(90)Y and (177)Lu labeling of a DOTA-conjugated vitronectin receptor antagonist useful for tumor therapy.

The (90)Y and (177)Lu complexes (RP697 and RP688, respectively) of a DOTA-conjugated vitronectin receptor antagonist (SU015: 2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl)acetyl-Glu(cyclo[Lys-Arg-Gly-Asp-D-Phe])-cyclo[Lys-Arg-Gly-Asp-D-Phe]) were prepared by reacting SU015 with the radiometal chloride in ammonium acetate buffer (pH > 7.2) in the presence of an antioxidant (sodium gentisate, GA). Through a series of radiolabeling experiments, it was found that there are many factors influencing the rate of (90)Y chelation and the radiolabeling efficiency of SU015. These include the purity of SU015, the pH, reaction temperature, and heating time, as well as the presence of trace metal contaminants, such as Ca(2+), Fe(3+), and Zn(2+). The chelation of (90)Y by SU015 is slow, so that heating at elevated temperatures (50-100 degrees C) is needed to complete the (90)Y-labeling. The rate of (90)Y chelation is also dependent on the pH of the reaction mixture. Under optimized radiolabeling conditions (pH 7.2-7.8 and heating at 50-100 degrees C for 5-10 min), the minimum amount of SU015 required to achieve 95% RCP for RP697 is approximately 25 microg for 20 mCi of (90)YCl(3) corresponding to a SU015:(90)Y ratio of approximately 30:1.     

Anaerobic 90Y- and 177Lu-labeling of a DOTA-conjugated nonpeptide vitronectin receptor antagonist

This study describes the discovery and development of an anaerobic formulation for the routine preparation of (90)Y and (177)Lu complexes ((90)Y-TA138 and (177)Lu-TA138) of a DOTA-conjugated nonpeptide vitronectin receptor antagonist (TA138: 3-sulfon-N-[[4,7,10-tris(carboxymethyl)1,4,7,10-tetraazacyclododec-1-yl]acetyl]-l-alanyl-N-[2-[4-[[[(1S)-1-carboxy-2[[[1,4-dihydro-7-[(1H-imidazol-2-ylamino]meth-yl]-1-methyl-4-oxo-3-quinolinyl]carbonyl]amino]ethyl]amino]-sulfonyl]-3,5-dimethylphenoxy]-1-oxobutyl]amino]ethyl]-3-sulfo-l-alaninamide). Since (90)Y-TA138 and (177)Lu-TA138 are very sensitive to radiolytic degradation, exclusion of oxygen is necessary during the radiolabeling. Using the anaerobic formulation, (90)Y-TA138 and (177)Lu-TA138 can be prepared in high yield and high specific activity. The anaerobic formulation described in this study is particularly useful for (90)Y- and (177)Lu-labeling of DOTA-conjugated small biomolecules, which are sensitive to the radiolytic degradation during radiolabeling.     

Synthesis of a novel 'smart' bifunctional chelating agent 1-(2-[beta,D-galactopyranosyloxy]ethyl)-7-(1-carboxy-3-[4-aminophenyl]propyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (Gal-PA-DO3A-NH2) and its Gd(III) complex

A new synthetic pathway to 1-(2-[beta,D-galactopyranosyloxy]ethyl)-7-(1-carboxy-3-[4-aminophenyl]propyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (Gal-PA-DO3A-NH2) and 1-(2-[beta,D-galactopyranosyloxy]ethyl)-4,7,10-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane (Gal-DO3A) chelating agents was developed involving full hydroxyl- and carboxyl-group protection in precursors to product. Two sequences of cyclen-N-functionalisation were subsequently investigated, one successfully, towards synthesis of the novel 'smart' bifunctional Gal-PA-DO3A-NH2 chelate. The longitudinal proton relaxivities of the neutral [Gd-(Gal-PA-DO3A-NH2)] and [Gd-(Gal-DO3A)] complexes were increased by 28% and 37% in the presence of beta-galactosidase, respectively.     

