Francesco P. Fanizzi

Four-versus five-co-ordination in palladium(II) and platinum(II) complexes containing 2,9-dimethyl-1,10-phenanthroline (dmphen). Crystal structures of [PtCl2(dmphen)] and [Pt(η2-C2H4)Cl2(dmphen)]

The four-co-ordinate complexes with 2,9-dimethyl-1,10-phenanthroline [MX2(dmphen)](M = Pt, X2= Cl21, ClBr 2, Br23, or I24; M = Pd, X2= Cl25, ClBr 6, Br27 or I28) have been prepared for the first time. The crystal structure of [PtCl2(dmphen)]1, has been determined by X-ray diffraction methods. The complex has a square-planar geometry around the metal and the steric interaction between the methyl groups of dmphen and the cis chlorine ligands causes a narrowing of the Cl–Pt–Cl angle [85.8(1)°], a displacement of the two chlorine atoms from the N–Pt–N plane [0.286(4) and 0.372(4)A respectively], a bending of the phenanthroline (ca. 17°), and a rotation of the overall ligand plane with respect to the platinum co-ordination plane (ca. 28°). All interligand steric constraints are released in the five-co-ordinate complexes obtained from the four-co-ordinate species by direct uptake of olefins, [M(η2-olefin)X2(dmphen)](olefin = ethylene, a; propene, b; but-1-ene, c; cis-but-2-ene, d; trans-but-2-ene, e; or styrene, f). The structure of [Pt(η2-C2H4)Cl2(dmphen)]1a, has been determined by X-ray diffraction methods. The complex has a trigonal-bipyramidal geometry around the Pt atom; the phenanthroline ligand and the olefinic carbons occupy the equatorial plane while the two chlorine atoms are in axial positions. Bond distances and angles are similar to those found in other five-co-ordinate complexes of platinum(II). The rate of uptake of olefin by the four-co-ordinate complexes, the equilibrium constant (Kf) of the formation reaction [MX2(dmphen)]+ olefin ⇌[M(η2-olefin)X2(dmphen)], and the activation energy for olefin rotation in the five-co-ordinate complexes have been measured for different olefins and halogen ions. The uptake, in chloroform, takes place in a one-step process and the reaction rate increases by a factor of 104 going from the chloro 1 to the iodo 4 complex. The equilibrium constant for the formation reaction decreases by a factor of 103 going from ethylene to trans-but-2-ene and increases by a factor of 102 going from the chloro 1 to the iodo 4 species. The activation energy for olefin rotation (ethylene and propene)(ca. 20.5 kcal mol–1) is higher than any reported value for platinum complexes and does not appear to depend upon the nature of the halogen atoms.

Phytochemical analysis of a herbal tea from Artemisia annua L.

Strategies to control diffusion of malaria needs to account for the increase of resistance of the parasite to the conventional antimalarial drugs. It has been proposed that a traditional aqueous preparation from Artemisia annua, with a low content of the active compound, artemisinin, may reduce the risk of resistance of the protozoa and be relatively more effective in the treatment of the disease. The solubility properties of the molecule have been the matter of concern about the therapeutic usefulness of herbal teas from A. annua. The present study aimed at analysing the chemical profile of a tea infusion from A. annua. Tea from A. annua was prepared through infusion of the plant aerial parts in water for 1, 24 and 48 h. Content of artemisinin was determined by HPLC-ELSD. Overall chemical characterization of the extracts was carried out by a combination of metabolomic techniques. The artemisinin content varied only slightly in the three different extracts (about 0.12%). A series of mono-caffeoyl- and mono-feruloyl-quinic acids, di-caffeoyl- and di-feruloyl-quinic acids was identified as main components of the tea infusion, together with some flavonoids. Reconstitution of the same extracts in less polar or apolar solvents resulted in a different composition with no phenolics and a much lower concentration of artemisinin.

