Oxorhenium Complexes Research Articles

Somatostatin Receptor-Binding Peptides Suitable for Tumor Radiotherapy with Re-188 or Re-186. Chemistry and Initial Biological Studies

Somatostatin derivative peptides previously designed for radiodiagnostic purposes (99mTc P829 or 99mTc depreotide) were reoptimized for radiotherapy of tumors with rhenium radioisotopes. An optimized pharmacophore peptide P1839 was derived by in vitro binding affinity assay to AR42J rat pancreatic tumor cell membranes. Peptides with chelating domains and their oxorhenium(V) complexes were tested in vitro for binding to NCI H69 human SCLC tumor membranes. Further optimization entailed radiolabeling with 99mTc and biodistribution in an AR42J xenograft mouse model. Kidney uptake was decreased substantially by removing positively charged residues. Neutral N3S diamide amine thiol chelators with no adjacent positive charges had the best overall properties. Substituting an aromatic amino acid into the chelator approximately doubled the tumor uptake. The final optimized peptide P2045 (39) radiolabeled with 99mTc exhibited increased tumor uptake ( approximately 25 %ID/g at 1.5 h), lower kidney uptake ( approximately 4.8 %ID/g at 1.5 h), and extensive urinary excretion (59 %ID at 1.5 h). Finally, comparison biodistribution studies between 99mTc and 188Re (39) showed a good correlation between the two metal complexes and demonstrated prolonged tumor retention (> or =24 h).

Oxorhenium complexes with the 8-quinolinolato ligand. X-ray structure and DFT calculations for [ReOX2(hqn)(AsPh3)] and [ReOX2(hqn)(PPh3)] complexes

The reactions of [ReOX3(AsPh3)2] and [ReOX3(PPh3)2] with 8-hydroxyquinoline (Hhqn) have been examined and the complexes [ReOX2(hqn)(AsPh3)] and [ReOX2(hqn)(PPh3)] (X=Cl, Br) have been obtained, respectively. The crystal and molecular structures of [ReOCl2(hqn)(AsPh3)] (1) and [ReOBr2(hqn)(PPh3)] (4) have been determined. The electronic structure of 1 has been calculated with the density functional theory (DFT) method. The spin-allowed electronic transitions of 1 have been calculated with the time-dependent DFT method, and the UV–Vis spectrum of [ReOCl2(hqn)(AsPh3)] has been discussed on this basis.

New oxorhenium complexes with the 8-quinolinolato ligand: X-ray structure and DFT calculations for [ReOBr(hqn) 2

The reactions of [ReO(OEt)X 2(PPh 3) 2] (X = Cl or Br) with 8-hydroxyquinoline (Hhqn) have been examined and the [ReOX(hqn) 2] complexes have been obtained. The crystal and molecular structures of [ReOBr(hqn) 2] have been determined. The electronic structure of [ReOBr(hqn) 2] has been calculated with the density functional theory (DFT) method, and additional information about binding in the ReO 3+ unit has been obtained by NBO analysis. The spin-allowed electronic transitions of [ReOBr(hqn) 2] have been calculated with the time-dependent DFT method, and the UV–Vis spectra of the [ReOX(hqn) 2] compounds have been discussed on this basis.

Synthesis and structure of a ‘4 + 1’ oxorhenium(V) complex containing imidazole derivatives

The ‘4 + 1’ concept was used to prepare the complex salt [ReO(iao)Br]Br (1) from the reaction of (n-Bu4N)[ReOBr4(OPPh3)] with the ligand bis{2′-methyl(1′-methylimidazole)}-2-aminoethanol (Hiao) in methanol. The single-crystal X-ray crystal structure of 1 shows that iao acts as a monoanionic, tetradentate, N3O-donor chelate. When the reaction was carried out in acetonitrile, the neutral complex [ReO(iao)Br2] (2) was isolated. Elemental analyses and IR data suggest that iao acts as a tridentate, N2O-donor ligand in 2.

