonding interactions reach a maximum yielding a log KR6 of 6.08. This species has been further characterized by means of X-ray diffraction analysis showing that the oxalate guest molecule is situated inside the macrocyclic cavity of the P2 host. X-ray diffraction analysis has also been carried out for the complex [(H6Bn)(Od)2](Br)2.6H2O, where now the oxydiacetate is bonded to the host but outside the macrocyclic cavity. Competitive distribution diagrams and total species distribution diagrams are used to graphically illustrate the most salient features of these systems, which are the following: (a) The Bd and P2 ligands bind Ox significantly much more stronger than Od. This is clearly manifested for the P2:Ox:Od competitive system, where a selectivity of 92.5% in favor of the P2-Ox complexation against P2-Od is obtained at p[H] = 2.8. (b) No isomeric effect is found when comparing binding capacities of oxalate with two isomeric ligands such as P2 and Bd since their affinity to bind the substrate is relatively similar. (c) Bn and P3 ligands have a similar behavior as described in (a) for P2 and Bd except that due to the increase of cavity size the differentiation becomes smaller. (d) Less basic ligands containing two methylenic units Bd (log betaH6 = 40.42) and P2 (40.42) bind stronger to the substrates than those containing three methylenic units Bn (50.32) and P3 (50.64) even though their relative predominance depends on p[H].

Selective recognition of thymidylylthymidine (TpT) and antitumor effects of a macrocyclic dizinc(II) complex.

A polyamino dizinc(II) complex, [(N-bisdien)Zn2(II)Cl2](ClO4)2, (LZn), has been synthesized as a new nucleobase receptor molecule in aqueous solution at physiological pH, and shows to be highly selective in recognizing deoxythymidine (dT) and thymidylylthymidine (TpT). The strong acidic Zn(II) ions in LZn at the fifth coordination sites interact with a variety of nucleosides. The binding and recognition processes have been studied by potentiometric titration. The X-ray crystal analysis of LZn shows that the two zinc ions are out of the basal plane of the macrocycle, favoring the effective recognition of TpT on the single strand of DNA. In vitro antitumor investigation shows that LZn is a patent inhibitor of tumor cell growth with IC50 values below 10 micromolar.

Systematic evaluation of molecular recognition phenomena. 3. Selective diphosphate binding to isomeric hexaazamacrocyclic ligands containing xylylic spacers.

The crystal structure of 3,7,11,18,22,26-hexaazatricyclo[26.2.2.2(13,16)]tetratriaconta-1(31),13(34),14,16(33),28(32),29-hexaene hexahydrobromide salt [(H6P3)Br6] has been determined by means of X-ray diffraction analysis. It crystallizes with an additional molecule of ethanol and half a molecule of water per molecule of the hydrobromide P3 ligand. The protonation constants of P3 and its host-guest interactions with monophospate (Ph) and pyrophosphate (Pp) have been investigated by potentiometric equilibrium methods. Ternary complexes are formed in aqueous solution as a result of hydrogen bond formation and Coulombic interactions between the host and the guest; formation constants for all the species obtained are reported and compared with the isomeric 3,7,11,19,23,27-hexaazatricyclo[27.3.1.1(13,17)]tetratriaconta-1(33),13, 15,17(34),29,31-hexaene (Bn) ligand. For the H6P3Pp(2+) those bonding interactions reach a maximum yielding a log KR6 of 5.87. The selectivity of the P3 ligand with regard to the monophosphate and pyrophosphate substrates (S) is discussed and illustrated with global species distribution diagrams showing a strong preference for the latter over the former as a consequence of the much stronger formation constants with pyrophosphate. An analysis of the isomeric effect is also carried out by comparing the P3-S versus Bn-S systems. In the best case, a selectivity of over 88% is achieved for the diphosphate complexation when using the meta isomer over the para, due solely to the size and shape of the receptors cavity.

Self-assembly of achiral and chiral macrocyclic ligands: synthesis, protonation constants, conformation and asymmetric catalysis.

