Synthesis of oxorhenium(V) and oxotechnetium(V) [SN(R)S/S] mixed ligand complexes containing a phenothiazine moiety on the tridentate SN(R)S ligand.

Two oxorhenium and two oxotechnetium [SN(R)S/S] mixed ligand complexes bearing the phenothiazine moiety on the tridentate ligand SN(R)S have been synthesized and characterized. The corresponding complexes at tracer level (99mTc) have also been prepared.     

Development of novel mixed-ligand oxotechnetium [SNS/S] complexes as potential 5-HT1A receptor imaging agents

The "3 + 1" ligand system [SN(R)S/S combination] was applied in order to synthesize neutral mixed-ligand oxotechnetium complexes of the general formula 99mTcO[SN(R)S]/[S] as potential 5-HT1A receptor imaging agents. The complexes are carrying the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, either on the monodentate ligand [S] or on the tridentate ligand [SN(R)S]. The complexes MO[EtN(CH2CH2S)2] [o-MeOC6H4N(CH2CH2)2NCH2CH2S] (3), MO[o- MeOC6H4N(CH2CH2)2N(CH2)3N(CH2CH2S)2][PhS] (6) and MO[o-MeOC6H4N(CH2CH2)2N(CH2)3N(CH2CH2S)2] [PhCH2CH2S] (9), where M = 99mTc, were prepared at tracer level using 99mTc glucoheptonate as precursor. For structural characterization, the analogous oxorhenium (M = Re, 1, 4 and 7, respectively) and oxotechnetium (M = 99gTc, 2, 5 and 8, respectively) complexes were prepared by ligand exchange reactions. All products were characterized by elemental analysis and spectroscopic methods. Complexes 1, 4 and 7 were further characterized by crystallographic analysis. For 1, the coordination geometry about rhenium can be described as trigonally distorted square pyramidal (tau = 0.36), while for 4 and 7, as distorted trigonal bipyramidal (tau = 0.66 and tau = 0.61, respectively). The coordination sphere about oxorhenium in all complexes is defined by the SNS donor atom set of the tridentate ligand and the sulfur atom of the monodentate coligand. The structure of the 99mTc complexes 3, 6 and 9 was established by comparative HPLC using authentic oxorhenium and oxotechnetium samples. The binding affinity of oxorhenium compounds for the 5-HT1A receptor subtype was determined in rat brain hippocampal preparations (IC50 = 6-31 nM). Preliminary tissue distribution data in healthy mice revealed the ability of all three 99mTc complexes to cross the intact blood-brain barrier (0.49-1.15% ID at 1 min p.i.). In addition, complexes 6 and 9 showed significant brain retention. These promising results have demonstrated that the SNS/S mixed-ligand system can be used in the development of 99mTc complexes as potential 5-HT1A receptor imaging agents.     

Novel oxorhenium and oxotechnetium MO(NS)(S)2 complexes in the development of 5-HT1A receptor imaging agents

The [NS][S](2) mixed-ligand system was applied to synthesize oxorhenium and oxotechnetium complexes of the general formula MO(o-CH(3)OC(6)H(4)N(CH(2)CH(2))(2)NCH(2)CH(2)S)(p-CH(3)C(6)H(4)S)(2) (M=Re in 1, M=(99)Tc in 2, and M=(99m)Tc in 3). The bidentate [NS] ligand includes the 1-(2-methoxyphenyl)piperazine moiety which is a fragment of the true 5-HT(1A) antagonist WAY 100635. The oxorhenium complex 1 was prepared by a ligand exchange reaction using ReOCl(3)(PPh(3))(2) as precursor while [Bu(4)N][(99)TcOCl(4)] and (99)Tc-gluconate were used as precursors in the synthesis of the oxotechnetium-99 complex 2. Both complexes were characterized by elemental analysis and spectroscopic methods. Crystallographic analysis of 1 showed that the rhenium coordination geometry is trigonal bipyramidal. The basal plane of the trigonal bipyramid is defined by the oxo group and two sulphur atoms, one belonging to the [NS] ligand and the other to an aromatic thiol, while the apical positions are occupied by the nitrogen of the [NS] ligand and the sulphur of the second aromatic thiol. The oxotechnetium-99 complex 2 has almost identical unit cell parameters to those of the oxorhenium complex 1 indicating, in combination with the other analytical data, that the complexes are isostructural. The binding affinity of the oxorhenium complex 1 for the 5-HT(1A) receptor subtype was determined in rat brain hippocampal preparations (IC(50)=106 nM). The oxotechnetium-99m complex 3 was prepared by a ligand exchange reaction using (99m)Tc-glucoheptonate as the precursor. Its structure was established by comparative HPLC studies using the oxotechnetium-99 complex 2 as a reference. Complex 3 was administered by intravenous injection in rats. At 2 min post injection, 0.153% of the injected dose per gram of tissue was measured in rat brain.     