The Oxorhenium(VII)-Catalyzed Direct Condensation of Phosphoric Acid with an Alcohol

Come together …︁ over Re: Oxorhenium(VII) complexes catalyze the direct condensation of phosphoric acid with an alcohol to selectively give the corresponding phosphoric acid monoester on a 2–100-mmol scale (see scheme). This method should be useful for the industrially important synthesis of phosphoric acid monoesters.

Novel zwitterionic oxorhenium(V) complexes: synthesis, characterization and crystal structure of [ReOX2(Hdhp)(PPh3)] (X = Cl, Br; H2dhp = 2,3-dihydroxypyridine)

Dois novos complexos zwitterionicos de oxorrenio(V), [ReOCl2(Hdhp)(PPh3)] (1) e [ReOBr2(Hdhp)(PPh3)] (2) (H2dhp = 2,3-dihidroxipiridina), foram sintetizados e caracterizados por espectroscopia de absorcao no infravermelho, ressonância magnetica nuclear de 1H e 31P, analise elementar e determinacao da estrutura cristalina e molecular por difracao de raios X em monocristais. Os complexos apresentam geometria de coordenacao octaedrica bastante distorcida, com os dois ligantes haletos arranjados em posicoes cis equatoriais, o ligante trifenilfosfina em posicao trans a um dos haletos e o ligante Hdhp- coordenado de forma bidentada atraves de seus atomos de oxigenio, sendo um em posicao trans ao ligante oxo e o outro em posicao trans com relacao ao outro haleto. Este ligante tem seu atomo de nitrogenio protonado. Os compostos 1 e 2 apresentam empacotamento cristalino bastante diferente, influenciado em ambos os casos por ligacoes de hidrogenio intermoleculares dos tipos N-H...X (X = Cl, Br) e N-H...O.

Synthesis and Vibrational Circular Dichroism of Enantiopure Chiral Oxorhenium(V) Complexes Containing the Hydrotris(1-pyrazolyl)borate Ligand

The infrared and vibrational circular dichroism (VCD) spectra of six chiral oxorhenium(V) complexes, bearing a hydrotris(1-pyrazolyl)borate (Tp) ligand, have been investigated. These complexes are promising candidates for observation of parity violation (symmetry breaking due to the weak nuclear force). New chiral oxorhenium complexes have been synthesized, namely, [TpReO(eta2-O(CH3)CH2CH2O-O,O)] (4a and 4b) diastereomers and [TpReO(eta2-N(CH3)CH2CH2O-N,O)] (5) and [TpReO(eta2-N(tBu)CH2CH2O-N,O)] (6) enantiomers. All compounds could be obtained in enantiomerically pure form by using either column chromatography or HPLC over chiral columns. VCD spectroscopy of these compounds and of [TpReO(eta2-N(CH3)CH(CH3)CH(Ph)O-N,O)] (2) and [TpReO(eta2-N(CH2)3CHCO2-N,O)] (3) (with chiral bidentate ligands derived, respectively, from ephedrine and proline) were studied. This allowed the absolute configuration determination of all compounds together with their conformational analysis, by comparing calculated and experimental spectra. This is the first VCD study of rhenium complexes which further demonstrates the applicability of VCD spectroscopy in determining the chirality of inorganic complexes.