New 30-membered achiral and chiral polyaza macrocyclic ligands, L1 and L2 were synthesized directly from [3 + 3] condensation of phthalic dicarboxaldehyde with cis- and (1R,2R)-diaminocyclohexane, respectively. The trimeric macrocyclic structures were confirmed by electrospray ionization mass spectrometry (ESI-MS), 1H NMR, 13C NMR spectroscopy and elemental analysis. Potentiometry was used to determine the protonation constants of the ligands. UV-vis spectrophotometric titration was employed to investigate the coordination and conformational properties of the chiral ligand (L2). Direct enantioselective aldol reaction has been successfully performed using 4-nitrobenzaldehyde and acetone in the presence of the chiral macrocycle and its zinc(II) complexes as catalysts.

Synthesis and DNA binding properties of a cationic 2,2':6',2"-terpyridine cobalt(II) complex containing an oligopeptide.

The first example of DNA metallointercalator containing an oligopeptide moiety is presented. The ternary cobalt(II) complex [(DOTA)Co(II)(TPY)](ClO(4))(2) (DOTA=1,4,7,10-tetraaza-cyclododecane-2,9-dione, TPY=2, 2':6',2"-terpyridine) was found to be efficient in binding ct-DNA. The binding constant was determined by spectrophotometric titration. In vitro antitumor studies shows that this complex has significant antitumor activity. The single-crystal of a six coordinated oligopeptide cobalt(II) complex [Co(II)(DOTA)(2)](ClO(4))(2) is also reported. The stabilities and species distributions of Co(II)-DOTA (1:1) and DOTA-Co(II)-TPY (1:1:1) systems were investigated by potentiometry titration.

In vivo behavior of copper-64-labeled methanephosphonate tetraaza macrocyclic ligands.

Copper-64 ( T(1/2)=12.7 h; beta(+): 0.653 MeV, 17.4%; beta(-): 0.578 MeV, 39%) is produced in a biomedical cyclotron and has applications in both imaging and therapy. Macrocyclic chelators are widely used as bifunctional chelators to bind copper radionuclides to antibodies and peptides owing to their relatively high kinetic stability. In this paper, we evaluated three tetraaza macrocyclic ligands with two, three, and four pendant methanephosphonate functional groups. DO2P [1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphonic acid)], DO3P [1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid)], and DOTP [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanephosphonic acid)] were all radiolabeled with (64)Cu in high radiochemical yields. Copper-64-labeled DO2P and DOTP were highly stable in rat serum out to 24 h, while (64)Cu-DO3P remained 73% intact, with the remainder possibly forming a (64)Cu(.)2DO3P dimer by 24 h. The biodistribution experiments were performed in normal Sprague-Dawley rats. Of the three complexes, (64)Cu-DO2P demonstrated the most optimal clearance through the blood and liver. Copper-64-DO3P and (64)Cu-DOTP exhibited higher liver uptake and longer retention of liver activity, possibly because of the large negative charge of the complexes under physiological conditions. All three (64)Cu-labeled complexes showed high accumulation in bone, likely due to the binding of the methanephosphonate groups to hydroxyapatite. These results suggest that this series of methanephosphonate macrocyclic ligands may be useful as potential bone-imaging agents. The thermodynamic stability constants of the Cu(II) complexes with these three ligands were determined, and were found to be significantly higher than those of their acetate analogues. The Cu(II)-DO2P complex exhibited the highest stability constant among divalent transition metal ion DO2P complexes. Metabolism studies of (64)Cu-DO2P in rat liver suggest that the DO2P ligand may be used as a bifunctional chelator for copper radionuclides in radiodiagnostic or radiotherapeutic studies.

Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands.

Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of (64)Cu(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-di-pendant arm derivatives: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochemical yields. The (64)Cu-2 complex was neutral, while (64)Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague-Dawley rats indicated that (64)Cu-1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas (64)Cu-2 cleared rapidly from all tissues. The rapid clearance of the (64)Cu-2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.

Molecular Recognition of Activated and Unactivated Phosphate Diesters.