Steric constraints and addition reactions in platinum(II) complexes containing 2,9-dimethyl-1,10-phenanthroline (Me2-phen). X-ray crystal structures of [PtBr2(Me2-phen)] and [PtI2(Me2-phen)]

Abstract [PtX 2 (Me 2 -phen)] complexes (X  Cl ( 1 ), Br ( 2 ), I ( 3 ); Me 2 -phen=2,9-dimethyl1,10-penanthroline) react with dimethylsulfoxide, dimethylsulfide and nitrosobenzene to give the addition products [PtX 2 (Me 2 -phen)(L)] (L  DMS, 1–3a ; DMSO, 1–3b ; PhNO, 1–3c ) containing mono-coordinated Me 2 -phen. The equilibrium constants for the addition reactions ( K f ) have been determined by 1 H NMR spectroscopy and found to be strongly dependent upon the bulkiness of the halogen atoms; log K f increases linearly with the van der Waals radius of the halogens. The crystal structures of the complexes [PtBr 2 (Me 2 -phen ( 2 ) and [PtI 2 (Me 2 -phen)] ( 3 ) have been determined by X-ray diffraction methods. Crystal data for 2 : monoclinic, space group P 2 1 / n , a = 12.155(4), b = 7.933(2), c = 14.522(2) A , β = 93.74(2)°, Z = 4, R = 0.046 . Crystal data for 3 : monoclinic, space group P 2 1 / n , a = 12.542(2), b = 7.957(1), c = 14.976(3) A , β = 94.49(3)°, Z = 4, R = 0.036 . The distortions in the square-planar coordination geometry are compared to those found for the analogous chloro species and correlated to differences in reactivity.

Sublethal concentrations of the platinum(II) complex [Pt(O,O′‐acac)(γ‐acac)(DMS)] alter the motility and induce anoikis in MCF‐7 cells

Background and purpose:  We showed previously that a new Pt(II) complex ([Pt(O,O′‐acac)(γ‐acac)(DMS)]) exerted high and fast apoptotic processes in MCF‐7 cells. The objective of this study was to investigate the hypothesis that [Pt(O,O′‐acac)(γ‐acac)(DMS)] is also able to exert anoikis and alter the migration ability of MCF‐7 cells, and to show some of the signalling events leading to these alterations.

Water-soluble organometallic analogues of oxaliplatin with cytotoxic and anticlonogenic activity.