Synthesis and structural characterization of neutral “3 + 2” oxorhenium and oxotechnetium complexes of the 2-mercaptoethyl-N-glycine (SNO)/2,2′-bipyridine (NN) mixed ligand system

Neutral, hexacoordinated “3 + 2” mixed ligand oxorhenium (1) and oxotechnetium (2) complexes of the general formula MO[SNO][NN], where M = Re or ⁹⁹Tc, SNO is 2-mercaptoethyl-N-glycine and NN is 2,2′-bipyridine (bpy), were synthesized by simultaneous action of the tridentate SNO and the bidentate NN ligand on ReOCl₃(PPh₃)₂ or ⁹⁹TcO-gluconate precursors in a 1:1:1 molar ratio. Both complexes were characterized by elemental analysis, IR and NMR spectroscopy. X-ray structure determination of rhenium complex 1 revealed a distorted octahedral coordination geometry where the SNO donor atoms of the tridentate ligand and one bpy nitrogen atom occupy the equatorial positions of the octahedron, whereas the second bpy nitrogen atom and the oxo-group fill the apical positions.     

Encapsulation of platinum(II)-based DNA intercalators within cucurbit[6,7,8]urils

The partial encapsulation of platinum(II)-based DNA intercalators of the type [Pt(5-Cl-phen)(ancillary ligand)](2+), where 5-Cl-phen is 5-chloro-1,10-phenanthroline and the ancillary ligand is ethylenediamine, (1S,2S)-diaminocyclohexane (S,S-dach) or (1R,2R)-diaminocyclohexane, within cucurbit[n]uril (CB[n], where n is 6, 7 or 8) has been examined by (1)H and (195)Pt NMR and mass spectrometry. For CB[7], the molecule encapsulates over the ancillary ligand of all metal complexes, whether this is ethylenediamine or diaminocyclohexane. For CB[8], encapsulation occurs over the sides of the 5-Cl-phen ligand at low [Pt(5-Cl-phen)(S,S-dach)](2+) (5CLSS) to CB[8] ratios (i.e. 0.25:1) but over the ancillary ligand at higher ratios (i.e. 2:1). For CB[6] binding, 5CLSS exhibits both portal and cavity binding, with the ancillary ligand displaying chemical shifts consistent with fast exchange kinetics on the NMR timescale for portal binding and slow exchange kinetics for cavity binding. Binding constants could not be determined using UV-vis, circular dichroism or fluorescence spectrophotometry, but a binding constant for binding of 5CLSS to CB[6] of approximately 10(5) M(-1) was determined using (1)H NMR. Finally, the effect of CB[n] encapsulation on the cytotoxicity of the metal complexes was examined using L1210 murine leukaemia cells in vitro growth inhibition assays. The cytotoxicity is highly dependent on both the metal complex and the CB[n] size, and whilst CB[7] and CB[8] generally decreased cytotoxicity, it was found that CB[6] increased the cyotoxicity of 5CLSS up to 2.5-fold.     

Chelate oxorhenium to assemble new integrin antagonists

Assembly of independent chemical modules through oxorhenium coordination by a NS₂ + S chelation motif was applied to the synthesis of RGD (Arg-Gly-Asp) analogs. Modules were assembled through oxorhenium chelation to give a series of 18 metal complexes in good yields and satisfactory purities. Screening of these oxorhenium coordinates as antagonists of integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 3 bioactive compounds that exhibit submicromolar affinities for the 3 integrins. Preliminary studies showed that the corresponding oxotechnetium complexes are stable in mice plasma and therefore could be proposed for the molecular imaging of pathologies that overexpress integrins αVβ3 and αVβ5.     

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.     

