Cyclometallated platinum(IV) compounds as promising antitumour agents

Since the discovery of the anticancer activity of cisplatin by Rosenberg, extensive research has been carried out in order to develop new and more efficient platinum-containing drugs. In recent years, platinum(IV) compounds are appealing due to their inertness and high lipophilicity. On the other hand, interest in organometallic platinum compounds such as cyclometallated platinum(II) compounds is based on their stability and on the fact that the presence of a σ(Pt-C) bond increases the lability of the ligand in trans. In contrast, cyclometallated platinum(IV) compounds which combine the properties imparted by the presence of a platinum(IV) centre and a cyclometallated ligand have received little attention. The aim of this review is to present the results obtained so far for cyclometallated platinum(IV) compounds tested as antitumour agents. These compounds are prepared either by intramolecular oxidative addition from electron-rich platinum precursors and adequate ligands or by intermolecular oxidative addition to previously obtained cyclometallated platinum(II) compounds. Tridentate [C,N,N'] cyclometallated platinum(IV) compounds containing one, two or three carbon donor ligands exhibit a remarkable cytotoxicity, in most cases greater than that of cisplatin, against a panel of human cancer cell lines. In contrast, compounds containing a [C,N] platinacycle are less active. For the most active tridentate [C,N,N'] platinum(IV) compounds studies of DNA interaction, topoisomerase I, IIα, and cathepsin B inhibition and ROS generation are presented

Diarylplatinum(II) compounds as versatile metallating agents in the synthesis of cyclometallated platinum compounds with N-donor ligands

This review deals with the reactions of diarylplatinum(II) complexes with N-donor ligands to produce a variety of cycloplatinated compounds including endo-five-, endo-seven-, endo-six- or exo-five-membered platinacycles. The observed reactions result from a series of oxidative addition/reductive elimination processes taking place at platinum(II)/platinum(IV) species and involving C-X (X = H, Cl, Br) bond activation, arene elimination, and, in some cases, Caryl-Caryl bond formation

Química Organometálica

La química organometálica estudia los compuestos que contienen al menos un enlace entre un átomo de carbono de una molécula o un fragmento orgánico y un metal o, por extensión, un elemento más electropositivo que el carbono. La química organometálica constituye un área de la química extraordinariamente amplia e interdisciplinaria ya que involucra aspectos no sólo de química orgánica y química inorgánica, sino también de catálisis, ciencia de materiales o bioinorgánica, disciplinas en las que los compuestos organometálicos presentan importantes aplicaciones. El objetivo de este texto es que pueda ser utilizado en una asignatura optativa de grado de 3 créditos como se imparte actualmente en el Grado de Química de la Universidad de Barcelona, es decir intentar aportar una versión de la química organometálica que, aun siendo breve, permita recorrer los aspectos más básicos y esenciales de esta materia. El texto, como es habitual en química organometálica, se ha estructurado siguiendo la tabla periódica para los elementos de los bloques s y p, y según la naturaleza de los ligandos para los complejos de metales de transición. A continuación, se tratan brevemente los compuestos organometálicos del bloque f y finalmente, se comentan algunas de las aplicaciones de los compuestos organometálicos en catálisis

Kinetico-mechanistic studies on the formation of seven-membered [C,N]-platinacycles: the effect of methyl or fluoro substituents on the aryl ancillary ligands

The reactions of dinuclear [Pt2(4-RC6H4)4(μ-SEt2)2] (R = Me or F), or mononuclear [Pt(4-RC6H4)2(SMe2)2] (R = Me or H), platinum(II) compounds with imines of the general formula 2-X,6-YC6H3CH[double bond, length as m-dash]NCH2Ph (X = Br, Y = F; X = Cl, Y = F; X = Br, Y = H) produced seven-membered [C,N]-platinacycles. The reaction consists of the initial formation of cyclometallated platinum(IV) compounds followed by a three step process: reductive elimination, isomerisation of the resulting non-cyclometallated intermediate and a final cycloplatination process. Combined 1H NMR and UV-Vis kinetico-mechanistic studies indicated that the rate determining step of the process depends on the nature of the aryl-Pt ligand (phenyl, p-tolyl or p-fluorophenyl)

