Renzo Cini

fac-{Ru(CO)3}2+ Selectively Targets the Histidine Residues of the β-Amyloid Peptide 1-28. Implications for New Alzheimer's Disease Treatments Based on Ruthenium Complexes

The reaction of the ruthenium(II) complex fac-[Ru(CO)(3)Cl(2)(N(1)-thz)] (I hereafter; thz = 1,3-thiazole) with human beta-amyloid peptide 1-28 (Abeta(28)) and the resulting {Ru(CO)(3)}(2+) peptide adduct was investigated by a variety of biophysical methods. (1)H NMR titrations highlighted a selective interaction of {Ru(CO)(3)}(2+) with Abeta(28) histidine residues; circular dichroism revealed the occurrence of a substantial conformational rearrangement of Abeta(28); electrospray ionization mass spectrometry (ESI-MS) suggested a prevalent 1:1 metal/peptide stoichiometry and disclosed the nature of peptide-bound metallic fragments. Notably, very similar ESI-MS results were obtained when I was reacted with Abeta(42). The implications of the above findings for a possible use of ruthenium compounds in Alzheimers disease are discussed.

Cisplatin/Hydrogel Complex In Cancer Therapy

Hydrogels containing alpha-amino acid residues (L-phenylalanine, L-histidine) were used to complex the chemotherapeutic agent cisplatin. The release of the drug in phosphate buffer solution showed an initial burst effect, followed by a near zero-order release phase over the seven days of reported period. Unlike the nonreleasing pattern of the hydrogel poly(N-acryloyl-L-phenylalanine-co-N-isopropylacrylamide) (CP2), the homopolymer poly(N-acryloyl-L-phenylalanine) (P9) hydrogel showed a released amount of cisplatin loaded from a water/DMSO mixture that was three times greater than that loaded from simple water. The hydrogel P9 formed with cisplatinum(II) complex species of well-defined stoichiometry; the drug species was released by a chemically controlled process. The Pt(II)/L (L is the monomeric unit of the polymer) stoichiometric molar ratio of 0.5, corresponding to two close carboxylate groups per Pt(II), was found by the viscometric data on the soluble polymer analogue. The platinum species released from cisplatin-loaded (from water) hydrogel retained its cytotoxic activity toward Me665/2/21 human melanoma cell line, in the same manner shown by the native cisplatin. On the contrary, the platinum species released from cisplatin-loaded (from water/DMSO) hydrogel was devoid of any cytotoxic effect.

Synthesis, X-ray structural characterization and solution studies of metal complexes containing the anti-inflammatory drugs meloxicam and tenoxicam