Mono-vitamin B6 complexes of palladium(II) and their interactions with nucleosides

The interactions of potassium tetrachloropalladate(II) with the B6 vitamins pyridoxal, pyridoxine, and pyridoxamine in 1:1 molar ratio have been studied. From DMF solutions, the ionic trichloro (pyridoxal or pyridoxine) palladates(II) were isolated. Pyridoxamine, on the other hand, in aqueous solutions gave the dimeric complex bis [mu-chloro-pyridoxaminato-palladium(II)]. In the first two complexes, the ligands coordinated to palladium through their pyridine nitrogen while, in the last one, pyridoxamine acted as a chelating ligand through its phenolic oxygen and aminomethyl nitrogen. All three complexes reacted with nucleosides, yielding the complexes [Pd(PL)(Nucl)Cl2], [Pd(PN)(Nucl)Cl2], and [Pd(PM-H+)(Nucl)Cl], respectively. Those complexes with one ionizable N(1)H imino proton underwent deprotonation, and the new mixed ligand complexes [Pd(PL)(Nucl-H+)Cl], [Pd(PN)(Nucl-H+)], and [Pd(PM-H+)(Nucl-H+)] were formed. In all mixed ligand complexes, the B6 vitamins maintained their coordination modes. The nucleosides, on the other hand, exhibited their usual coordination sites, i.e., in the nondeprotonated complexes, purine nucleosides coordinated only through their N7 atom. In the deprotonated complexes, they acted as bidentate ligands and coordinated through their N7 and O6 atoms. All complexes were characterized with elemental analyses, conductivity measurements, and various spectroscopic techniques.     

Assigning stereodiversity of the 27-Me group of furostane-type steroidal saponins via NMR chemical shifts

Applicability of (13)C and (1)H NMR chemical shifts for the assignment of the 25R/25S configuration of the 27-methyl group in the case of furostane-type steroidal saponins has been investigated. A comparative study of (13)C NMR data suggest that chemical shift values for C-20, C-21, C-22, C-23, C-24, C-25, C-26 and C-27 resonances were not much influenced by R/S configuration of the 27-Me group, thus reflecting limited application of (13)C NMR chemical shifts for such stereochemical determinations. In contrast, (1)H NMR chemical shifts (delta(a), delta(b)) for geminal protons of glycosyloxy methylene (H(2)-26) exhibit pronounced dependence and the difference (Delta(ab)=delta(a)-delta(b)) among their chemical shifts [Delta(ab)= or <0.48 for 25R; Delta(ab)= or >0.57 for 25S] seems to be of general applicability for ascertaining 25R/25S orientation of the 27-methyl group of furostane-type steroidal saponins.     

Solution 1H nuclear magnetic resonance determination of the distal pocket structure of cyanomet complexes of genetically engineered sperm whale myoglobin His64 (E7)-->Val, Thr67 (E10)-->Arg. The role of distal hydrogen bonding by Arg67 (E10) in modulating ligand tilt.

Sequence-specific 2D methodology has been used to assign the 1H NMR signals for all active site residues in the paramagnetic cyano-met complexes of sperm whale synthetic double mutant His64[E7]-->Val/Thr67[E10]-->Arg (VR-met-MbCN) and triple mutant His64[E7]-->Val/Thr67[E10]-->Arg/Arg45[CD3]-->Asn (VRN-metMbCN). The resulting dipolar shifts for noncoordinated proximal side residues were used to quantitatively determine the orientation of the paramagnetic susceptibility tensor in the molecular framework for the two mutants, which were found indistinguishable but distinct from those of both wild-type and the His64[E7]-->Val single point mutant (V-metMbCN). The observed dipolar shifts for the E helix backbone protons and Phe43[CD1], together with steady-state nuclear Overhauser effect between the E helix and the heme, were analyzed to show that both the E helix and Phe43[CD1] move slightly closer to the iron to minimize the vacancy resulting from the His64[E7]-->Val substitution, as found in V-metMbCN (Rajarathnam, K., J. Qin, G.N. LaMar, M. L. Chiu, and S. G. Sligar. 1993. Biochemistry. 32:5670-5680). The dipolar shifts of the mutated Val64[E7] and Arg67[E10] allow the determination of their orientations relative to the heme, and the latter residue is shown to insert into the pocket and provide a hydrogen bond to the coordinated ligand, as found in the naturally occurring ValE7/ArgE10 genetic variant, Aplysia limacina Mb. The oxy-complex of both A. limacina Mb and VR-Mb, VRN-Mb have been proposed to be stabilized by this hydrogen bonding interaction (Travaglini Allocatelli, C. et al. 1993. Biochemistry. 32:6041-6049). The magnitude of the tilt of the major magnetic axes from the heme normal in VR-metMbCN and VRN-metMbCN, which is related to the tilt of the ligand, is the same as in wild-type or V-metMbCN, but the direction of tilt is altered from that in V-metMbCN. It is concluded that the change in the direction of the ligand tilt in both the double and triple mutants, as compared to WT metMbCN and V-metMbCN single mutant, is due to the attractive hydrogen-bonding between ArgE10 and the bound cyanide.     

