Maria Rosaria Plutino

Drug Delivery with a Calixpyrrole–trans-Pt(II) Complex

A meso-p-nitroaniline-calix[4]pyrrole derivative trans-coordinated to a Pt(II) center was synthesized and its structure solved by X-ray analysis. Adenosine monophosphate (AMP) was used as a model compound to evaluate the potential for the assisted delivery of the metal to the DNA nucleobases via the phosphate anion-binding properties of the calix[4]pyrrole unit. An NMR investigation of the kinetics of AMP complexation in the absence of an H-bonding competing solvent (dry CD(3)CN) was consistent with this hypothesis, but we could not detect the interaction of the calix[4]pyrrole with phosphate in the presence of water. However, in vitro tests of the new trans-calixpyrrole-Pt(II) complex on different cancer cell lines indicate a cytotoxic activity that is unquestionably derived from the coexistence of both the trans-Pt(II) fragment and the calix[4]pyrrole unit.

Structural properties of the metallointercalator cationic complex (2,2′:6′,2″-terpyridine)methylplatinum(II) ion

Abstract The complex [Pt(tpy)(Me)]+(BPh4)− (tpy=2,2′:6′,2′′-terpyridine) crystallizes in the triclinic space group P1 with a=13.463(2) A, b=13.618(3) A, c=20.151(4) A, α=73.59(2), β=74.56(3), γ=65.82(2)° and Z=4. The final conventional R factor is 0.035. In the unit cell a couple of weakly interacting dimers are formed by stack of two [Pt(tpy)(Me)]+ cations in a head-to-tail fashion with intermolecular Pt⋯Pt distances of 4.437(1) and 4.931(1) A, respectively. The absorption spectra of [Pt(tpy)(Me)]+(BPh4)− in acetonitrile show bands assigned to π–π* and to MLCT transitions. The analysis of the dependence of the spectra on complex concentration gives a fairly low value for the dimerization equilibrium constant (Kd=180±52 M−1 at 298 K). These fluid solutions are not emissive. The room-temperature solid-state emission spectra of the salts [Pt(tpy)(Me)]X are strongly dependent on the counterion (X=BPh4−, Cl−, PF6−, ClO4−, CF3SO3−). The cationic complex shows a considerable stability upon acidification and carbonilation in water.

Ring Closure Kinetics of Bidentate Hemilabile P,N and P,S Ligands on a Platinum(II) Complex

Complexes of the type cis-[PtPh2(CO)(η1-P−N)] and cis-[PtPh2(CO)(η1-P−S)], where bidentate phosphorus−nitrogen and phosphorus−sulfur ligands are bound to the metal centre in a monodentate fashion [P−N = Ph2PC5H4N (Ph2PPy), Ph2P(CH2)2C5H4N (ppye), Ph2P(o-C6H4)NMe2 (PNMe2), Ph2P(CH2)nNMe2 (n = 2, 3, i.e., peNMe2 and ppNMe2) and P−S = Ph2P(CH2)2SEt (P−SEt), Ph2P(CH2)nSPh (n = 1, 2, i.e., P−CH2SPh and P−SPh)], were prepared in situ by reaction of the hybrid ligands with cis-[PtPh2(CO)(SEt2)]. In each case, the first observed process was the fast substitution of diethyl sulfide by the phosphanyl group leading to the monosubstituted ring-open cis-[PtPh2(CO)(η1-P−X)] (X = N or S) complexes, which were characterised in solution by 1H and 31P{1H} NMR spectroscopy. These initially formed species undergo a slow ring closure process with extrusion of carbon monoxide and formation of the chelate [PtPh2(P−X)] products, except in the case of the short-bite Ph2PPy and P−CH2SPh ligands and of ppNMe2, where ring closure was not observed. The chelate complexes were isolated as solids from the reaction of the ligands with cis-[PtPh2(Me2SO)2]. A single-crystal X-ray diffractometric study of cis-[PtPh2(P−SEt)] (18) was performed. The crystal packing showed linear chains originated by weak intermolecular Pt···H−C hydrogen bonding interactions. The chelation kinetics of P−X in the cis-[PtPh2(CO)(η1-P−X)] complexes have been monitored in [D]chloroform by 1H and 31P{1H} NMR. The rates of ring closure were found to be strongly dependent on the nature (S or N) and steric hindrance of the chelating end of the monocoordinated bidentate P−X ligand, and on the size of the ring formed. In contrast, ring size plays a negligible role, if any, in the dechelation reactions of cis-[PtPh2(S−S)] [S−S = 1,2-bis(phenylthio)ethane, dpte and 1,3-bis(phenylthio)propane, dptp] using diphosphanes (dppm and dppp) as reagents. These kinetic data, together with those of previous work, give useful insight into the factors controlling cyclisation reactions and the stability of the rings in square planar platinum(II) complexes.