Abstract The reaction of tenoxicam (H2ten, 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide), with M(CH3COO)2 (M=Cd, Co, Zn; 2:1 molar ratio) in hot methanol produced the microcrystalline compounds: CdII(Hten)2·2CH3OH, 1, CoII(Hten)2CH3OH3H2O, 2, ZnII(Hten)22CH3OH, 3. Single crystals of trans,trans-[CdII(Hten)2(dmso)2] 4 (dmso, dimethylsulfoxide) were obtained on cooling hot dmso solutions of 1. trans-[PtCl2(η2-C2H4)(H2ten)], 5 and trans-[PtCl2(η2-C2H4)(H2mel)]·0.5C6H6, 6·0.5C6H6 were obtained from the reaction of the Zeises salt (K[PtCl3(η2-C2H4)]·H2O) with tenoxicam and meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxammide-1,1-dioxide), respectively (1:1 molar ratio) in ethanol solution and subsequent recrystallization from benzene. Microcrystalline FeII(Hmel)2·4H2O·2CH3OH, 7, was prepared by reacting Fe(CH3COO)2 with H2mel in refluxing methanol at a 1:2 molar ratio, under an atmosphere of ultrapure nitrogen. The X-ray diffraction structure of 4 consists of pseudo-octahedral complex molecules in which the two chelating Hten− anions (trans to each other) occupy the equatorial positions through the O-amide (CdO(15), 2.214(2) A) and the N-pyridyl (CdN(1′), 2.303(3) A) atoms. The conformation is ZZZ around the C(3)C(14), C(14)N(16) and N(16)C(2′) bonds. The coordination sphere is completed by two oxygen atoms from two dmso ligands at the apical positions. The sulfur atom from the thieno system as well as the SO2 function are not involved in any interactions to the metal; they contribute to the crystal packing via S⋯HC and O⋯HC hydrogen bond type interactions. The structures of 5 and 6 are similar each other as regards the coordination mode and overall conformation of the ligands (H2ten and H2mel, respectively). The platinum center links the nitrogen atom from pyridyl and thiazolyl rings with PtN bond lengths 2.077(5) and 2.072(13) A, respectively. The EZE conformation of the neutral ligand molecules facilitates the formation of O(17)H⋯O(15) strong intramolecular hydrogen bonds. The (N(16))H⋯Pt intramolecular contact distances are 2.54(1) (5) and 2.93(1) A (6), suggesting that an attractive interactions may exist for 5 on the basis of van der Waals radii for H and Pt. The 1H NMR data for 1 in dmso-d6 show a general shift towards higher fields for signals of Hten− ligand with respect to those of free H2ten. On the contrary the signals for H2ten and H2mel relevant to 5 and 6 (CDCl3) undergo significant low field shifts upon the coordination to the platinum center. It is worth note that the signal for the H(16) atom is moved downfield by 1.93 ppm for 5, and this can be related to the short intramolecular Pt⋯H contact distance (see above). The infrared data for 5 and 6 at the solid state show intense and sharp bands at 1524 and 1528 cm−1, respectively, attributable to the CH2CH2 stretching vibration coupled to the CH2 bending mode, some 100 cm−1 lower energy than the band for free ethylene.

Preparation and physico-chemical properties of the ternary complexes formed between adenosine 5′-triphosphoric acid, bis(2-pyridyl)amine, and divalent metal ions. Crystal and molecular structures of the compounds containing MgII and CaII

Ternary compounds formed between M (MgII, CaII, SrII, MnII, CoII, CuII, or ZnII), adenosine 5′-triphosphate [adenosine 5′-triphosphate(4–)= atp], and bis(2-pyridyl)amine(bipyam) have been prepared. The solid compounds are crystalline and have a stoicheiometry described by the formula M(Hatp)(Hbipyam)·nH2O (n= 2–9). X-Ray powder diffraction patterns are similar. Potentiometric titrations in aqueous solution show the presence of two ionizable protons. Visible spectra suggest an octahedral co-ordination geometry. I.r. spectra indicated essentially the same type of metal–ligand interactions in all the complexes and show that Hatp3– co-ordinates to the metal through the oxygen atoms of the α, β, and γ phosphate groups. The ternary compounds where M = MgII(1) or CaII(2) have been studied by single-crystal X-ray diffraction techniques and their molecular structures determined. The two species are isostructural and can be formulated as [Mg(H2O)6][Hbipyam]2[Mg(Hatp)2]·12H2O (1) and [Ca(H2O)6][Hbipyam]2[Ca(Hatp)2]·9H2O (2). Both (1) and (2) crystallise in space group C2221(Z= 4), with a= 22.734(3), b= 10.233(3), c= 30.997(4)A for (1) and a= 22.965(3), b= 10.154(3), c= 32.390(4)A for (2). X-Ray diffraction data were collected on a Philips automatic diffractometer and the structures solved by direct methods using the SIR (Semi-invariant Representation) package and refined by full-matrix least squares to final R values of 0.111 and 0.124 (1 088 and 1 008 independent observed reflections) for (1) and (2) respectively. In the [M(Hatp)2]4– units the metal ions lie on a two-fold axis with an octahedral co-ordination geometry completed by the oxygen atoms of the α, β, and γ phosphate groups of two symmetry-related Hatp3– molecules. The co-ordination polyhedron of (1) is nearly regular but in (2) it is significantly distorted. The phosphate chains have a folded configuration in both (1) and (2). In both complexes there are no bonding interactions between the metal ions and the adenine base. The metal atoms of the [M(H2O)6]2+ cations are also located on two-fold axes while the six co-ordinated water molecules form hydrogen bonds with the phosphate chains. The Hbipyam+ molecules do not co-ordinate to the metal ions and are disordered around two-fold axes. Strong stacking interactions exist between Hbipyam+ and purine rings.