Preparation and Biological Characterization of Isomeric 188Re(V) Oxocomplexes with Tetradentate S4 Ligands Derived from meso-Dimercaptosuccinic Acid for Labeling of Biomolecules

A new type of tetradentate S4 ligand has been synthesized by bridging two molecules of meso-2,3-dimercaptosuccinic acid for stable binding and easy conjugation of rhenium-188 to tumor targeting structures. The stereoisomeric tetrathiolato S4 ligands form very robust anionic five-coordinated oxorhenium(V) and oxotechnetium(V) complexes. Two routes for the preparation of the (188)Re(V) oxocomplexes with (iBu)2N(O)C-C(SH)C(SH)C(O)NH(CH2)3NH(CH2)3NHC(O)C(SH)C(SH)C(O)N(iBu)2 (ligand 1) and its hydrophilic crown ether derivative (ligand 2) were tested and optimized. Several isomers were separated by HPLC from the preparation solutions and characterized in vitro and in vivo. The identity of the species obtained was determined by comparison with the HPLC profiles of reference (185/187)Re analogues and (99/99m)Tc complexes which were characterized by ESI-MS. All of them were absolutely stable in rat and human plasma solutions. Challenge experiments with cysteine corroborated the high inertness of the isomers toward ligand exchange reactions. Various in vivo samples, taken off at different times from blood, intestine, and urine of rats, confirmed the high in vivo stability of the (188)Re-S4 complexes. Biodistribution studies using male Wistar rats were performed and exhibited a high uptake and fast clearance from the liver of the more lipophilic cis and trans isomers of complex I (log P(o/w) between 1.5 and 1.7), whereas the isomers of the hydrophilic complex II (log P(o/w) about -1.75) were rapidly excreted via the renal and the hepatobiliary pathway. The low level of activity in the stomach confirms good in vivo stability. Thus, these new (188)Re-S4 complexes fulfill the requirements for a stable and high specific activity labeling of biomolecules with rhenium-188.

Oxorhenium(V) complexes containing bidentate N,O-donor ligands of the pyridyl type

The reaction of equimolar quantities of trans-[ReOCl3(PPh3)2] and 8-hydroxyquinoline (Hhqn) in benzene led to the isolation of the six-coordinate complex [ReOCl2(hqn)(PPh3)] (1). With 2-pyridine-ethanol (Hhep) the compound [ReOCl2(hep)(PPh3)] (2) was obtained. Both hqn and hep ligands act as monoanionic bidentate N,O-donor chelates. Although the two complexes are very similar, there are some significant differences in certain bond distances and angles in them. Both complexes contain the nearly linear trans O=Re–O axis, with this angle equal to 160.9(2)° and 167.8(1)° in 1 and 2, respectively.

Oxorhenium(V) complexes with tetradentate NSNO pyridylthioazophenolates: syntheses, spectral and electrochemical studies

A family of oxorhenium(V) complexes of newly designed pyridylthioazophenolate ligands has been synthesized and isolated in pure form. The solid state structure of an organic compound (HL1) has been established by X-ray crystallography. The molecular structure observed in the solid state is that the two molecules of the ligand (HL1) in the asymmetric unit have similar geometries, except for the orientation of the pyridine ring. This series of organic moieties acts as tetradentate monobasic NSNO donor chelators in oxorhenium(V) complexes which has been characterized by elemental analyses, IR, 1H-NMR, UV–Vis. The complexes are 1:1 electrolytes in nature in MeOH solution, the counter anion being ClO 4 − . The electrochemical studies of the [ReVO(L)Cl]ClO4 complexes in MeCN using TBAP as supporting electrolyte exhibit quasi-reversible voltammogram showing one-electron couple for [ReVIO(L)Cl]2+−[ReVO(L)Cl]+ in the 1.11–1.29 V vs SCE range.

Combinatorial Self‐Assembly of Cyclophilin hCyp‐18 Ligands through Rhenium Coordination

Re ligands. The combinatorial assembly of independent modules A and B through oxorhenium(V) coordination was investigated, and the oxorhenium complexes A⋅ReVO⋅B were evaluated as novel ligands of cyclophilin hCyp-18. Two rhenium complexes that bind to hCyp-18 with an affinity more than one order of magnitude higher than that of the corresponding modules were selected from two libraries (288 rhenium complexes).

