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Platinum amidine complexes represent a new class of potential antitumor drugs that contain the imino moiety HN=C(sp(2)) bonded to the platinum center. They can be related to the iminoether derivatives, which were recently shown to be the first Pt(II) compounds with a trans configuration endowed with anticancer activity. The chemical and biological properties of platinum amidine complexes, and more generally of platinum imino derivatives, can be rationally modified through suitable synthetic procedures with the aim of improving their cytotoxicity and antitumor activity. The addition of protic nucleophiles to nitriles coordinated to platinum in various oxidation states can offer a wide variety of complexes with chemical, structural, and physical properties specifically tuned for a more efficacious biological response.

The reactivity of the cyclic primary aliphatic amines cyclopropyl-, cyclopentyl- and cyclohexylamine with cis- and trans-[PtCl 2 (NCMe) 2 ], under the same experimental conditions, is compared. Whereas cis-[PtCl 2 (NCMe) 2 ] yields the neutral diamidine compounds, the reactions with trans-[PtCl 2 (NCMe) 2 ] take place either with addition or substitution processes yielding the neutral diamidine complexes trans-[PtCl 2 (Amidine) 2 ], the monocationic trans-[PtCl(Amine)(Amidine) 2 ]Cl and the dicationic trans-[Pt(Amine) 2 (Amidine) 2 ]Cl 2 salts. An NMR and ESI study indicate that the main species formed is the monocationic trans-[PtCl(Amine)(Amidine) 2 ]Cl complex. The X-ray structure of trans{PtCl 2 {N(H)=C(CH 3 )NHCHCH 2 CH 2 } 2 ] is reported and its supramolecular arrangement is described.

The reaction of cis - and trans -[PtCl 2 (NCCH 2 Ph) 2 ] with a 5-fold excess of MeNH 2 and Me 2 NH in CH 2 Cl 2 at −10 °C affords in high yield the bis-amidine derivatives cis - and trans -[PtCl 2 { Z -N(H) C(NHMe)CH 2 Ph} 2 ] ( 1a , 2a ) and cis - and trans -[PtCl 2 { E -N(H) C(NMe 2 )CH 2 Ph} 2 ] ( 3a , 4a ), respectively. The complexes were characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques. The X-ray diffraction analysis was carried out for trans -[PtCl 2 { Z -N(H) C(NHMe)CH 2 Ph} 2 ] ( 2a ). Moreover, the in vitro cytotoxicity for the new derivatives was evaluated in a wide panel of human tumor cell lines.

In this paper it is reported the synthesis of the phosphonium salts [Ph 2 P(CH 2 ) n (Ph) 2 PCH 2 COOMe]Br ( n = 1 ( 1 ), 2 ( 2 )) and [Ph 2 P(CH 2 COOMe)(CH 2 ) n (Ph) 2 PCH 2 COOMe]Br 2 ( n = 3 ( 3 )) derived from the reactions of the diphosphines dppm, dppe and dppp with methyl bromoacetate. By reaction of the monophosphonium salt of dppm and dppe with the strong base Na[N(SiMe 3 ) 2 ] the corresponding carbonyl stabilized ylides Ph 2 P(CH 2 ) n (Ph) 2 P CHCOOMe ( n = 1 ( 4 ), 2 ( 5 )) were obtained. The Ph 2 P(CH 2 ) 2 (Ph) 2 P CHCOOMe ( 5 ) ylide was reacted with Pd(II) and Pt(II) substrates. From these reactions were isolated exclusively complexes in which the ylide was chelated to the metal through the free phosphine group and the ylidic carbon atom. A further reaction of the Ph 2 P(CH 2 ) 2 (Ph) 2 P CHCOOMe ( 5 ) ylide with 1.5 equiv. of Na[N(SiMe 3 ) 2 ] gives the bifunctionalized ketenylidene Ph 2 P(CH 2 ) 2 (Ph) 2 P C C O ( 6 ) system. This cumulenic ylide reacts with Pt(II) complexes to form a chelated derivative in which IR and NMR spectra suggest the breaking of the C C bond of the –C C O group.