Synthesis of new N2S2 ligands and Re(V)O(N2S2) analogues of 99mTc renal imaging agents. Characterization by NMR spectroscopy, molecular mechanics calculations, and X-ray crystallography

Abstract Two new N2S2 ligands [S-trityl- l -cysteine-acetamide-ethanethiol ethyl ester (Tr- l -CAATH2-Et, 1) and S-trityl- d -penicillamine-acetamide-(2-methyl-2-propanethiol) ethyl ester (Tr- d -TMCAATH2-Et, 2)] were prepared. These ligands, with the electron-withdrawing carboxyl group separated by only two bonds from the NH amine group, belong to monoamide-monoamine-dithiol (MAMA) class of chelates that typically form M(V)O(N2S2) (M=Tc, Re) complexes with the ligand secondary amine pKa of ∼6–7 and both syn and anti isomers. Re(V)O(N2S2) complexes were prepared from 1 and 2 with the dangling ester either syn or anti to the ReO intact or hydrolyzed; the latter, ReO( l -CAATH2) and ReO( d -TMCAATH2) have a carboxyl group needed for renal imaging when M=Tc. The gross structure of syn-ReO( l -CAATH-Et) (3) is typical of Re(V)O(N2S2) complexes. However, within the cys moiety of 3, an intramolecular H-bond between the ester carbonyl oxygen O(4) and the NH (N(2)⋯O(4) distance=2.80 A) causes the cys chelate ring to adopt an unusual conformation with the αC (C(5)) atom 0.42 A below the plane defined by the cys S, Re, and N(2) atoms with respect to the ReO group. From molecular mechanics (MM) analysis of ReO( l -CAATH2) models, the lowest-energy syn-ReO( l -CAATH2) structure has a corresponding region similar to that of the X-ray structure for 3, an N(2)H endo with respect to ReO group, a N(2)H⋯O(4) hydrogen bond (2.69 A N(2)⋯O(4) distance) contributing ∼5 kcal mol−1 to its stability and an αC atom deviating 0.24 A from the cys S, Re, and N(2) plane. Computed structures with an exo N(2)H are ∼6 kcal mol−1 less stable than the lowest-energy endo analogue. Below pH ∼7, the 1H NMR spectrum of syn-ReO( d -TMCAATH2) exhibited changes in two pH regions, consistent with sequential protonation of the amine and of the carboxylic group. These experimental and MM results reinforce previous hypotheses about the factors favoring one syn form in one ionization state of M(V)O(N2S2) compounds at physiological pH.

Platinum amides from platinum nitriles: X-ray crystal structure of trans-dichloro-bis(1-imino-1-hydroxy-2,2-dimethylpropane)platinum(II)