Ligand exchange and substitution at platinum(II) complexes: evidence for a dissociative mechanism

Abstract Square-planar complexes of the type cis -[Pt(Me) 2 (Me 2 SO)(PR 3 )] ( 1 – 6 ) where PR 3 represents a series of isosteric tertiary phosphanes [P( 4 -MeOC 6 H 4 ) 3 , P( 4 -MeC 6 H 4 ) 3 , P(C 6 H 5 ) 3, P( 4 -FC 6 H 4 ) 3 , P( 4 -ClC 6 H 4 ) 3 , P( 4 -CF 3 C 6 H 4 ) 3 ] have been synthesised and fully characterised through elemental analysis, 1 H and 31 P{ 1 H} NMR. The coupling constants 1 J PtP with the isotopically abundant 195 Pt (33%, I =1/2) of 1 – 6 , as those of the pyridine cis -[Pt(Me) 2 (py)(PR 3 )] derivatives ( 7 – 12 ), show linear dependencies on the basicity of the coordinated phosphane. The rates of dimethyl sulfoxide exchange for all the complexes have been measured at relatively low temperatures by 1 H NMR isotopic labelling experiments with deuterated chloroform as the solvent. Pyridine for dimethyl sulfoxide substitution has been studied at higher temperatures through conventional spectrophotometric techniques. The rates of both processes show no dependence on ligand concentration, for each complex the value of the rate of ligand substitution is in reasonable agreement with the value of the rate of ligand exchange at the same temperature, and the kinetics are characterised by largely positive entropies of activation. There is a compensation-effect between Δ H ‡ and Δ S ‡ , i.e., a greater Δ H ‡ is accompanied by a larger positive Δ S ‡ , indicating that all complexes react via the same mechanism. The basicity of the phosphane does not affect significantly the reaction rates. The general pattern of behaviour indicates that the rate determining step for substitution is the dissociation of the sulfoxide ligand and the formation of a three-coordinated [Pt(Me) 2 (PR 3 )] uncharged intermediate.

Mechanistic insight into protonolysis and cis-trans isomerization of benzylplatinum(II) complexes assisted by weak ligand-to-metal interactions. A combined kinetic and DFT study.

Low-temperature NMR measurements showed that protonolysis and deuterolysis by H(D)X acids on meta- and para-substituted dibenzylplatinum(II) complexes cis-[Pt(CH(2)Ar)(2)(PEt(3))(2)] (Ar = C(6)H(4)Y(-); Y = 4-Me, 1a; 3-Me, 1b; H, 1c; 4-F, 1d; 3-F, 1e; 4-Cl, 1f; 3-Cl, 1g; 3-CF(3), 1h) in CD(3)OD leads directly to the formation of trans-[Pt(CH(2)Ar)(PEt(3))(2)(CD(3)OD)]X (4a-4h) and toluene derivatives. The reaction obeys the rate law k(obsd) = k(H)[H(+)]. For CH(2)Ar = CH(2)C(6)H(5)(-), k(H) = 176 ± 3 M(-1) s(-1) and k(D) = 185 ± 5 M(-1) s(-1) at 298.2 K, ΔH(double dagger) = 46 ± 1 kJ mol(-1) and ΔS(double dagger) = -47 ± 1 J K(-1) mol(-1). In contrast, in acetonitrile-d(3), three subsequent stages can be distinguished, at different temperature ranges: (i) instantaneous formation of new benzylhydridoplatinum(IV) complexes cis-[Pt(CH(2)Ar)(2)(H)(CD(3)CN)(PEt(3))(2)]X (2a-2h, at 230 K), (ii) reductive elimination of 2a-2h to yield cis-[Pt(CH(2)Ar)(CD(3)CN)(PEt(3))(2)]X (3a-3h) and toluene derivatives (in the range 230-255 K), and finally (iii) spontaneous isomerization of the cis cationic solvento species to the corresponding trans isomers (4a-4h, in the range 260-280 K). All compounds were detected and fully characterized through their (1)H and (31)P{(1)H} NMR spectra. Kinetics monitored by (1)H and (31)P{(1)H} NMR and isotopic scrambling experiments on cis-[Pt(CH(2)Ar)(2)(H)(CD(3)CN)(PEt(3))(2)]X gave some insight onto the mechanism of reductive elimination of 2a-2h. Systematic kinetics of isomerization of 3a-3h were followed in the temperature range 285-320 K by stopped-flow techniques. The process goes, as expected, through the relatively slow dissociative loss of the weakly bonded solvent molecule and interconversion of two geometrically distinct T-shaped three-coordinate intermediates. The dissociation energy depends upon the solvent-coordinating ability. DFT optimization reveals that along the energy profile the cis-like [Pt(CH(2)Ar)(PMe(3))(2)](+) intermediate is strongly stabilized by a Pt···η(2)-C1-C(ipso) bond between the unsaturated metal and benzyl carbons. The value of the ensuing stabilization energy was estimated by computational data to be greater than that found for similar β-agostic Pt···η(2)-CH interactions with alkyl groups containing β-hydrogens. An observed consequence of the strong stabilization of cis-[Pt(η(2)-CH(2)Ar)(PMe(3))(2)](+) is the remarkable acceleration of the rate of isomerization, greater than that produced by the so-called β-hydrogen kinetic effect. Kinetic and DFT data concur to indicate that electron donation by substituents on the benzyl ring leads to further stabilization of the cis-[Pt(η(2)-CH(2)Ar)(PMe(3))(2)](+) cationic species.