The synthesis and spectroscopic characterization of the new hydroxo-bridged platinum(II) complex [P(μ-OH)(Pom-Pom)] 2 [BF 4 ] 2 ( 3 ) containing the electron-poor P–P ligand 1,2-bis(dimethoxyphosphino)ethane, (OMe) 2 PCH 2 CH 2 P(OMe) 2 (Pom-Pom), is reported. This compound has been used in the Baeyer–Villiger oxidation of a series of cyclic ketones using 35% hydrogen peroxide as oxidant. The reactions were performed at 25 °C and at 70 °C in chlorinated solvent/H 2 O biphasic system. The catalytic activity and the Lewis acidity of the complex ( 3 ) has been compared to other Pt(II) complexes previously investigated.

2-(Azidomethyl)phenyl isocyanide, 2-(CH2N3)C6H4NC (AziNC), coordinates to some cationic Pt(II) and Pd(II) species to afford isocyanide complexes of the type trans-[MCl(AziNC)(PPh3)2][BF4] (M=Pt, l; Pd, 2). AziNC is coordinated also in some neutral Pt(II) and Pd(II) species such as [MCl2(AziNC)2] (M=Pt, 3; Pd, 4) derived from the reactions of 2 equiv. of AziNC with [PtCl2(COD)] and [PdCl2(MeCN)2], respectively. Complexes 1 and 2 react with 1 equiv. of PPh3 affording the heterocyclic carbene complexes trans-[MCl{ (H)}(PPh3)2][BF4] (M=Pt, 5; Pd, 6). Complexes 3 and 4 react with 1 equiv. of PPh3 displacing the isocyanide with the formation of the complexes cis-[MCl2(AziNC)(PPh3)] (M=Pt, 7; Pd, 8). These latter ones react with 2 equiv. of PPh3 affording as the final products the cationic carbene species trans-[MCl{ (H)}(PPh3)2][Cl] (M=Pt, 9; Pd, 10). Complex 5 was also characterized by single crystal X-ray diffraction. The carbene complex is square-planar and the angle formed between the platinum square plane and the heterocyclic carbene ligand is 87.9(2)°. The C(1)–N(1) and C(1)–N(2) bond distances in the latter of 1.32(2) and 1.30(2) A, respectively, are short for a single bond and indicate extensive π-bonding between the nitrogen atoms and the carbene carbon.

The reactions of the nitrile complexes cis- and trans-[PtCl2(NCR)2] (R = Me, Et, CH2Ph, Ph) with an excess of ethanethiol, EtSH, in the presence of a catalytic amount of n-BuLi in tetrahydrofuran (THF), afforded in good yield the bis-imino thioether derivatives cis-[PtCl2{E-N(H)?C(SEt)R}2] (R = Me (1), Et (2), CH2Ph (3), Ph (4)) and trans-[PtCl2{E-N(H)?C(SEt)R}2] (R = Me (5), Et (6), CH2Ph (7), Ph (8)). The imino thioether ligands assumed the E configuration corresponding to a cis addition of the thiol to the nitrile triple bond. The spectroscopic properties of these complexes have been reported along with the molecular structures of 1, 2, and 7 as established by X-ray crystallography which indicated that these compounds exhibit square-planar coordination geometry around the platinum center. Four N-H···Cl intermolecular contacts (N-H···Cl ca. 2.5-2.7 Å) between each chlorine atom and the N-H proton of the imino thioether ligand gave rise to "dimers" Pt2Cl4L4 (L = imino thioether) formed by two PtCl2L2 units. The cytotoxic properties of these new platinum(II) complexes were evaluated against various human cancer cell lines. Among all derivatives, trans-[PtCl2{E-N(H)?C(SEt)CH2Ph}2] showed the greatest in vitro cytotoxic activity being able to decrease cancer cell viability roughly 3-fold more effectively than cisplatin.

Platinum amidine complexes represent a new class of potential antitumor drugs that contain the imino moiety HN=C(sp(2)) bonded to the platinum center. They can be related to the iminoether derivatives, which were recently shown to be the first Pt(II) compounds with a trans configuration endowed with anticancer activity. The chemical and biological properties of platinum amidine complexes, and more generally of platinum imino derivatives, can be rationally modified through suitable synthetic procedures with the aim of improving their cytotoxicity and antitumor activity. The addition of protic nucleophiles to nitriles coordinated to platinum in various oxidation states can offer a wide variety of complexes with chemical, structural, and physical properties specifically tuned for a more efficacious biological response.