Abstract The bisamide complex trans-[PtCl2HN=C(OH)But2] (1) has been prepared by hydrolysis of dichlorobis(tertiary-butylnitrile)-platinum(II) and characterized via single crystal X-ray diffraction. The complex crystallizes in the Pbcn (No. 60) space group with the cell parameters a = 11,.692(2), b = 22.214(3) and c = 18.515(2) A . Twelve complex molecules are present in the cell where triplets of the are stabilized by intermolecular hydrogen bonds involving N, Cl and O atoms. The structure has a strict similarity with that previously reported (D.B. Brown, R.D. Burbank and M.B. Robin, J. Am. Chem. Soc., 91 (1969) 2895) (the refinement, however, showed all the non-H atoms and converged to R = 0.0471 for 1003 observed reflections (Fb > 6 σ(Fe)) in the present work, whereas the structure analysis of the previous work did not show most of the atoms of a molecule in the asymmetric unit and the refinement converged to R = 0.107 for 2047 observed reflections) and proposed to contain, besides the yellow bisamide (1 ∼ 70%), also a second yellow material (II. ∼ 20%) and a third blue material (III. ∼ 10%). The latter two had an analytical composition similar to that of the first one and were formulated as isomeric dichlorobis(amidato)platinum(IV) species. The mixed amidenitrile species trans-[PtCl2[HN=C(OH)But)(NCBut)] (2 has also been characterized. It has NMR signals coincident with those of compound II, its space group and cell parameters are very close to those of 1, and it has a tendency to cocrystallize with 1 in the molar ratio 2:1 in favor of 2. The geometry of the amide ligands in the enol tautomeric form appears to be ideal for favoring the face-to-face association of platinum units stabilized by interfacial hydrogen bonds. In the case of cis geometry (corresponding cis isomer of 1), platinum dimers with an intermetallic distance of 3.165(1) A were formed: in contrast, in the case of trans geometry (compound 1 presently investigated) platinum triplets with an intermetallic distance of 3.668(1) A were established. In both cases the preferred conformation is staggered and the shortest distance between platinum atoms in different dimers (cis isomer) or triplets (trans isomer) is in excess of 4.17 A. Therefore, a special role of the coordination geometry appears to be in determining the mode of association of platinum monomers in oligomers.

Oxygen Radical Scavenger Activity, EPR, NMR, Molecular Mechanics and Extended-Hückel Molecular Orbital Investigation of the Bis(Piroxicam)Copper(II) Complex.

The oxygen radical scavenger activity (ORSA) of [CuII(Pir)2] (HPir = Piroxicam = 4-hydroxy -2- methyl -N-2- pyridyl -2H- 1,2-benzothiazine -3- carboxamide 1,1-dioxide) was determined by chemiluminescence of samples obtained by mixing human neutrophils (from healthy subjects) and [CuII(Pir)2(DMF)2] (DMF = N,N -dimethylformammide) in DMSO/GLY/PBS (2:1:2, v/v) solution (DMSO = dimethylsulfoxide, GLY = 1,2,3-propantriol, PBS = Dulbecco’s buffer salt solution). The ratio of the residual radicals, for the HPir (1.02·10−4M) and [CuII(Pir)2(DMF)2] (1.08·10−5M)/HPir (8.01·10−−5M) systems was higher than 12 (not stimulated) [excess of piroxicam was added (Cu/Pir molar ratio ≈1:10) in order to have most of the metal complexed as bischelate]. In contrast, the ratio of residual radicals for the CuCl2 (1.00·10−5M) and [CuII(Pir)2(DMF)2] (1.08·10−5M)/Hpir (8.01·10−5M)system was 5. The [CuII(Pir)2] compound is therefore a stronger radical scavenger than either HPir or CuCl2. A molecular mechanics (MM) analysis of the gas phase structures of neutral HPir, its zwitterionic (HPir+-) and anionic (Pir-) forms, and some CuII-piroxicam complexes based on X-ray structures allowed calculation of force constants. The most stable structure for HPir has a ZZZ conformation similar to that found in the CuII (and CdII complexes) in the solid state as well as in the gas phase. The structure is stabilized by a strong H bond which involves the N(amide)-H and O(enolic) groups. The MM simulation for the [CuII(Pir)2(DMF)2] complex showed that two high repulsive intramolecular contacts exist between a pyridyl hydrogen atom of one Pir- molecule with the O donor of the other ligand. These interactions activate a transition toward a pseudo-tetrahedral geometry, in the case the apical ligands are removed. On refluxing a suspension of [CuII(Pir)2(DMF)2] in acetone a brown microcystalline solid with the Cu(Pir)2·0.5DMF stoichiometry was in fact prepared. 13C spin-lattice relaxation rates of neutral, zwitterionic and anionic piroxicam, in DMSO solution are explained by the thermal equilibrium between the three most stable structures of the three forms, thus confirming the high quality of the force field. The EPR spectrum of [CuII(Pir)2(DMF)2] (DMSO/GLY, 2:1, v/v, 298 and 110 K) agrees with a N2O2+O2 pseudo-octahedral coordination geometry. The EPR spectrum of [CuII(Pir)2·0.5DMF agrees with a pseudo-tetrahedral coordination geometry. The parameters extracted from the room temperature spectra of the solution phases are in agreement with the data reported for powder and frozen solutions. The extended-Hückel calculations on minimum energy structures of [CuII(Pir)2(DMF)2] and [CuII(Pir)2] (square planar) revealed that the HOMOs have a relevant character of dx2−y2. On the other hand the HOMO of a computer generated structure for [CuII(Pir)2] (pseudo-tetrahedral) has a relevant character of dxy atomic orbital. A dxy orbital is better suited to allow a dπ-pπ interaction to the O2- anion. Therefore this work shows that the anti-inflammatory activity of piroxicam could be due in part to the formation of [CuII(Pir)2] chelates, which can exert a SOD-like activity.