REACTIVITY OF TERTIARY PHOSPHINES TOWARD A CYCLOMETALLATED PLATINUM(II) COMPLEX : EVALUATION OF STERIC AND ELECTRONIC CONTRIBUTIONS

Abstract An extended series of phosphines (L), having widely different steric and electronic properties, was used to study the kinetics of chloride substitution on the cyclometallated complex [Pt(N-N-C(Cl] (N-N-CH=6-(1-methylbenzyl)-2,2′-bipyridine). The final cationic products [Pt(N-N-C)(L)]+ were fully characterised by 1H and 31P{1H} NMR spectroscopy in CDCl3 solution. The values of the 1J(PtP) coupling constants for these complexes showed interesting dependencies upon the size and the σ-donor ability of the ligands. The reaction, in dichloromethane as solvent at 298.2 K, takes place by way of a direct bimolecular attack of the ligand on the substrate, with no evidence of a significant solvent contribution. The order of reactivity is that expected on the basis of the nucleophilic reactivity constants (nptp), derived from previous studies. The values of the second-order rate constants (k2 M−1 s−1) can be resolved quantitatively into steric, electronic and aryl contributions of the phosphine ligands, by use of a four-parameter equation log k2 = α+β(pKn′)+γ(θ)+δ(Ear) where pKa′ measures the σ-donor ability of the phosphines, θ (Tolmans cone angle) is a measure of the size of the P-donor ligand, and Ear is related to the number of aryl groups attached to the ligand phosphorus atom. This is the first reported example of an aryl effect contributing to the nucleophilicity of phosphines as entering ligands on square-planar complexes. No steric threshold is observed. Steric and electronic profiles for the substitution process can be plotted showing the dependence of rates on the size and the σ-donor ability of the phosphines. The sensitivity of the rates to pAa′ is significant (β = 0.20 ± 0.04) and this is related to the structural properties of the substrate.

Chelate ring closure kinetics in the reaction of a platinum(II) complex with diphosphines

The reactions of PPh2(CH2)nPPh2 (n=1–4, P-P) and PPh3 with cis- [PtPh2(CO)(SEt2)] have been studied in chloroform-d by 1H- and 31P{1H}-n.m.r. When n=2 or␣3 the first product observed is [PtPh2(P-P)], where the diphosphine is acting as a chelate, and ring closure is fast compared to the rate of entry of the phosphine into the complex. When n=1 or 4 the first observed product is [PtPh2(CO)(P-P)], with P-P acting as monodentate, and the second observable stage of reaction is ring closure. The rate constants and activation parameters kc at 298K (s−1), ΔH‡ (kJmol−1), ΔS‡ (JK−1mol−1) for the dppm and dppb complexes are 0.0198, 88±1, +17±3; and 0.00273, 38±2, −169±6, respectively. The formation of the large seven-membered ring is a “strainless” process, comparable to the intermolecular process. The increase in the enthalpy of activation as ring size decreases is due to ring strain and inter-atomic repulsions associated to the conformation of the four-membered chelate ring.