Novel gadolinium(III) polyaminocarboxylate macrocyclic complexes as potential magnetic resonance imaging contrast agents

Two novel Gd(III) complexes with functionalised polyaminocarboxylate macrocycles, 1,4,7-tris(carboxymethyl)-9,24-dioxo-14,19-dioxa-1,4,7,10,23- pentaazacyclododecane (L(1)) and 1,4,7-tris(carboxymethyl)-9,25-dioxo-14,17,20-trioxa-1,4,7,10,23- pentaazacyclotridecane (L(2)), were prepared in good yield. Their potential use as magnetic resonance imaging (MRI) contrast agents (CAs) was evaluated by investigating their relaxation behaviour as a function of pH, temperature and magnetic field strength. The 1/T(1) proton relaxivities at 20 MHz and 25 degrees C of GdL(1) (5.87 mM(-1) s(-1)) and GdL(2) (6.14 mM(-1) s(-1)) were found to be significantly higher than the clinically used Gd 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd(DOTA)(-)) and Gd diethylenetriaminepentaethanoic acid (Gd(DTPA)(2-)). The complexes possess one water molecule in the inner coordination sphere whose mean residence lifetime was estimated to be 1.1 and 1.5 micros at 25 degrees C by variable temperature (VT) (17)O NMR spectroscopy.     

Oligonucleotide conjugates of Eu(III) tetraazamacrocycles with pendent alcohol and amide groups promote sequence-specific RNA cleavage

Eu(III) complexes of two neutral bifunctional tetraaaza macrocyclic ligands {1-[1-carboxamido-3-(4-nitrophenyl)propyl]-4,7,10-tris(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane and 2-(4-nitrobenzyl)-1,4,7,10-tetrakis(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane} are prepared. Eu(III) complexes of the isothiocyanate derivatives of these macrocycles are treated with oligonucleotides containing 2′-O-propylamine linkers to form conjugates. Hydrolytic cleavage of an oligoribonucleotide is promoted by Eu(III) macrocyclic oligonucleotide conjugates containing complementary (antisense) sequences. Cleavage is not observed in the presence of Eu(III) conjugates containing scrambled sequences nor by free complex. Despite the fact that one of the free macrocyclic complexes is more reactive than the other, the extent of cleavage observed is similar for conjugates containing either Eu(III) macrocyclic complex.     

The Zn(2+) complex of 1,4,7,10-tetraazacyclododecane as an artificial nucleobase

{2-Deoxy-3-O-[2-cyanoethoxy(diisopropylamino)phosphino]-5-O-(4,4'-dimethoxytrityl)-α-D- erythro-pentofuranosyl}-N-{2-[4,7,10-tris(2,2,2-trifluoroacetyl)-1,4,7,10-tetraazacyclododecan-1- yl]ethyl}acetamide (1) was prepared and incorporated into a 2'-O-methyl oligoribonucleotide. The hybridization of this oligonucleotide with complementary 2'-O-methyl oligoribonucleotides incorporating one to five uracil bases opposite to the azacrown structure was studied in the absence and presence of Zn(2+). Introduction of Zn(2+) moderately stabilized the duplex with U-bulged targets.     

Synthesis and characterization of two (111)In-labeled DTPA-peptide conjugates.

This report describes the synthesis and characterization of two (111)In-labeled DTPA-peptide conjugates (DTPA-MA and DTPA-BA). It is surprising to find that (111)In(DTPA-MA) and (111)In(DTPA-BA) are more hydrophilic than their corresponding (90)Y analogues, suggesting a different coordination sphere in (111)In and(90)Y complexes of the same DTPA-peptide conjugate. By a reversed phase HPLC method, both (111)In(DTPA-MA) and (111)In(DTPA-BA) showed only one radiometric peak in their respective HPLC chromatogram due to a rapid interconversion of different isomers (particularly cis and trans isomers for (111)In(DTPA-MA); cis-cis, cis-trans, trans-cis, and trans-trans isomers for (111)In(DTPA-BA)). The interconversion of different isomers involves the "wagging" of the diethylenetriamine backbone, "shuffling" of the NO or NO(2) donor sets, and a rapid inversion at the terminal amine-nitrogen atoms.     