that determine the antitumor activity of platinum complexes have been outlined, such as the neutrality of the compounds. 7] For this reason, the majority of cisplatin analogues that have been tested for anticancer activity are neutral compounds of the type cis-[PtA2X2] [8, 9] and cis-[PtA2X4], [10–13] in which A is an amine ligand, and X is an anionic leaving group. Moreover, it was found that the effectiveness of cisplatin and its analogues could be greatly improved by substituting the labile chlorido ligands with other leaving groups. This approach led to the development of second-generation platinum drugs such as carboplatin, cis-[diammine(1,1-cyclobutanedicarboxylato-O,O’)platinum(II)] and nedaplatin, cis-[diammineglycoloato-O,O’-platinum(II)] , which are now in clinical use. Members of a third generation of platinum-based drugs, characterized by replacement of both the ammonia carrier ligands and the chlorido leaving groups of cisplatin, are now undergoing clinical trials. Many such third-generation platinum drugs bear the (R,R)-1,2-diaminocyclohexane (R,R-chxn) carrier ligand, and a successful example is oxaliplatin, [Pt(R,R-chxn)(oxalatoO,O’)] (Figure 1), which was recently approved for clinical use. Importantly, oxaliplatin is currently the only clinically approved cisplatin analogue that has shown potential for use in cisplatin-resistant tumors under preclinical evaluations. The discovery of antitumor and/or mutagenic activity in cationic Pt complexes has resulted from the pursuit of pharmacological advantages by violating some of the classical structure–activity relationships of platinum-based drugs. This idea has recently gained strength, as favorable interactions between aquated cationic species and human organic cation transporters (hOCT) have demonstrated an improvement in the antitumor activity of cisplatin and oxaliplatin. In this context, our interest has been focused on the unstable cationic complexes of the type [PtCl(h-C2H4)(N N)] , in which N N is a dinitrogen ligand. In particular, we synthesized new cationic complexes of the type [PtCl(h-C2H4)(R,R-chxn)] + (1) (Figure 1) and [PtCl(h-C2H4)(S,S-chxn)] + (2), organometallic analogues of oxaliplatin and hOCT substrates, and determined their cytotoxicity in terms of potential antitumor activity. In aqueous solution, complexes 1 and 2 are readily hydrolyzed into well-known antitumor-active oxaliplatin metabolites (i.e. , [PtCl2(R,R-chxn)] (3), [PtCl(H2O)(R,R-chxn)] + (5), and [Pt(H2O)2(R,R-chxn)] + (7) ; Figure 1) or the corresponding enantiomers (i.e. , [PtCl2(S,S-chxn)] (4), [PtCl(H2O)(S,S-chxn)] + (6), and [Pt(H2O)2(S,S-chxn)] 2 + (8)). Compounds 1 and 2 were synthesized by a method similar to that previously reported by Maresca and co-workers by allowing the lithium derivative of Zeise’s salt, Li[PtCl3(h -C2H4)] , to react with the appropriate diamine in methanol at low temperature (0 8C). Under these conditions, all reactants are soluble in the reaction medium, and products 1 and 2 can be obtained as white precipitates and isolated in high yields (~90 %) within a few hours (~3 h). The H NMR spectra of the enantiomeric complexes 1 and 2 in D2O show coupled multiplets (COSY) in the range of 1.2–2.7 ppm. These are attributed to the aliphatic protons of the coordinated cyclohexanediamine. A sharp singlet at 4.71 ppm flanked by two satellites due to coupling with the Pt nucleus (J(Pt H) = 56 Hz) can be assigned to the h-olefin on the basis of the olefin H chemical shift range observed for analogous cationic compounds. 44–47] Moreover, the presence of only one signal for all the olefin protons at room temperature in D2O indicates that the rotation around the platinum–olefin bond is fast on the NMR time Figure 1. Comparison of the structures of cisplatin, oxaliplatin, and [PtCl(hC2H4)(R,R-chxn)] + (1), and the hydrolysis products formed from both 1 and oxaliplatin: [PtCl2(R,R-chxn)] (3), [PtCl(H2O)(R,R-chxn)] + (5), and [Pt(H2O)2(R,Rchxn)] + (7) ; the latter of which are responsible for the antitumor activity of oxaliplatin.

Modulation of properties in analogues of Zeise's anion on changing the ligand trans to ethene. X-Ray crystal structures of trans-[PtCl2(OH)(η2-C2H4)]− and trans-[PtCl2(η1-CH2NO2)(η2-C2H4)]−

To get further insight in the reaction of nucleophilic substitution upon changing the ligand trans to a η(2)-olefin, the reactivity of some monoanionic platinum(II) complexes (trans-[PtCl(2)X(η(2)-C(2)H(4))](-), X = Cl(-), 1, OH(-), 2, and CH(2)NO(2)(-), 3) towards pyridines with different steric hindrance (py, 4-Mepy, and 2,6-Me(2)py) has been tested. All crystallographic (2 and 3 reported for the first time) and spectroscopic data are in accord with a platinum-olefin interaction decreasing in the order 2 > 1 > 3, paralleling the decreasing electronegativity of the donor atom (O > Cl > C). Not only the platinum-olefin bond but also the bond between platinum and the ligand trans to the olefin appear to be strongest in 2 (Pt-O distance at the lower limit for this type of bond). In the reaction with py, the ligand trans to the olefin is displaced in 1 and 2. Moreover the reaction is in equilibrium in the case of sterically hindered 2,6-Me(2)py, the equilibrium being shifted moderately or prevalently toward the reagents in the case of 1 and 2, respectively. In the case of 3, the reaction with pyridines leads to substitution of the olefin instead of the carbanion. This is in accord with the observation that carbanions strongly weaken the trans Pt-olefin bond.