New pinch-porphyrin complexes with quantum mixed spin ground state S=3/2,5/2 of iron (III) and their catalytic activity as peroxidase

New complexes of the pinch-porphyrin family were obtained from the dimethylester of (proto-, meso-, and deutero-porphyrinato)iron(III) with the ligand [N,N'-bis-pyridin-2-ylmethyl-propane-1,3-diamine] 1-3 and with the ligand [N-pyridin-2-ylmethyl-N'-[3-[(pyridin-2-ylmethyl)-amino]-propyl]-propane-1,3-diamine] 4-6. The UV/VIS studies of 1-6 indicate an increase in the distortion of the ligand field excited state. The 1H NMR spectra of 1-6 at RT and over the range 223-328 K show iron(III)-complexes with quantum mixed spin state (qms) S=5/2, S=3/2. The chemical shifts of the meso protons are consistent with qms state S=3/2, S=5/2, where the S=3/2 spin state is lowest in energy. For methyl-heme the chemical shifts are also consistent with a qms state but now the S=5/2 ground state is lowest in energy. ESR spectra of 1-6 show two different species, B and C, of iron(III) with qms, S=5/2, S=3/2 consistent with the 1H NMR results. Species B with 70% of S=5/2 and species C with 72.5% of S=3/2. The catalytic activity as peroxidase of 1-6 was quantified by guaiacol test; their theoretical maximum rate constants were k(cat) approximately 10(2)-10(3) M(-1) s(-1). A quantitative empirical correlation is found: the higher the 32 spin contribution to the qms state and the higher proportion of this species into the samples, the higher the peroxidase activity. Such a correlation was also obtained for pinch-porphyrins already reported.     

Novel six-coordinate oxorhenium(V) ‘3+2’ mixed-ligand complexes carrying the SNO/SN donor atom set

Ligand exchange reactions of oxorhenium(V) precursors with bidentate SN and tridentate Schiff bases derived from the condensation of ketones or aldehydes with dithiocarbazic acid methyl ester (H₂NNHC(S)SCH₃) produce novel ‘3+2’ mixed-ligand complexes carrying the SNO/SN donor atom set. Thus, reactions of either [NBu₄][ReOCl₄] or Na[ReO(Gluconate)₂] with SNO ligands (H₂Lⁿ) or a mixture of bidentate SN (HL^m) and tridentate SNO (H₂Lⁿ) in methanol solutions lead, respectively, to the six-coordinated mixed ligand oxorhenium(V) compounds of types [ReO(Lⁿ)(HLⁿ)] and [ReO(Lⁿ)(L^m)], combining one tridentate dianionic S⁻NO⁻ donor Schiff base (L) and one bidentate anionic S⁻N donor ligand (HL). Coordination geometry around rhenium is distorted octahedral with the two SN donor atom sets of each ligand defining the equatorial plane, while apical positions are occupied by the oxo group and the oxygen atom of the tridentate SNO ligand (L), as shown by single-crystal X-ray diffraction structure of [ReO(L¹)(HL¹)] 1.     

Synthesis and characterization of technetium(V) complexes with tridentate schiff base ligands. X-ray crystal structure of chloro[N-(2-hydroxyphenyl)salicylideneiminato]oxotechnetium(V)

Five-coordinate technetium(V) complexes of the form TcO(L)Cl where L is one of the two tridentate Schiff base ligands N-(2-oxidophenyl)salicylideneiminate or N-(2-mercaptophenyl)salicylideneiminate have been synthesized and characterized. These neutral complexes precipitate from methanol upon reaction of the Schiff base ligand with TcOCl₄^?. A single crystal X-ray structure determination shows that the chloro [[N-(2-oxidophenyl)salicylideneiminato](2?)-N,O,O′]oxotechnetium(V) complex, [TcO(C₁₃H₉NO₂)Cl], formula weight 362, has a distorted square pyramidal coordination geometry with the oxo ligand in the axial position. The steric requirements of the oxo group cause the Tc atom to be displayed 0.67 Å out of the mean equatorial plane of the other four donor atoms. This complex crystallizes in the monoclinic space group P2₁/a with a = 13.423(6) Å, b = 12.570(5) Å, c = 7.769(3) Å, β = 106.53(5)°, V = 1256.7(9) ų, and Z = 4. The structure has been refined to R = 0.047 for 1775 observed reflections.     