Synthesis, X-ray structures and solution studies of new organo-rhodium(III) complexes with stibine, pyridine and pyrimidine derivatives

Abstract The synthesis, X-ray structure and spectroscopic characterization of new organo-rhodium(III) compounds is reported. From the reaction of RhCl3 with SbPh3 (Ph−C6H5, 1:3–4 molar ratio), in boiling ethanol, a mixture of [trans-RhCl2(Ph)(SbPh3)3] (1) and [mer-RhCl3(SbPh3)3] (2) was obtained. A previous hint on this reaction is given by R. Cini, G. Giorgi and E. Periccioli, Acta Crystallogr., Sect. C, 47 (1991) 716. The separation of 1 and 2 was carried out by recrystallizing the mixture from acetone: 1·(CH3)2CO precipitates first. 1 was separated from 2 also through chromatographic techniques (SiO2 column, CH2Cl2 eluent). High yield preparation of 1 was carried out on adding Ag(CF3SO3) to the suspension obtained by refluxing a mixture of RhCl3 and SbPh3 (Rh/ Sb/Ag molar ratio of 1:4:1). High yield synthesis of 2 was obtained by refluxing an ethanol mixture of RhCl3 and SbPh3 (1:3) in the presence of an excess of Cl−, or by refluxing a mixture of RhCl3 and SbPh3 (1:10) in ethanol solvent. Orange crystals of 1·0.45(CH3)2CO belong to the triclinic system, space group P 1 (No. 2) with a=12.686(2), b=14.906(2), c=15.523(3) A, α=107.73(2), β=95.10(2), γ=93.62(2)°, Z=2, Dc=1.60 g cm−3. The structure was refined to R=0.0594 and Rw=0.0651. The complex molecule consists of an octahedrally coordinated Rh(III) center linked to two trans Cl− ions, and to a Ph and to three SbPh3 ligands in the basal plane. A RhSb bond is much lengthened by a strong trans influence from the Ph ligand. 1 reacted with an excess of pyridine (Py) and 3,5-dimethylpyridine (3,5-lutidine, Lu) in refluxing methanol to produce [trans-RhCl2(Ph)(Py)3] (3) and [trans-RhCl2(Ph)(Lu)3] (4), respectively. 1 reacted also with boiling CH3CN to produce [RhCl2(Ph)- (CH3CN)(SbPh3)2] 3 reacted with an excess of 4-methylpyrimidine (Mp) in refluxing methanol to produce [trans- RhCl2(Ph)(Py)2(Mp)] (5). Yellow needles of 3 belong to the tetragonal system, space group I41/acd (No. 142), with a=15.660(2), c=17.044(2) A, Z=8, Dc=1.55 g cm−3. The structure was refined to R=0.0402 and Rw=0.0446. Yellow prisms of 4 belong to the tetragonal system, P4/nnc (No. 126), a=11.522(3), c=10.289(2) A, Z=2, Dc=1.39 g cm−3. The structure was refined to R=0.0579 and Rw=0.0601. Both 3 and 4 contain two Cl− ligands trans to each other, a Ph group and three Py or Lu molecules in the equatorial sites. Their 1H NMR spectra show large downfield shifts for the signals relevant to the Py or Lu ligand molecule trans to Ph. The 1H NMR spectrum of 5 shows that the two Py ligands are trans to each other and that Mp is coordinated through N(1), which occupies the position trans to Ph. The complex molecules of 3, 4 and 5 are stable in CHCl3 solution, at room temperature for periods of hours. The reaction of 2 with an excess of Py in refluxing methanol produced the well known complex [trans-RhCl2(Py)4]+.