A quinazoline-derivative DOTA-type gallium(III) complex for targeting epidermal growth factor receptors: synthesis, characterisation and biological studies

The novel DOTA-like chelator 1,4,7,10-tetraazacyclododecane-1-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}propionamide-4,7,10-triacetic acid (H₃L) was synthesised by alkylation of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(t-butyl acetate) with N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-bromopropionamide, followed by hydrolysis of the ester groups with trifluoracetic acid. H₃L has been fully characterised by multinuclear NMR spectroscopy, mass spectrometry and high-performance liquid chromatography (HPLC). Five protonation constants, log K _Hi , of H₃L were determined by potentiometry and UV–vis spectrophotometry and the values found are 10.47, 9.18, 5.24, 4.00 and 2.23. These methods, complemented with variable-pH ⁷¹Ga NMR studies, allowed us to ascertain the stability constant of the Ga(III) complex of L. GaL has a remarkably high thermodynamic stability constant (log K _ML = 24.5). The radioactive complex ⁶⁷GaL was prepared in high yield and high radiochemical purity. Its HPLC chromatogram is identical to that obtained for the GaL complex prepared at the macroscopic level. At pH 7.4, ⁶⁷GaL has an overall neutral charge, is highly hydrophilic (log D = −1.02 ± 0.03) and presents high in vitro stability in physiological media and in the presence of an excess of diethylenetriaminepentaethanoic acid . In vitro studies indicated that H₃L and GaL do not inhibit the cell growth of epidermal growth factor receptor expressing cell lines, such as A431 cervical carcinoma cells, a result which agrees with the very low cell internalisation found for ⁶⁷GaL in the same cell line. Biodistribution studies in mice indicated high in vivo stability for ⁶⁷GaL, a high total excretion rate and a relatively slow blood clearance, in full accordance with its hydrophilic character and the relatively important protein binding. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Isomerism and solution dynamics of (90)Y-labeled DTPA--biomolecule conjugates

This report describes the synthesis of two DTPA-conjugated cyclic peptides, cyclo(Arg-Gly-Asp-D-Phe-Lys)DTPA (SQ169) and [cyclo(Arg-Gly-Asp-D-Phe-Lys)](2)DTPA (SQ170), and a chromatographic study of their (90)Y complexes (RP762 and RP763, respectively). The goal is to study the solution structure and the possible isomerism of (90)Y-labeled DTPA-biomolecule conjugates at the tracer level (approximately 10(-10) M). RP762 was prepared in high radiochemical purity (RCP > 95%) by reacting 2 microg of SQ169 with 20 mCi of (90)YCl(3) (corresponding to a SQ169:Y ratio of approximately 4:1) in the 0.5 M ammonium acetate buffer (pH 8.0) at room temperature. RP763 was prepared in a similar fashion using SQ170. In both cases, the (90)Y-chelation was instantaneous. By a reversed-phase HPLC method, it was found that RP762 exists in solution as a mixture of two detectable isomers (most likely cis and trans isomers), which interconvert at room temperature. The interconversion of different isomeric forms of RP762 involves a rapid exchange of "wrapping isomers" via the "wagging" of the diethylenetriamine backbone, "shuffling" of the two NO(2) donor sets, and inversion at the ternimal amine-nitrogen atom. The inversion at a terminal nitrogen atom requires simultaneous dissociation of the NO(2) donor set. For RP763, the interconversion of different isomers is much faster than that for RP762 due to the weak bonding of two carbonyl-oxygen donors. Therefore, RP763 shows only one broad radiometric peak in its HPLC chromatogram. The rapid interconversion of different isomers is intramolecular via a partial dissociative mechanism. The results obtained in this study are consistent with the lack of kinetic inertness of (90)Y- and (111)In-labeled DTPA-biomolecule conjugates. Thus, the design of new BFCs should be focused on those which form lanthanide complexes with high thermodynamic stability and more importantly kinetic inertness.     

New chelating ligands for Co(III)-based peptide-cleaving catalysts selective for pathogenic proteins of amyloidoses

The Co(III) complex of 1,4,7,10-tetraazacyclododecane has been employed as the catalytic center of target-selective peptide-cleaving catalysts in previous studies. As new chelating ligands for the Co(III) ion in the peptide-cleaving catalysts, 1-oxo-4,7,10-triazacyclodedecane, 1-aryl-1,4,7,10-tetraazacyclodecane, and 7-aryl-1-oxo-4,7,10-triazacyclodecane were examined in the present study. A chemical library comprising 612 derivatives of the Co(III) complex of the new chelating ligands was constructed. The catalyst candidates were tested for their activity to cleave the soluble oligomers of amyloidogenic peptides amyloid β-42 and human islet amyloid polypeptide (h-IAPP), which are believed to be the pathogenic species for Alzheimer’s disease and type 2 diabetes mellitus, respectively. One derivative of the Co(III) complex of 1-aryl-1,4,7,10-tetraazacyclodecane was found to cleave the oligomers of h-IAPP. Cleavage products were identified and cleavage yields were measured at various catalyst concentrations for the action of the new catalyst. The present results reveal that effective catalytic drugs for amyloidoses may be obtained by using Co(III) complexes of various chelating ligands.     