The molecular recognition of two simple phosphate diesters by a terpyridine-copper (TCu) complex was studied by X-ray crystallography and potentiometry. Molecular recognition of the substrate is the first step in a hydrolysis reaction. The two phosphate diesters bis(p-nitrophenyl) phosphate (BNP) and diphenyl phosphate (DPP) coordinate axially to an approximate square pyramidal copper complex where a chloride and three terpyridine nitrogens form the corners of the base. The coordination geometries are almost identical. The molecular recognition constants for the formation of TCu-BNP and TCu-DPP were measured potentiometrically and have log values of 1.2 and 2.5, respectively. By a significant margin, the TCu complex favors DPP over BNP in solution. A pH versus rate constant profile shows that TCu-OH can hydrolyze BNP but not DPP. Activated and unactivated phosphate diesters are typically hydrolyzed by similar mechanisms. In this study the difference in reactivity lies outside the process of molecular recognition. Activating (electron-withdrawing) effects of the p-nitro groups on the nature of the leaving groups must play an important role in the susceptibility of phosphate diesters to hydrolysis.

Host-Guest Interactions of Inorganic Phosphates with the Copper(II) Complexes of the Hexaaza Macrocyclic Ligand 3,6,9,17,20,23-Hexaazatricyclo[23.3.1.1(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene.

The host-guest interactions between ortho-, pyro-, and tripolyphosphate anions and the mono and dinuclear copper(II) complexes of the hexaaza macrocyclic ligand BMXD (3,6,9,17,20,23-hexaazatricyclo[23.3.1.1(11,15)]triaconta-1(29),11(30),12,14,25,27-hexaene) were investigated by potentiometric equilibrium methods. Ternary complexes are formed in aqueous solution as a result of coordinate bonding, hydrogen bond formation, and Coulombic attraction between the host and guest. Formation constants for all the species found are reported. The dinuclear copper(II) complexes of BMXD show strong selectivity for pyrophosphate ions in the presence of orthophosphate ions over the whole p[H] range; the pyrophosphate/tripolyphosphate selectivity is p[H] dependent. The dinuclear copper(II) complex of BMXD, (Cu(2)-BMXD)(SO(4))(2), crystallizes in the orthorhombic space group Pccn, with a = 15.73(2) Å, b = 20.27(1) Å, c = 9.045(5) Å, and Z = 4. The sulfate counterions are found to bridge the copper(II) ions in adjacent molecules leading to an extended polymeric structure.

Stability and Structure of Activated Macrocycles. Ligands with Biological Applications.

Single p-toluic acid pendant groups were attached to 1,4,7,10,13-pentaazacyclopentadecane (15aneN5) and 1,4,8,11-tetraazacyclotetradecane (cyclam) to prepare bifunctional reagents for radiolabeling monoclonal antibodies with (64,67)Cu. The ligands are 1,4,7,10,13-pentaazacyclopentadecane-1-(alpha-1,4-toluic acid) (PCBA) and 1,4,8,11-tetraazacyclotetradecane-1-(alpha-1,4-toluic acid) (CPTA). For the parent macrocycles and their pendant arm derivatives, the 1:1 Cu(2+) complexes dissociate only below pH 2. At pH 0.0 and 25 degrees C the CPTA-Cu complex has a half-life toward complete dissociation of 24 days. A new approach was developed for the estimation of the Cu(2+) stability constant for the kinetically robust CPTA. All other formation constants were determined at 25.0 degrees C with batch spectrophotometric techniques. Potentiometric titrations were used to determine the protonation constants of the macrocyclic ligands as well as of the metal chelates. The protonation constants, stability constants, and pM's are discussed in terms of both molecular mechanics calculations and the ligands' potential applicability as copper(II) radiopharmaceuticals.

Copper(II) Complexes of the Hexaaza Macrocyclic Ligand 3,6,9,16,19,22-Hexaaza-27,28-dioxatricyclo[22.2.1.1(11,14)]octacosa-1(26),11,13,24-tetraene and Their Interaction with Oxalate, Malonate, and Pyrophosphate Anions.