Rhenium Inhibitors of Cathepsin B (ReO(SYS)X (Where Y = S, py; X = Cl, Br, SPhOMe-p)): Synthesis and Mechanism of Inhibition

The synthesis of four new oxorhenium(V) complexes containing the "3 + 1" mixed-ligand donor set, ReO(SYS)X (where Y = S, py; X = Cl, Br), is described. All of the complexes tested exhibited selectivity for cathepsin B over K. Most notably, compound 6, ReO(SSS-2,2')Br (IC50(cathepsin B) = 1.0 nM), was 260 times more potent against cathepsin B. It was also discovered that complexes containing the same tridentate (SSS) ligand were more potent when the leaving group was bromide versus chloride (e.g., IC50(cathepsin B): ReO(SSS-2,2')Cl (4), 8.8 nM; ReO(SSS-2,2')Br (6), 1.0 nM). Mechanistic studies with cathepsin B showed that both compounds 2 (ReO(SpyS)(SPhOMe-p)) and 4 were active-site-directed. Compound 2 was determined to be a tight-binding, reversible inhibitor, while compound 4 was a time-dependent, slowly reversible inhibitor. The results described in this paper show that the oxorhenium(V) "3 + 1" complexes are potent, selective inhibitors of cathepsin B and have potential for the treatment of cancer.

Design and evaluation of “3 + 1” mixed ligand oxorhenium and oxotechnetium complexes bearing a nitroaromatic group with potential application in nuclear medicine oncology

The synthesis and evaluation of a series of oxotechnetium and oxorhenium complexes containing a nitroaromatic moiety as potential radiopharmaceuticals for targeting tumour hypoxia is presented. 99mTc labelling was performed in high yield (> 85%) and radiochemical purity (> 90%). Their structure was corroborated by means of the rhenium complexes. Reduction potentials were in the range for bioreducible compounds. 99mTc complexes III–VI were selected for “in vivo” experiments in view of the results of cytotoxicity studies. Biodistribution in normal animals was characterized by high initial blood, lung and liver uptake, fast blood and soft tissue depuration and preferential excretion via the hepatobiliary system. Initial tumour uptake was moderate but tumour/muscle ratios for complexes III and IV, were favourable at all time points. Although the results are encouraging further development is still necessary in order to achieve higher tumour uptake and lower gastrointestinal activity.

Synthesis, characterization and structure of oxorhenium(V) complexes with 2-methylmercaptobenzamide

The neutral, mononuclear complex [ReO(mta)2Cl] (1) [Hmta = 2-(methylmercapto)aniline] was prepared by reaction of trans-[ReOCl3(PPh3)2] with a twofold molar excess of Hmta in methanol. The oxo-bridged dimer (μ-O)[ReO(mta)2]2 (2) was synthesized by reacting [ReOCl3(PPh3)2] with a twofold excess of Hmta in a 9 : 1 acetone/water mixture. The compounds were characterized by spectroscopy and complex 1 also by X-ray crystallography. Complex 1 has a distorted octahedral geometry with the chloride coordinated trans to the oxo group, and with the chelating ligands in the equatorial plane in a cis-N cis-S configuration.

Synthesis and Characterization of Novel “3 + 2” Oxorhenium Complexes, ReO[SNO][NN

The present paper deals with the synthesis and structural characterization of novel neutral oxorhenium(V) complexes of the general formula ReO[SNO][NN]. The simultaneous action of the tridentate SNO ligand, N-(2-mercaptoacetyl)glycine (1), and the bidentate NN ligand, N-phenylpyridine-2-aldimine (2), on ReOCl3(PPh3)2 leads to the formation of two isomers 4a and 4b of the general formula ReO[SNO][NN], as a result of the different orientations of the NN ligand. In both cases, the SNO donor atoms of the tridentate ligand occupy the three positions in the equatorial plane of the distorted octahedron, whereas the oxo group is always directed toward one of the apical positions. In the first isomer, 4a, the imino nitrogen of the NN ligand occupies the fourth equatorial position and the pyridine type nitrogen is directed trans to the oxo group, while in the second isomer, 4b, the imino nitrogen of the NN ligand occupies the apical position trans to the oxo group and the pyridine type nitrogen completes the equatorial plane of the distorted octahedron. The [SNO][NN] mixed-ligand system was applied in the synthesis of the oxorhenium complex 5 in which the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, has been incorporated in the NN bidentate ligand (NN is N-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}pyridine-2-aldimine). In this case, high-performance liquid chromatography and NMR showed the existence of one isomer, 5, in which the pyridine nitrogen is trans to the oxo core, as demonstrated by crystal structure analysis.