Ligand-exchangeability of 2-coordinate phosphinegold(I) complexes with AuSP and AuNP cores showing selective antimicrobial activities against Gram-positive bacteria. Crystal structures of [Au(2-Hmpa)(PPh(3))] and [Au(6-Hmna)(PPh(3))] (2-H(2)mpa=2-mercaptopropionic acid, 6-H(2)mna=6-mercaptonicotinic acid)

Selective and effective antimicrobial activities against Gram-positive bacteria (B. subtilis and/or S. aureus) were found in 2-coordinate gold(I)-PPh(3) complexes with AuSP and AuNP cores, i.e. [Au(L)(PPh(3))] (HL=2-H(2)mna [H(2)mna=mercaptonicotinic acid] 3, D-H(2)pen [H(2)pen=penicillamine] 4, D,L-H(2)pen 5, 4-H(2)mba [H(2)mba=mercaptobenzoic acid] 8, Hpz [Hpz=pyrazole] 9, Him [Him=imidazole] 10, 1,2,3-Htriz [Htriz=triazole] 11, 1,2,4-Htriz 12, Htetz [Htetz=tetrazole] 13), whereas no activity was observed in 2-coordinate AuSP core complexes [Au(2-Hmba)(PPh(3))] 6 and [Au(3-Hmba)(PPh(3))] 7. The two novel AuSP core complexes, [Au(2-Hmpa)(PPh(3))] [H(2)mpa=mercaptopropionic acid] 1 and [Au(6-Hmna)(PPh(3))] 2, were prepared and characterized by elemental analysis, FT-IR, TG/DTA, and ((31)P, 1H and 13C) NMR spectroscopy. The crystal structures of 1 and 2 were determined as a supramolecular arrangement of the 2-coordinate AuSP core. Both 1 and 2 significantly showed antibacterial activities. As a model reaction of phosphinegold (I) complexes with the cysteine residue in the biological ligands, we examined if the ligand exchange reactions of the aromatic anions L(1)(-) in [Au(L(1))(PPh(3))] (HL(1)=6-H(2)mna 2, 2-H(2)mna 3, 2-H(2)mba 6, Hpz 9, Him 10, 1,2,3-Htriz 11, 1,2,4-Htriz 12) with aliphatic thiols HL(2) (HL(2)=2-H(2)mpa, D-H(2)pen) occurred under the mild conditions and, also, if the 'reverse' reactions, namely, the ligand exchange reactions of the thiolate anions in [Au(2-Hmpa)(PPh(3))] 1, [Au(D-Hpen)(PPh(3))] 4 and [Au(2-Hmba)(PPh(3))] 6 with the free ligands HL(1) took place under similar conditions. In this work, a relationship of the ligand-exchangeability among 2-coordinate gold(I) complexes (1-4, 6, 9-12) was revealed. Complex 6 was substitution-inert, whereas complexes 1-4 and 9-12 were substitution-labile. The ligand-exchangeability of Au-S and Au-N bonds in the 2-coordinate phosphinegold(I) complexes with AuSP and AuNP cores to form new AuSP cores, with retention of the Au-P bond, was closely related to the observed activities against Gram-positive bacteria, and the ease of the ligand-exchange reaction was strongly related to the intensity of the activities.     

Synthesis, characterization and biological evaluation of In(III) complexes anchored by DOTA-like chelators bearing a quinazoline moiety