The hexaaza macrocyclic ligand 3,6,9,16,19,22-hexaaza-27,28-dioxatricyclo[22.2.1.1(11,14)]octacosa-1(26),11,13,24-tetraene (BFBD), forms both mono- and dinuclear complexes, as well as several protonated and hydroxo chelates, with Cu(II) ions. These cationic species can bind inorganic and organic anions through coordination and hydrogen bonding. Stability constants of the mono- and dinuclear Cu(II) complexes of BFBD and their interaction with oxalate, malonate, and pyrophosphate anions have been measured potentiometrically. The nature of the bonding between the hosts and the guests is discussed. The crystal structures of two new dinuclear Cu(II) complexes, determined by X-ray crystallography, are also reported. [BFBDCu(2)(Cl)(3)]ClO(4).0.5H(2)O crystallizes in the monoclinic system, space group P2(1)/n, with a = 13.267(2) Å, b = 12.155(6) Å, c = 18.461 0 Å, beta = 90.86(2) degrees, and Z = 4. Each Cu(II) ion is coordinated by three nitrogen atoms from the diethylenetriamine unit of the macrocyclic ligand and two chloride anions, forming a square pyramidal geometry. [BFBDCu(2)(Ox)](BF(4))(1.8)Cl(0.2) crystallizes in the triclinic system, space group P1, with a = 6.772(1) Å, b = 10.646(2) Å, c = 11.517(2) Å, alpha = 64.74(3) degrees, beta = 79.79(3) degrees, gamma = 81.94(3) degrees, and Z = 1. The environment of each copper is intermediate between square pyramidal and trigonal pyramidal. The oxalate anion bridges in a bis-bidentate fashion between two Cu(II) ions.

N,N'-Ethylenedi-L-cysteine (EC) and Its Metal Complexes: Synthesis, Characterization, Crystal Structures, and Equilibrium Constants.

N,N'-ethylenedi-L-cysteine (EC) and its indium(III) and gallium(III) complexes have been synthesized and characterized. The crystal structures of the ligand and the complexes have been determined by single-crystal X-ray diffraction. EC.2HBr.2H(2)O (C(8)H(22)Br(2)N(2)O(6)S(2)) crystallizes in the orthorhombic space group P2(1)2(1)2 with a = 12.776(3) Å, b = 13.735(2) Å, c = 5.1340 (10) Å, Z = 2, and V = 900.9(3) Å(3). The complexes Na[M(III)EC].2H(2)O (C(8)H(16)MN(2)O(6)S(2)Na) are isostructural for M = In and Ga, crystallizing in the tetragonal space group P4(2)2(1)2 with the following lattice constants for In, (Ga): a = 10.068(2) Å, (9.802(2) Å), b = 10.068(2) Å, (9.802(2) Å), c = 14.932(2) Å, (15.170(11) Å), Z = 4 (4), and V = 1513.6(5) Å(3), (1457.5(11) Å(3)). In both metal complexes, the metal atoms (In and Ga) are coordinated by six donor atoms (N(2)S(2)O(2)) in distorted octahedral coordination geometries in which two sulfur atoms and two nitrogen atoms occupy the equatorial positions, and the axial positions are occupied by two oxygen atoms of two carboxylate groups. The structures of the complexes previously predicted by molecular mechanics are compared with the crystal structures of the Ga(III) and In(III) complexes obtained experimentally. In contrast to the oxygen donors in phenolate-containing ligands, such as 1,2-ethylenebis((o-hydroxyphenyl)glycine) (EHPG) and N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), the thiolate donors of EC enhances affinity for In(III) relative to Ga(III). The following stability sequence has been obtained: In(III) > Ga(III) >> Ni(II) > Zn(II) > Cd(II) > Pb(II) > Co(II). Evidence was also obtained for several protonated and hydroxo species of the complexes of both divalent and trivalent metals, where the corresponding protonation constants (K(MHL)) decrease with increasing stability of the chelate, ML(n)(-)(4), where M(n)()(+) represent the metal ion.