Oxygen Atom Transfer Catalytic Property of Oxorhenium(V) Complex with 2-Methylquinolin-8-ylamide and Tetrachlorocatecholate

Abstract New oxorhenium(V) complex was prepared and characterized by an X-ray crystal analysis. The complex showed characteristic releasing property of monodentate ligand and high oxygen atom transfer catalytic activity from 2,6-lutidine-N-oxide to PPh3.

Oxo-rhenium(V) complexes containing bis(diphenylphosphino)ethane and catecholate ligands

Bis(diphenylphosphino)ethane (dppe) complexes of the type ReOCl(dppe)(O–O), where O–O = catecholate or tetrachlorocatecholate dianion, were prepared by reacting ReOCl 3(dppe) with the catechol ligand in the presence of NEt 3. X-ray diffraction on the tetrachlorocatecholate compound showed that the molecule adopts a distorted octahedral structure, in which the dppe ligand and the bidentate catecholate lie in the equatorial plane, perpendicular to the O Re–Cl unit. In contrast, for ReOCl(PPh 3) 2(O–O), the position trans to the Re O bond is occupied by a catecholate oxygen, whereas the two PPh 3 ligands are trans to one another in the equatorial plane. The UV–Vis absorption spectrum of ReO(OMe)(dppe)(oxalate) is similar to those of ReO(OR)X 2(dppe) compounds, showing two weak bands for the spin-allowed d–d transitions from the filled interaxial d orbital in the xy plane into the inequivalent metal d xz and d yz orbitals, respectively. For the catecholate complexes, the spectra are dominated by charge-transfer transitions from the HOMO π orbital of the catecholate ligand into the d xz and d yz orbitals. Both the singlet–singlet and the singlet–triplet transitions are generally observed. No information could be obtained on the weaker d–d transitions for the catecholate compounds.

A new molecular mechanics force field for the design of oxotechnetium(V) and oxorhenium(V) radiopharmaceuticals

Force field parameters for the modeling of oxotechnetium(V) and oxorhenium(V) complexes with amine, amide, imine, carboxylate and thiolate donors have been derived and optimized based on 131 published solid state structures. An automated procedure, based on a simplex algorithm, was used to optimize the 35 sets of metal-dependent structural parameters for each metal ion. These were introduced into the established MOMEC97 force field. The application of the new force field in the prediction of a novel radiopharmaceutical’s structure was successful, the predicted structures of the two isomers compared well with the corresponding crystal structures obtained subsequently (RMS around the metal core: 0.153 and 0.035 Å, respectively).

Mechanism for Reduction Catalysis by Metal Oxo: Hydrosilation of Organic Carbonyl Groups Catalyzed by a Rhenium(V) Oxo Complex.

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Synthesis, metal complexation and biological evaluation of a novel semi-rigid bifunctional chelating agent for 99mTc labelling

A novel bifunctional chelating agent bearing an aromatic ring has been synthesised and characterised. This ligand formed well-defined oxorhenium complexes. The analogous 99mTcO-complex was obtained in an excellent yield with high radiochemical purity (>95%). The biodistribution of the 99mTc-complex after intravenous injection studied in normal rats showed that the activity was excreted mainly via renal-urinary pathway indicating its use for labelling peptides with 99mTc.