Synthesis and Structural Characterisation of a New Form of Bis(acyclovir)(ethylenediamine)platinum(II) − Correlation between the Puckering of the Carrier Ligand and the Canting of the Nucleobases

A new conformer of the [Pt(en)(acv)2]2+ cation (en = ethylenediamine; acv = acyclovir = 9-[(2-hydroxyethoxy)methyl]guanine) has been prepared by slow crystallisation of the [Pt(en)(acv)2]SO4·2.5H2O salt. X-ray diffraction studies have shown that the guanine moieties have a Head-to-Head conformation (HH) with the two C(8)-H vectors pointing towards the same side with respect to the platinum coordination plane; the dihedral angles formed by the purine planes and the coordination plane are 58.3(2)° and 41.5(2)°, respectively. There is a correlation between the canting of the purine bases (right or left handed) and the puckering of the ethylenediamine chelate ring (δ or λ). Right-handed canting is associated with λ puckering of the chelate ring and left-handed canting with δ puckering of the chelate ring, so that in both cases one of the two purines forms an O(6)···H−N hydrogen bond with a “quasi equatorial” NH of the ethylenediamine. The “quasi equatorial” character of the NH appears to be a common feature for intramolecular H-bonds between guanine bases and cis-amines. The purine not involved in the H-bond has the six-membered ring portion leaning towards the cis purine rather than towards the cis amine and may give rise to a weak O(6)···Pt attractive interaction. Such an interaction is supported by density functional (DFT) molecular orbital calculations carried out on the model systems [Pt(NH3)4(CH2O)]2+ and Head-to-Tailcis-[Pt(NH3)2{N(=CH2)−C(=CH2)−C(=O)−NH2}2]2+. The exocyclic chains linked to N(9) each have two different orientations, and all four are stretched away from the metal centre as well as from the purine N(1)H and N(2)H2 protons. The acv and the en NH protons are instead involved in H-bonds with the sulfate anion.

Interaction of Adenosine 5′-Triphosphate with Metal Ions X-ray Structure of Ternary Complexes Containing Mg(II), Ca(II), Mn(II), Co(II), ATP and 2,2′ -Dipyridylamine

The X-ray structures of the isomorphous Mg2+, Ca2+, Mn2+ and Co2+ complexes of ATP have been determined. The metal ions are wrapped in hexa-coordination by the alpha, beta and gamma phosphate groups of two ATP molecules thus blocking the interaction of the metal ions with the adenine base. A second metal ion which is fully hydrated, M(H2O)2+(6), is engaged in a strong hydrogen bond with the gamma phosphate group of ATP and suggests a possible step in facilitating the cleavage between the beta and gamma phosphates in phosphoryl transfer reactions.