NMR study of a lymphocyte differentiating thymic factor. An investigation of the Zn(II)-nonapeptide complexes (thymulin)

Detailed investigations of a serum peptide (less than Glu1-Ala2-Lys3-Ser4-Gln5-Gly6-Gly7-Ser8-++ +Asn9) were carried out by 1H and 13C NMR spectroscopy to elucidate the structure of the complex formed with Zn(II), thymulin, which has been found to be active in vivo. These experiments were performed in dimethyl sulfoxide-d6 solution at different metal:peptide ratios. The results suggest the following conclusions. (i) The Zn(II) complexation corresponds to a fast exchange on the NMR time scale. (ii) The evolution of 1H and 13C NMR chemical shifts indicates the existence of two types of complexes: a 1:2 species associating two peptide molecules and one Zn(II) ion and a complex with 1:1 stoichiometry. The former is predominant for metal:peptide ratios below unity. (iii) In the 1:2 complex, Zn(II) is coordinated by the Ser4-O gamma H and Asn9-CO2- sites, while in the 1:1 complex, Ser8-O gamma H is the third ligand to the Zn(II) ion. The results are compared with those for the [Ala4] and [Ala8] analogues, and those for the complexes of thymulin with other metal ions (Cu2+ and Al3+) in terms of its biological activity. These comparative studies suggested that the 1:1 complex is the only conformation recognized by the antibodies.     

Spectroscopic aspects of the coordination modes of 2,4-dithiohydantoins: Experimental and theoretical study on copper and nickel complexes of cyclohexanespiro-5-(2,4-dithiohydantoin)

The complexation of cyclohexanespiro-5-(2,4-dithiohydantoin), L, with copper and nickel was studied by means of experimental and theoretical methods. The Cu(I) and Ni(II) complexes were synthesized and characterized using ¹³C CPMAS NMR, IR and FAB-MS. Reduction of Cu(II) ions and the formation of Cu(I) complexes with dithiohydantoin was proved. Various coordination modes were investigated on the basis of calculated (DFT-GIAO) shielding constants of the free ligand and model structures of the complexes. General trends in the changes of spectroscopic parameters (NMR chemical shifts, vibrational modes) upon different types of coordination were outlined. Dimeric structures for the Cu(I) and Ni(II) complexes were proposed in which the ligands were coordinated in N3^S4- and N3^S2-bridging ways, respectively, acting as monoanions. The results demonstrate that the combined experimental (¹³C CPMAS NMR, IR) and theoretical (DFT) approach can be used to characterize the molecular structure of solid complexes for which crystallographic data are not available.     

Ru(II) complexes of crowded delocalized diimine ligands

The ligands 3,3′-dimethylene-2,2′-bibenzo[g]quinoline and bisbenzo[2,3:9,8]-1,10-phenanthroline have been coordinated with Ru(II) to form both tris- and mixed ligand complexes. These species are highly congested about the metal center but can be formed through the use of microwave irradiation. Shielding and deshielding effects on the chemical shifts of the aryl as well as the bridge protons reveal important conformational effects. Bathochromic shifts are observed in the electronic absorption spectra, associated with increased delocalization of the ligand and lowering of the π*-energy level. Similar effects are observed for the reduction potentials while the oxidation potentials are much less sensitive to ligand structure.     

Novel lipophilic amidate oxorhenium and oxotechnetium complexes as potential brain agents: synthesis, characterization and biological evaluation

Novel oxorhenium and oxotechnetium complexes based on the tetradentate 1-(2-hydroxybenzamido)-2-(pyridinecarboxamido)benzene, H3L, ligand have been synthesized and characterized herein. Thus, by reacting equimolar quantities of the triply deprotonated ligand L3- with the suitable MO3+ precursor, the following neutral MOL complexes could be easily produced following similar synthetic routes: M = Re (1), M = 99gTc (2), and M = 99mTc (3). Complexes 1 and 2, prepared in macroscopic amounts, were chemically characterized and their structure determined by single-crystal X-ray analysis. They are isostructural metal chelates, adopting a distorted square pyramidal geometry around the metal. The N3O donor atom set of the tetradentate ligand defines the basal plane and the oxygen atom of the M = O core occupies the apex of the pyramid. Complex 3 forms quantitatively at tracer level by mixing the H3L ligand with Na99mTcO4 generator eluate in aqueous alkaline media and using tin chloride as reductant in the presence of citrate. Its structure was established by chromatographic comparison with prototypic complexes 1 and 2 using high-performance liquid chromatographic techniques. When challenged with excess glutathione in vitro, complex 3 is rapidly converted to hydrophilic unidentified metal species. Tissue distribution data after administration of complex 3 in vivo revealed a significant uptake and retention of this compound in brain tissue.     