The reactions of cyclopropylamine, cyclopentylamine, and cyclohexylamine with trans-[PtCl2(NCMe)(2)] afforded the bis-cationic complexes trans-[Pt(amine)(2)(Z-amidine)(2)](2+)[Cl-](2), 1-3, The solution behavior and biological activity have been studied in different solvents (DMSO, water, polyethylene glycol (PEG 400), and polyethylene glycol dimethyl ether (PEG-DM E 500)). The biological activity was strongly influenced by the cycloaliphatic amine ring size, with trans-[Pt(NH2CH(CH2)(4)CH2)(2){N(H)=C(CH3)-N(H)CH(CH2)(4)CH2}(2)](2+)[Cl-](2) (3) being the most active compound. Complex 3 overcame both cisplatin and MDR resistance, inducing cancer cell death through p53-mediated apoptosis. Alkaline single-cell gel electrophoresis experiments indicated direct DNA damage, reasonably attributable to DNA adducts of trans-[PtCl(amine)(Z-amidine)(2)][Cl] species, which can evolve to produce disruptive and nonrepairable lesions on DNA, thus leading to the drug-induced programmed cancer cell death. Preliminary in vivo antitumor studies on C57BL mice bearing Lewis lung carcinoma highlighted that complex 3 promoted a significant and dose-dependent tumor growth inhibition without adverse side effects.

A series of new platinum(II) bis-amidine derivatives were prepared by addition of primary and secondary aliphatic amines to coordinated nitrile ligands in cis- and trans-[PtCl2(NCR)2] (R=Me, Ph, CH2Ph). The bis-amidine complexes were tested for their in vitro cytotoxicity on a panel of various human cancer cell lines. The results indicated that the trans isomers are more effective than the cis species, and in particular the benzamidine complex trans-[PtCl2{E-N(H)=C(NMe2) Ph}2] was the most active derivative and was able to circumvent acquired cisplatin resistance, thus suggesting a different mechanism of action compared to that exhibited by cisplatin. New benzyliminoether derivatives cis- and trans-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] were also prepared by addition of MeOH to cis- and trans-[PtCl2(NCCH2Ph)2] and the cytotoxic properties were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. The complex cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] was significantly more potent than cisplatin against all tumour cell lines, including cisplatin-resistant ones. Moreover, the in vivo studies, performed on two transplantable tumour models, showed that cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] exhibited a marked activity against murine L1210 leukaemia and Lewis lung carcinoma in terms of survival prolongation and tumour growth inhibition, respectively.

A series of new platinum(II) amidine derivatives of the type cis -[PtCl 2 { Z -NH C(NHR)Me} 2 ] (R = cyclopropyl, 1 ; cyclopentyl, 2 ; cyclohexyl, 3 ) were prepared in high yield by addition of the corresponding cyclic aliphatic amine RNH 2 to the coordinated acetonitrile ligands in cis -[PtCl 2 (NCMe) 2 ]. The solution behaviour of 1 – 3 has been studied in DMSO, PEG 400 (polyethylene glycol) and PEG-DME 500 (polyethylene glycol dimethylether). The amidine complexes 1 – 3 were evaluated for their cytotoxic properties against a panel of human tumor cell lines containing examples of cervix (HeLa), breast (MCF7), lung (A549) and colon (HCT-15) cancer. Moreover, the amidine complexes were tested for their cytotoxicity against normal human fibroblasts (HFF-1). For comparison purposes, the cytotoxicity of cisplatin was examined under the same experimental conditions. The results obtained showed that PEG and PEG-DME behave as good solvents to carry out biological assays with platinum complexes which are water-insoluble and unstable in DMSO. Complexes 2 and 3 exhibited a biological activity comparable to that of cisplatin.