Following previous studies with a DOTA-like bifunctional chelator (H(3)L1) containing an ethylenic linker between the macrocycle backbone and a quinazoline pharmacophore, we synthesized and fully characterized a congener macrocyclic ligand (H(3)L2) having a longer, five-carbon spacer for the linkage of the quinazoline moiety. Both H(3)L1 and H(3)L2 were used to prepare indium(III) complexes aiming at their evaluation as radioactive probes for in vivo targeting of EGFR-TK. The protonation constants (log K(Hi)) of H(3)L2 were determined by potentiometry and UV-Vis spectrophotometry and the values found are 12.18, 9.74, 4.99, 3.91 and 2.53. The stability and protonation constants of InL (L = L1, L2) were also obtained from a combined potentiometry and UV-VIS spectrophotometry study. The reaction of InCl(3) with H(3)L1 and H(3)L2 led to the formation of the well-defined complexes InL1 and InL2, containing In(iii) ions coordinated by a seven (N(4),O(3)) donor atom set. These new complexes were fully characterized by spectroscopic methods (IR, NMR, ESI-MS), HPLC and by X-ray diffraction analysis in the case of InL1. The radioactive congener (111)InL2 was prepared from the reaction of (111)In-chloride with H(3)L2, in high yield and high radiochemical purity. (111)InL2 is a neutral complex that presents a hydrophilic character and exhibits a high in vitro and in vivo stability. H(3)L2 and InL2 do not inhibit the cell growth of A431 cervical carcinoma cells. In this EGFR-expressing cell line, (111)InL2 has shown very low cell internalization. These findings indicate that these DOTA-like chelators are not the best suited bifunctional ligands to obtain In(iii) complexes with adequate biological properties for targeting the EGFR-TK.     

Monitoring proton dissociation and solution conformation of chiral ytterbium complexes with near-IR CD

The ytterbium complex [Yb((S)-THP)](3+) ((S)-THP = (1S,4S,7S,10S-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane) is investigated in solution through NMR, near-IR absorption, and CD spectroscopy. Quantitative analysis of the paramagnetic pseudocontact NMR shift shows Lambda helicity of the ligand cage around the metal. The NIR CD spectrum recorded at acidic pH is found to be very similar to that of [Yb((R)-DOTMA)](-) ((R)-DOTMA = (1R,4R,7R,10R)-alpha,alpha',alpha',alpha'-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), which in solution assumes a twisted square antiprism (TSA) conformation. The similarity of the NIR CD spectra is discussed, and it is the first proof of the Lambda(lambda,lambda,lambda,lambda) conformation of [Yb((S)-THP)](3+). NIR CD spectra recorded in the pH range of 2-9 allow one to easily follow proton dissociation and to calculate the pK of this equilibrium in water (pK(A) = 6.4 +/- 0.1). This value agrees well with that determined for [Lu((S)-THP)](3+) using potentiometric methods. This demonstrates once again that NIR CD spectroscopy is a powerful technique for investigating the solution structure and dynamics of these complexes.     

Hydride complexes of platinum(II) containing unsymmetrical di(phosphine) ligands: synthesis, characterization and evidence for pairwise addition of hydrogen based on parahydrogen induced polarization

Unsymmetrical di(phosphine) ligands (dpp)₂Rop (1a, b = bis(diphenylphosphino)-2-alkyl-3-oxapropane (alkyl = methyl and ethyl)) and (dpp)₂oCy (1c = trans-2-diphenylphosphinocyclohexyl diphenylphosphinite) and their Pt(II) dichloride complexes, PtCl₂((dpp)₂mop) (2a), PtCl₂((dpp)₂eop) (2b) and PtCl₂((dpp)₂oCy) (2c), have been synthesized and characterized by NMR spectroscopy. The crystal structures of 2b and 2c show that the geometry about the platinum centers is square planar. In 2b, the metal and di(phosphine) ligand chelate ring are in a chair conformation, whereas in 2c, the chelate ring conformation is a skewed boat. Initial reaction of sodium borohydride with 2a, b, c yields the monohydride monochloride complexes PtHCl((dpp)₂mop) (5a), PtHCl((dpp)₂eop) (5b) and PtHCl((dpp)₂oCy) (5c). At longer reaction times, fluxional dimeric species are obtained, [PtH((dpp)₂mop)]₂ (4a), [PtH((dpp)₂eop)]₂ (4b) and [PtH((dpp)₂oCy)]₂ (4c),and in the case of 4c two different isomers exist. The dihydride complexes PtH₂((dpp)₂mop) (3a), PtH₂((dpp)₂eop) (3b) and PtH₂((dpp)₂oCy) (3c), are prepared by further reaction of NaBH₄ and 2. Hydrogen cycling is facile in the dihydride complexes 3a, b, c, and oxidative addition of H₂ proceeds in a pairwise manner as determined by the observation of parahydrogen induced polarization (PHIP) in the ¹H NMR spectra. The reductive elimination of H₂ is also shown to be concerted by reaction of dihydride complexes with D₂. Crystal data: 2b (C₃₀H₃₂Cl₆OP₂Pt), monoclinic, space group P2₁/c (No. 14), a = 13.7040(1), b = 11.3430(7), c = 21.3880(9) Å, β = 97.923(9)°, V = 3292.9(2) ų and Z = 4; 2c (C₃₀H₃₀Cl₂OP₂Pt), monoclinic, space group P2₁ (No. 4), a = 11.7360(2), b = 8.4311(2), c = 14.2789(2) Å, β = 101.290(1)°, V = 1385.52(4) ų and Z = 2.     