Biaryl formation in the synthesis of endo and exo-platinacycles

The reactions of cis-[Pt2(4-MeC6H4)4(m-SEt2)2] with bifunctional ligands ArCH NCH2(2-XC6H4) containing a C-X bond at the ortho positions of the benzyl ring (Ar = 4-ClC6H4, X = Br (1d); Ar = 2,4,6-(CH3)3C6H2, X = Br (1e); Ar = 2,4,6-(CH3)3C6H2, X = Cl (1f); Ar = 2-CH3C6H4, X = Br (1h); Ar = 2,6-F2C6H3, X = Br (1i)) in refluxing toluene were studied. Several types of platinum(II) cyclometallated compounds containing a biaryl linkage were obtained: i) endo-five-membered with a Pt-C(sp2) bond (2d, 2h), ii) endo-six-membered with a Pt-C(sp3) bond (2e, 2f), and iii) exo-five membered with a Pt-C(sp2) bond (2i). The formed biaryl linkage involves the metallated ring for 2i and the non-metallated ring for the endo-metallacycles. The reaction of compounds 2 with PPh3 produced the corresponding phosphine derivatives, some of which (3d, 3e, 3h and 3i) were characterised crystallographically. In addition, compound [PtBr{2-CH3C6H3C6H4CH NCH2(2-C6H4Br)}SEt2] (2c) containing a seven-membered endo-metallacycle was also obtained and characterised crystallographically

Mono and dinuclear bis(ortho-tolyl)platinum(II) compounds containing diethyl sulfide ligands: Synthesis, DFT studies and use as precursors in cycloplatination reactions

The synthesis of bis(ortho-tolyl)platinum(II) compounds containing diethyl sulfide ligands from [PtCl2(SEt2)2] and ortho-tolyl-lithium is presented. Formation of a dimer [Pt(4-MeC6H4)2(μ-SEt2)]2 is evidenced by 1H NMR and HR-MS-ESI(+) spectra and the monomer trans-anti-[Pt(2-MeC6H4)2(SEt2)2] is characterized by X-ray diffraction analyses. Theoretical studies indicate that dimerization of the most stable form of the monomer (cis-syn) to the most stable conformer of the dinuclear species (αββα) is favored (ΔE = −10.1 kJ/mol). The reactions of the dimer [Pt(4-MeC6H4)2(μ-SEt2)] with imine ligands 4-ClC6H4CH = NCH2CH2NMe2 and 2-Br,6-FC6H3CH = NCH2Ph gave a tridentate [C, N, N'] five-membered and a bidentate [C, N] seven-membered platinacycles, respectively

Platinum(II) compounds containing cyclometalated tridentate ligands: Synthesis, luminescence studies, and a selective fluoro for methoxy substitution

Two series of potentially tridentate ligands of formula ArCH=N(CH2)2NMe2 and ArCH=N(CH2)3NMe2 (Ar = C6H5, 2-FC6H4, 4-FC6H4, 2,3,4-F3C6H2) were used to prepare [C,N,N′]-cyclometalated platinum compounds containing either a chloro or a methyl ancillary ligand. The synthesis of the compounds [PtCl{Me2N(CH2)xN=CHR}] (3a−h), via the corresponding compounds [PtCl2{Me2N(CH2)xN=CHAr}] (2), requires drastic conditions and proceeds more easily for ligands derived from N,N-dimethylpropylenediamine (x = 3). Along the process, an unexpected selective nucleophilic substitution of a fluoro for a methoxy substituent took place at the aryl ring for ligands 2,3,4-F3C6H2CH=N(CH2)xNMe2. The syntheses of compounds [PtMe{Me2N(CH2)xN=CHR}] (4a−h) using [Pt2Me4(μ-SMe2)2] as a precursor took place for all ligands under relatively mild conditions. All compounds were fully characterized, including molecular structure determination for [PtCl{Me2N(CH2)3N=CH(4-FC6H3)}] (3b) and [PtCl{Me2N-(CH2)3N=CH(2-OMe,3,4-F2C6H)}] (3g). The absorption and emission spectra were also studied for the [C,N,N′]-cyclometalated platinum(II) compounds, and all of the compounds were emissive in the solid state and in dichloromethane solution at room temperature (compounds 3) or at 77 K (compounds 4). The size of the [N,N′]-chelate ring and the number and position of the substituents in the aryl ring modulate the intensity and the energy of the emission