Vanadium(V) complexes with salicylaldehyde semicarbazone derivatives bearing in vitro anti-tumor activity toward kidney tumor cells (TK-10): crystal structure of [VVO2(5-bromosalicylaldehyde semicarbazone)

As a contribution to the development of novel vanadium complexes with pharmacologically interesting moieties, new dioxovanadium(V) semicarbazone complexes with the formula cis-VO(2)L, where L=5-bromosalicylaldehyde semicarbazone and 2-hydroxynaphtalen-1-carboxaldehyde semicarbazone have been synthesized and characterized by (1)H and (13)C NMR, Raman and FTIR spectroscopies. Results were compared with those previously reported for other three analogous complexes of this series. The five complexes were tested in three different human tumor cell lines for bioactivity as potential anti-tumor agents, showing selective cytotoxicity on TK-10 cell line. Results showed that structural modifications on the semicarbazone moiety could have a significant effect on the anti-tumor activity of the vanadium complexes. In addition, the electrochemical behavior of all the complexes was studied. No apparent correlation could be demonstrated between reduction potentials of the complexes and their anti-tumor activities. The molecular structure of the novel [V(V)O(2)(5-bromosalicylaldehyde semicarbazone)] complex was solved by X-ray diffraction methods. The vanadium atom shows a distorted square pyramidal coordination sphere. The (VO(2))(+) cation is coordinated to a nearly planar (L)(-) anion acting as a tridentate ligand through both oxygen and one nitrogen atoms.     

Platinum(II), platinum(IV), and palladium (II) complexes of amino substituted phosphine oxides: synthesis, characterization, and antitumor activity

The complexes [Pt(dapo)2Cl2], [PtNH3(dapo)Cl2], [Pt(py)(dapo)Cl2], [Pt(mbpo)Cl2].H2O, [Pt(mbpo)(OH)2Cl2].H2O, [Pd(dapo)2Cl2], and [Pd(mbpo)Cl2], where dapo is dimethyl aminomethylphosphine oxide and mbpo is methyl bis(aminomethyl)phosphite oxide have been synthesized and characterized by elemental analyses, electric conductivity, infrared, 1H NMR and electronic spectra. The ligands are found to be coordinated only via the amino groups. The complexes are of cis-square planar configuration with the exception of [Pt(mbpo)(OH)2Cl2].H2O which is pseudo-octahedral. An in vivo antitumor screening of the complexes against Leukemia L1210 was performed. A considerable activity (T/C = 233%) was observed for [PtNH3(dapo)Cl2]. The activity of the remaining complexes was below the accepted criterion.     

Cyclic and acyclic oxorhenium(V)-peptide conjugates as new ligands of the human cyclophilin hCyp-18

Peptide metalloconstructs display interesting conformations, activities, and resistance to proteolysis. However, introduction of a metal core close to the residues that interact with the protein might strongly affect the binding. We investigated the effects of a coordinated oxorhenium core on the binding of model peptides to cyclophilin hCyp-18, a protein implicated in important biological processes and several diseases. For this purpose, we synthesized a series of linear metalloconstructs bearing an oxorhenium(V) core (ReO3+), as well as a peptide cyclized through oxorhenium(V) coordination. All these peptides contain an Ala-Pro-Xaa-pNA moiety (Xaa = Cys derivative) and are anticipated to bind simultaneously to the S1-S1' and S2'-S3' subsites of hCyp-18. Therefore, the metal core is coordinated to both the cysteine residue and exogenous or endogenous NS2 tridentate systems. Cyclization of the peptide through metal coordination did not affect the affinity whereas bimolecular oxorhenium metalloconstructs bind hCyp-18 with a slightly better affinity than the corresponding nonmetalated peptide. Peptide labeling with a 99mTcO3+ core was also carried out successfully.