Preparation and characterisation of Ni(II), Pd(II) and Pt(II) complexes of 1-diphenylphosphino-2-bis (m -trifluoromethylphenyl)phosphinoethane,(m -CF3 P-P)

A series of four-coordinate, square-planar, dia- magnetic 1-diphenylphosphino-2-bis(_m-trifluoro- methylphenyl)phosphinoethane complexes of type cis-[MX₂(_m-CF₃P-P)] (M = Ni, Pd, Pt; X = Cl, Br, I or NCS) have been prepared. These complexes have been characterized by ³¹P {₁H} NMR, ¹H NMR, IR and UV spectroscopy, elemental analyses and magnetic susceptibility measurements. The effects of various substituents on the phenyl groups of the ditertiary phosphines on the solubility characteristics of the metal complexes are discussed.     

The Zn2+ Complex of 1,4,7,10-Tetraazacyclododecane as an Artificial Nucleobase

{2-Deoxy-3-O-[2-cyanoethoxy(diisopropylamino)phosphino]-5-O-(4,4′-dimethoxytrityl)-α-D- erythro-pentofuranosyl}-N-{2-[4,7,10-tris(2,2,2-trifluoroacetyl)-1,4,7,10-tetraazacyclododecan-1- yl]ethyl}acetamide (1) was prepared and incorporated into a 2′-O-methyl oligoribonucleotide. The hybridization of this oligonucleotide with complementary 2′-O-methyl oligoribonucleotides incorporating one to five uracil bases opposite to the azacrown structure was studied in the absence and presence of Zn²⁺. Introduction of Zn²⁺ moderately stabilized the duplex with U-bulged targets.     

Studies on organomercury(II) complexes of isoniazid

A number of organomercury(II) complexes involving isoniazid (I), of the type RHgCl(L)(II) [R = phenyl(C6H5), o-hydroxyphenyl (o-HOC6H4), p-hydroxyphenyl (p-HOC6H4), p-acetoxyphenyl (p-AcOC6H4), 2-furyl (2-C4H3O); L = isoniazid] have been synthesized and characterized. Conductance measurements indicate that the complexes are nonelectrolytes. From IR and UV studies, it is concluded that isoniazid acts as a bidentate ligand, coordinating through hydrazinic nitrogen and carbonyl oxygen. 1H and 13C NMR support the stoichiometry of the complexes. From fluoroscence studies a number of photochemical parameters have been elucidated. For the C6H5HgCl(L), p-HOC6H4HgCl(L), and p-AcOC6H4HgCl(L) complexes, thermogravimetric studies have been carried out and relevant kinetic and thermodynamic parameters for thermal degradation have been enumerated. In addition, the fragmentation pattern of the complexes has been analyzed on the basis of mass spectra. The C6H5HgCl(L) and p-HOC6H4HgCl(L) complexes have been screened for tuberculosis activity.     

Platinum(II) complexes with l-methionylglycine and l-methionyl-l-leucine ligands: synthesis, characterization and in vitro antitumoral activity