Kinetico-mechanistic study on the reduction/complexation sequence of PtIV/PtII organometallic complexes by thiol-containing biological molecules

The kinetics of the reaction of [PtIV(4X-Cph,N,N')Cl(Y)2] complexes (2-X-Y) (X=Cl or F and Y=OH or Cl) with biological thiols (glutathione, cysteine, thiolactic acid) and methionine, has been monitored by UV-Vis spectrophotometry. The reactions have been followed at varying pHs and chloride concentrations (within the physiological range) and different temperatures and pressures. The bis-chlorido derivatives, 2-X-Cl, have been found to react with cysteine, glutathione and thiolactic acid, while the bis-hydroxido 2-X-OH derivatives are not reduced due to the high potential of the PtIV/PtII pair, as measured in aqueous solution. The lack of reactivity of methionine is related with its tioether nature preventing deprotonation of the S donor. In all remaining cases, two consecutive reaction steps have been found to occur. For cysteine the two steps can be kinetically resolved, the first step being neatly related to a PtIV to PtII reduction and the second step corresponding to the substitution of the remaining Cl− ligand by cysteine. The nature of the second step has been also confirmed by ESI-MS, as well as by the associative character of the activation parameters determined (low ΔH╪ and very negative ΔS╪ and ΔV╪). For glutathione and thiolactic acid, the rate and thermal and pressure activation parameters for the reduction step has been found similar to that obtained for the reaction with cysteine, but the substitution step could not be resolved kinetically. The substitution step, as measured from the reduced [PtII(4X-Cph,N,N')Cl] complex, is faster than the reduction process, and also much faster than that observed for the reaction with cysteine. In both cases the final product resulting for the reduction reactions corresponds thus to the final substituted complex as found for the reaction with cysteine

Reductive Elimination from Cyclometalated Platinum(IV) Complexes To Form Csp2−Csp3 Bonds and Subsequent Competition between Csp2−H and Csp3−H Bond Activation

Reductive elimination reactions of the cyclometalated platinum(IV) compounds [PtMe2Br{C6H4CH NCH2(4-ClC6H4)}L] (L = SMe2, PPh3) to form Csp3−Csp2 bonds, followed by either exclusive Csp2−H bond activation (L = SMe2) or competition between Csp2−H and Csp3−H bond activation (L = PPh3) are reported. Reductive elimination to form a C−Br bond is also reported.</p

Kinetico-mechanistic studies on intramolecular C-X bond activation (X = Br, Cl) of amino-imino ligands on Pt(II) compounds. Prevalence of a concerted mechanism in nonpolar, polar and ionic liquid media

The C–Br and C–Cl oxidative addition reactions of molecules containing a set of {N-amino,N-imino} chelating donor groups (2-X,6-YC6H4CHNCH2CH2NMe2, X = Br, Cl; Y = Cl, H) attached to a {PtII(Ar)2} (Ar = Ph, 4-MeC6H4) have been studied. The Pt(IV) complexes formed, [PtAr2X{2-YCC5H3CH═NCH2CH2NMe2}], containing a metalated tridentate [C,N,N′] ligand have been fully characterized by the usual techniques, and the X-ray crystal structure of the complex with Ar = 4-MeC6H4 and X =Y = Cl has been determined. Monitoring of the reactions at varying temperatures and pressures and in different solvents agrees with a mechanism that involves the preliminary decoordination of the N-amino donor from the ligand to produce a three-coordinated intermediate. This evolves, via a concerted C–X bond activation, to form a second pentacoordinated intermediate species that, on coordination of the N-amino donor, produces the final complex. The kinetico-mechanistic parameters measured indicate that the concerted character of the process is maintained from nonpolar (xylene and toluene) to polar (acetone) and ionic liquid ((Bmin(NTf2)) media. Furthermore, the ΔV⧧ values measured indicate that, for the (2,6-Cl)C6H3CH═NCH2CH2NMe2 ligand, the existence of hydrogen bonding within the metalating molecule is a determinant for the acceleration observed