Boat versus chair conformation in N-methyl- and N,N′-dimethylpiperazine platinum(II) complexes studied by X-ray analysis. A rare example of metal chelate piperazine: cis-[PtCl2(Me2ppz)] Part I

Abstract The square-planar platinum(II) complexes [PtCl3(H2Meppz)] (1), trans-[PtCl2(H2Meppz)2]2+2Cl−·2H2O (2), and cis-[PtCl2-(Me2ppz)] (3) (HMeppz=N-methylpiperazine, Me2ppz=N,N′-dimethylpiperazine) have been synthesized and characterized by IR, 1H NMR and X-ray diffraction analysis. In complexes 1 and 2 the hexaatomic ring of N-methylpiperazine adopts a chair conformation with the NCH3 and NPt bonds in equatorial position and the two NH bonds in axial position. The coordination to platinum(II) always occurs through the unmethylated nitrogen atom while the methylated nitrogen is protonated, producing a positive charge on the outside surface of the molecule. In addition, complex 1 is present as an amphilonic species since N+HCH3 is balanced by -PtCl3−. In contrast, in complex 3N,N′-dimethylpiperazine adopts a boat conformation stabilized by chelation of the nitrogen donors to platinum(II) so that complex 3 represents a rare example of piperazine chelated to platinum(II). An attempt is also made to correlate the biological activity of chair and boat piperazine complexes with their structural parameters.

Five-coordinate platinum (II) alkyne complexes: synthesis, ab initio calculations and crystal and molecular structure of [PtI2(Me2phen)η2PhCCPh]·CHCl3

Abstract [PtX2(Me2phen)] complexes (1)Me2phen = 2,9-dimethyl-1,10-phenanthroline; X = Br, Iy; I, Iz), having a highly distorted square-planar geometry, undergo alkynes uptake in chlorinated solvents to give the five-coordinate trigonal-bipyramidal species [PtX2(Me2phen)-(alkyne)] (2) (alkyne = ethyne, a; propyne, b; 2-butyne, c; 1-pentyne, d; phenylacetylene, e; methylphenylacetylene, f; diphenylacetylene, g). The equilibrium constants for formation (K1) decrease in the order (1>Br) already observed for the analogous reaction with alkenes to give the [PtX2(Me2phen)(alkene)] complexes (3) (1>Br>Cl) although the differences in K1 values are much greater in the case of alkynes. In contrast, the number and bulk of substituents at the metal-coordinated carbons have practically no effect on the K1 of the alkyne complexes, while they greatly reduce the stability of the five-coordinate olefin compounds. Finally, the ΔG of activation for rotation around the Ptalkyne bond calculated by variable temperature 1H NMR spectroscopy (71.5 ± 0.8 kJ mol−1 for 2zb) is considerably smaller than the value found for the corresponding five-coordinate propene complex (86.2 ± 0.8 kJ mol−1). The crystal and molecular structure of the chloroform solvate of [PtI2(Me2phen(η3-PhCCPh)] (2zg·CHCl3) has been determined by X-ray diffraction methods. In the crystals two crystallographically independent complexes and chloroform molecules are present: space group Cmc2, a = 14.367(3), b = 15.529(3), c = 26.959(5)A, Z = 8, R = 0.0444. The average bending back of the phenyl groups with respect to the CC triple bond axis is 25(1)°. Spectroscopic and crystal data show that the conformation of the coordinated alkynes in these five-coordinate complexes is intermediate between those found for the trigonal Pt(0) and the square-planar Pt(II) alkyne complexes. Ab initio Hartfree-Fock calculations and constrained space orbital variation analyses have shown that in the five-coordinate species ethylene exhibits better σ-donating and π-accepting properties than acetylene.

trans-(η2-Alkene)(4′-alkyloxy-4-stilbazole)dichloroplatinum; low melting organometallic mesogens

trans-[PtCl2(CnH2n+1OC6H4CHCHC5H4N)(η2-CH2CHCmH2m+1)](2) form stable smectic A mesophases on heating (for n7, m7; n8, m5; n9, m2; and n11, m0); melting temperatures below 50 °C can easily be achieved.

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.