Direct evidence for a rate determining chelate ring closure mechanism in the reaction of a platinum(II) complex with bidentate nitrogen ligands

Abstract A spectrophotometric and 1 H NMR kinetic study of the reactions of cis -[PtPh 2 (CO)(SEt 2 )] with an extended series of dinitrogen chelating ligands (N-N) of widely different steric and electronic properties has been carried out in dichloromethane solution. The contemporary presence in the starting substrate of a labile (SEt 2 ) and a relatively inert (CO) ligand in trans to firmly bonded phenyl groups makes it possible to distinguish three different reactivity patterns, according to the nature of the bidentate ligands used. Relatively stable open-ring species of the type cis -[PtPh 2 (CO)(N-N)] were isolated with the long chain ligand 1,4-diaminobutane and with N -phenyl-1,2-diaminoethane in which one of the two nitrogens exhibits very low basicity and considerable encumbrance. For the other dinitrogen ligands, the relative magnitude of the rates of attack at the metal and of ring closure dictates whether the chelate formation is seen as a simple conversion of the starting complex into the final chelate [PtPh 2 (N-N)] or as a two stage process with evidence for the formation of an open-ring species. With rigid or highly sterically hindered ligands such as 2,2′-dipyridyl, 1,10-phenanthroline, dicyclohexylethylenediimine or N , N , N ′, N ′-tetramethylethylenediamine a single stage process from the starting complex to the final chelate compound was observed. The rate determining step is thought to involve slow dissociation of SEt 2 from the complex followed by fast ring closing. With 1,2-diaminoethane, 1,3-diaminopropane, 2-aminomethylpyridine, 2-aminoethylpyridine, 2,2′-dipyridylamine and 2,2′-dipyridylsulfide a slow ring closure of the open-ring complex follows the fast entry of the first end of the ligand. The substrate shows a remarkable selectivity between the two nucleophilic ends of an unsymmetrical bidentate ligand with a clear preference for the most basic and the less hindered end. Open-ring reaction intermediates cis -[PtPh 2 (CO)(N-N)] were characterised in solution by their IR, 1 H and 13 C NMR spectra and their spectroscopic characteristics are compared to those of the parent amine and phosphine compounds. The final chelate compounds [PtPh 2 (N-N)] were either isolated as solids or characterised in solution.

Sol-gel 3-glycidoxypropyltriethoxysilane finishing on different fabrics: The role of precursor concentration and catalyst on the textile performances and cytotoxic activity

In this paper, the influence of 3-glycidoxypropyltriethoxysilane (GPTES) based organic-inorganic coatings on the properties of treated textile fabrics was studied. All experimental results were deeply analyzed and thereafter correlated with the employed silica precursor concentration and with the presence of the BF3OEt2 (Boron trifluoride diethyl etherate), used as epoxy ring opening catalyst. SEM analysis, FT-IR spectroscopy, X-ray Photoelectron Spectroscopy (XPS), thermogravimetric analysis (TGA) and washing fastness tests of the sol-gel treated cotton fabric samples were firstly exploited in order to characterize the morphological and structural features of the achieved coatings. Finally, the influence of the resulting nanohybrid coatings was explored in terms of abrasion resistance, tensile strength and elongation properties of treated cotton, polyester and silk fabrics. The catalyst amounts seem to strongly improve the formation of coatings, but still they do not influence the wear resistance of treated textile fabrics to the same extent. Indeed, it was found that increasing catalyst/GPTES ratio leads to a more cross linked inorganic 3D-network. GPTES itself was not found to affect the bulk properties of the selected textile and the resulting coatings were not so rigid to hardly modify the mechanical properties of the treated samples. Finally, it is worth mentioning that in all case the obtained 3-glycidoxypropyltriethoxysilane-based chemical finishing have shown no cytotoxic effects on human skin cells.

New insights for the use of quercetin analogs in cancer treatment

AIMnQuercetin (Q1) is a flavonoid widely present in plants and endowed with several pharmacological properties mostly due to its antioxidant potential. Q1 shows anticancer activity and could be useful in cancer prevention. On the other hand, Q1 is poorly soluble in water and unstable in physiological systems, and its bioavailability is very low.nnnMETHODSnA small set of Q1 derivatives (Q2-Q9) has been synthesized following opportunely modified chemical procedures previously reported. Anticancer activity has been evaluated by MTT assay. Human Topoisomerases inhibition has been performed by direct enzymatic assays. Apoptosis has been evaluated by TUNEL assay. ROS production and scavenging activity have been determined by immunofluorescence.nnnRESULTSnThe anticancer profile of a small library of Q1 analogues, in which the OH groups were all or partially replaced with hydrophobic functional groups, has been evaluated. Two of the studied compounds demonstrated an interesting cytotoxic profile in two breast cancer models showing the capability to inhibit human Topoisomerases.nnnCONCLUSIONnThe studied compounds represent suitable leads for the development of innovative anticancer drugs. [Formula: see text].