Four dipeptide complexes of the type [PtX(2)(dipeptide)] x H(2)O (X=Cl, I, dipeptide=l-methionylglycine, l-methionyl-l-leucine) were prepared. The complexes were characterized by (1)H, (13)C, (195)Pt NMR and infrared spectroscopy, DTG and elemental analysis. From the infrared, (1)H and (13)C NMR spectroscopy it was concluded that dipeptides coordinate bidentately via sulfur and amine nitrogen donor atoms. Confirmed with (13)C and (195)Pt NMR spectroscopy, each of the complexes exists in two diastereoisomeric forms, which are related by inversion of configuration at the sulfur atom. The (1)H NMR spectrum for the platinum(II) complex with l-methionylglycine and chloro ligands exhibited reversible, intramolecular inversion of configuration at the S atom; DeltaG( not equal)=72 kJ mol(-1) at coalescence temperature 349 K was calculated. In vitro cytotoxicity studies using the human tumor cell lines liposarcoma, lung carcinoma A549 and melanoma 518A2 revealed considerable activity of the platinum(II) complex with l-methionylglycine and chloro ligands. Further in vitro cytotoxic evaluation using human testicular germ cell tumor cell lines 1411HP and H12.1 and colon carcinoma cell line DLD-1 showed moderate cytotoxic activity for all platinum(II) complexes only in the cisplatin-sensitive cell line H12.1. Platinum uptake studies using atomic absorption spectroscopy indicated no relationship between uptake and activity. Potential antitumoral activity of this class of platinum(II) complexes is dependent on the kind of ligands as well as on tumor cell type.     

Rh(I) complexes containing tris(pyrazolyl)amine and bis(pyrazolyl)amine ligands: synthesis and NMR studies

The tris(pyrazolyl)amine ligands: tris[2-(1-pyrazolyl)methyl]amine (tpma), tris [3,5-dimethyl-1-pyrazolyl)methyl]amine (tdma), tris[2-(1-pyrazolyl)ethyl]amine (tpea), tris[2-(3,5-dimethyl-1-pyrazolyl)ethyl]amine (tdea) and bis(pyrazolyl)amine ligands: bis[2-(1-pyrazolyl)ethyl]amine (bpea) and bis[2-(3,5-dimethyl-1-pyrazolyl)ethyl]amine (bdea) react with [RhCl(cod)]₂ in presence of NaBF₄ (tpma, tdma and bdea) or AgBF₄ (tpea, tdea and bpea) to lead to [Rh(cod)L] (BF₄) (L=tpma (1), tdma (2), bdea (3), tpea (4), tdea (5) and bpea (6)). These complexes have been characterised by elemental analyses, conductivity, IR, ¹H and ¹³C NMR spectroscopy and liquid mass (with electrospray) spectrometry. The ¹H NMR spectra of 1, 2 show the presence of two isomers in solution in a 3:1 ratio (coordination κ² or κ³ type) in a thermodynamic equilibrium. The steric bulk of cyclo-octa-1,5-diene causes it to prefer the κ² mode of bonding as majority. Similar to previous published results, complexes 4 and 5 exist in a sole form in solution (probably κ² isomer). Finally, the complexes 3 and 6 are fluxional. A NMR study shows that this fluxional process is not frozen at 183 K.     

Synthesis, solution equilibria and antiproliferative activity of copper(II) aminomethyltriazole and aminomethylthioxotriazoline complexes

The aim of the present study was the synthesis, the determination of formation constants, and the evaluation of the antiproliferative activity of two copper(II) complexes formed with triazole-type ligands. The synthesis of the unsymmetrical triazole ligand 4-amino-3-aminomethyl-5-methyl-1,2,4-triazole (L1), and its copper(II) complex is reported. The ligand was prepared by functionalization of the carboxylate function of tert-butyloxycarbonyl (BOC) protected glycine O-methyl ester. All intermediates and final products were isolated and characterized with IR, 1H NMR, and elemental analysis. X-ray structures of the ligand as a sulfate salt ((H2L1)2SO4.H2O) and the copper(II) complex [CuCl2(L1)(2)] are described. The ligand forms a (N,N) bidentate chelate with the amino group and one triazole nitrogen atom. The tetragonally distorted octahedral coordination of Cu(II) results from two axially coordinated chloride ions. Protonation constants for L1 and speciation of the Cu(II)/L1 system were determined in 0.1 M aqueous KCl solution at 25 degrees C. Complexes formed in solution were also characterized by visible spectrophotometry. Ligand substitution competition between L1 and glycine has also been studied using potentiometric titrations. Antiproliferative activities of ([CuCl2(L1)2]) and [CuCl2(H2L2)]Cl, where HL2 is the 5-thioxo analog of L1, against human tumor cell lines HT1080 and HT29 as well as normal human fibroblasts (HF) are presented along with the antiproliferative activities of L1, CuCl2, and cisplatin. Activity of these two complexes are discussed and compared with the activity of analogous compounds reported in the literature which contain pyridyl groups in place of the aminomethyl group. In particular, it is suggested that a lypophilic residue such as a pyridyl group is important for antiproliferative activity of this class of compounds.