New substituted benzyl iminoether derivatives of the type cis - and trans -[PtCl 2 { E -N(H) C(OMe)CH 2 –C 6 H 4 – p –R} 2 ] (R = Me ( 1a , 2a ), OMe ( 3a , 4a ), F ( 5a , 6a )) have been synthesized and characterized by elemental analyses, FT-IR spectroscopy and NMR techniques. The iminoether ligands are in the E configuration, which is stable in solution and in the solid state, as confirmed by the 1 H NMR data. Complex trans -[PtCl 2 { E -N(H) C(OMe)CH 2 –C 6 H 4 – p –F} 2 ] ( 6a ) was also characterized by an X-ray diffraction study. Complexes 1a – 6a have been tested against a panel of human tumor cell lines in order to evaluate their cytotoxic activity. cis -Isomers were significant more potent than the corresponding trans -isomers against all tumor cell lines tested; moreover, complexes 1a and 5a showed IC 50 values from about 2-fold to 6-fold lower than those exhibited by cisplatin, used as reference platinum anticancer drug.

New benzyliminoether derivatives [PtCl2{N(H)dC(OMe)CH 2Ph}2] of cis(1a , 1b) and trans(2a , 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum-(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H) dC(OMe)CH 2Ph}2](1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups.

A series of bis-phosphine monoxide (BPMO) palladium(II) and platinum(II) cationic complexes of the type [M(BPMO-κ 2 - P , O ) 2 ][X] 2 (M = Pd, Pt; BPMO = Ph 2 P–(CH 2 ) n –P(O)Ph 2 with n = 1 (dppmO), 2 (dppeO), 3 (dpppO); X = BF 4 , TfO) were prepared from the corresponding chlorides [MCl 2 (BPMO-κ 1 - P ) 2 ] upon treatment with 2 equiv. of AgX in wet acetone/CH 2 Cl 2 or MeOH solutions. They were characterized by 1 H and 31 P{ 1 H} NMR spectroscopies and, in the case of the complex [Pt(dppeO-κ 2 - P , O ) 2 ][BF 4 ] 2 , also by X-ray crystallography. These complexes were tested as catalysts in some Diels–Alder and oxidation reactions with different substrates. In the latter reaction Pt(II) complexes showed moderate activity, while for the former one, both classes of complexes were active in the C–C coupling, in particular the Pt(II) species showed interesting high endo / exo diasteroselectivity depending on the counteranion.

The di-nitrile complexes trans -[PtCl 2 (N CR) 2 ] (R = Me, Ph, CH 2 Ph) react with an excess of gaseous NH 3 in CH 2 Cl 2 at −10 °C to form, in high yield, the corresponding di-amidine complexes trans -[PtCl(NH 3 ){HN C(NH 2 )R} 2 ]Cl in which also one chlorine ligand has been displaced by NH 3 . The 1 H NMR spectra in DMSO showed the formation of different species which were characterized through NOESY, TOCSY and 1 H/ 13 C heteronuclear correlations as trans -[Pt(NH 3 ){HN C(NH 2 )R} 2 (DMSO)]Cl 2 and trans -[PtCl{HN C(NH 2 )R} 2 (DMSO)]Cl.

The ESI mass spectrometric behaviour of a series of Pt(II) amidine complexes of the type cis- and trans-[PtCl2{NHC(R)NR′R″}2] (R=Me, Ph; R′=H, R″=Me, Et, But, Pri; R′=R″=Me, Et) and trans-[PtCl2(RCN){NHC(R)NR′R″] (R=Me, Ph; R′=R″=Me, Et) is reported. The bis-amidine complexes have been prepared by nucleophilic attack of primary and secondary amines on acetonitrile and benzonitrile ligands coordinated to Pt(II) substrates, while the mono-amidine complexes are obtained by reaction of secondary amines with trans-[PtCl2(RCN){NHC(R)NR′R″}] (R=Me, Ph; R′=R″=Me, Et). The protonated molecular ions or cationized ions are usually observed. The fragmentation processes are extremely reduced and in any case related to the original structure. As a general feature, cis and trans compounds give rise to different ESI spectra. Additions of Na+ and/or K+ are observed. From these data, ESI mass spectrometry, due to the soft ionisation, furtherly proposes as an efficient method for the characterisation of metal complexes in solution.