Toward Near-Infrared Emission in Pt(II)-Cyclometallated Compounds: From Excimers' Formation to Aggregation-Induced Emission.

Two series of Pt(II)-cyclometallated compounds containing N^C^N tridentate and alkynyl-chromophore ligands have been synthesized and structurally characterized. The N^C^N ligands differ on the presence of R1 = H or F in the central aromatic ring, while six different chromophores have been introduced to the alkynyl moiety. Single-crystal X-ray structures for some of the compounds reveal the presence of weak intermolecular contacts responsible for the formation of some dimers or aggregates. The photophysical characterization shows the presence of two emission bands in solution assigned to the 3π-π* transition from the N^C^N ligands mixed with 3MLCT/3ILCT transitions (higher energy band) in deaerated samples. The formation of excimers has also been identified as a broad band at longer wavelengths [near-infrared (NIR) emission] that becomes the main emission band for compounds containing phenanthrene as the chromophore. NIR emission behavior has also been explored using acetonitrile/water mixtures, and the presence of aggregates that emit at ca. 650 nm has also been detected.

Room-Temperature Phosphorescence and Efficient Singlet Oxygen Production by Cyclometalated Pt(II) Complexes with Aromatic Alkynyl Ligands.

The synthesis of five novel cyclometalated platinum(II) compounds containing five different alkynyl-chromophores was achieved by the reaction of the previously synthesized Pt-Cl cyclometalated compound (1) with the corresponding RC≡CH by a Sonogashira reaction. It was observed that the spectral and photophysical characteristics of the cyclometalated platinum(II) complexes (Pt-Ar) are essentially associated with the platinum-cyclometalated unit. Room-temperature emission of the Pt-Ar complexes was attributed to phosphorescence in agreement with DFT calculations. Broad nanosecond (ns)-transient absorption spectra were observed with decays approximately identical to those obtained from the emission of the triplet state. From the femtosecond-transient absorption (fs-TA) data, two main excited-state decay components were identified: one in the order of a few picoseconds was assigned to fast intersystem crossing to populate the triplet excited-state and the second (hundreds of ns) was associated with the decay of the transient triplet state. In general, efficient singlet oxygen photosensitization quantum yields were observed from the triplet state of these complexes.

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models.

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N')PtIV compounds derived from amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.

Synthesis, characterization and biological activity of new cyclometallated platinum(iv) complexes containing a para-tolyl ligand.

The synthesis of three new cyclometallated platinum(ii) compounds containing a para-tolyl ligand and a tridentate [C,N,N'] (cm1) or a bidentate [C,N] ligand and an additional ligand such as SEt2 (cm2) or PPh3 (cm3) is reported. The X-ray molecular structure of platinum(ii) compound cm3 is also presented. Intermolecular oxidative addition of methyl iodide or iodine upon cm1, cm2 and cm3 produced six novel cyclometallated platinum(iv) compounds. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), DNA interaction, topoisomerase I, IIα, and cathepsin B inhibition, and cell cycle arrest, apoptosis and ROS generation of the investigated complexes are presented. The best results for antiproliferative activity were obtained for platinum(iv) compounds cm1MeI and cm1I2 arising from oxidative addition of methyl iodide and iodine, respectively, to cm1. Cyclometallated platinum(iv) compounds cm1MeI and cm3MeI induce significant changes in the mobility of DNA and, in addition, cm1MeI, cm3MeI and cm1I2, showed considerable topoisomerase IIα inhibitory activity. Moreover, the compounds exhibiting the higher antiproliferative activity (cm1MeI and cm1I2) were found to generate ROS and to supress HCT-116 colon cancer cell growth by a mixture of cell cycle arrest and apoptosis induction. 1H NMR experiments carried out in a buffered aqueous medium (pH 7.40) indicate that compound cm1MeI is not reduced by common biologically relevant reducing agents such as ascorbic acid, glutathione or cysteine.

Synthesis, characterization and biological activity of new cyclometallated platinum(iv) iodido complexes.

The synthesis of six novel cyclometallated platinum(iv) iodido complexes is accomplished by intermolecular oxidative addition of methyl iodide (compounds 2a-2c) or iodine (compounds 3a-3c) upon cyclometallated platinum(ii) compounds [PtX{(CH3)2N(CH2)3NCH(4-ClC6H3)}] (1a-1c: X = Cl, CH3 or I). The X-ray molecular structures of platinum(ii) compound 1c and platinum(iv) compounds 3b and 3a' (an isomer of 3a) are reported. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), DNA interaction, topoisomerase I, IIα, and cathepsin B inhibition, and cell cycle arrest, apoptosis and ROS generation of the investigated complexes are presented. Remarkable antiproliferative activity was observed for most of the synthesized cycloplatinated compounds (series 1-3) in all the selected carcinoma cell lines. The best inhibition was provided for the octahedral platinum(iv) compounds 2a-2c exhibiting a methyl and an iodido axial ligand. Preliminary biological results point to a different mechanism of action for the investigated compounds. Cyclometallated platinum(ii) compounds 1a-1c modify the DNA migration as cisplatin. In contrast, cyclometallated platinum(iv) compounds 2a-2c and 3a-3c did not modify the DNA tertiary structure neither in the absence nor in the presence of ascorbic acid, which made them incapable of reducing platinum(iv) compounds 2b and 2c in a buffered aqueous medium (pH 7.40) according to 1H NMR experiments. Remarkable topoisomerase IIα inhibitory activity is reported for platinum(iv) complexes 2b and 3a and in addition, for the last one, a moderate cathepsin B inhibition is reported. Cell cycle arrest (decrease in G0/G1 and G2 phases and arrest in the S phase), induction of apoptosis and ROS generation are related to the antiproliferative activity of some representative octahedral cyclometallated platinum(iv) compounds (2b and 2c).

On the stability and biological behavior of cyclometallated Pt(IV) complexes with halido and aryl ligands in the axial positions.

A series of cyclometallated platinum(IV) compounds (3a, 3a' and 3b') with a meridional [C,N,N'] terdentate ligand, featuring an halido and an aryl group in the axial positions has been evaluated for electrochemical reduction and preliminary biological behavior against a panel of human adenocarcinoma (A-549 lung, HCT-116 colon, and MCF-7 breast) cell lines and the normal bronquial epithelial BEAS-2B cells. Cathodic reduction potentials (shifting from -1.463 to -1.570V) reveal that the platinum(IV) compounds under study would be highly reluctant to be reduced in a biological environment. Actually ascorbic acid was not able to reduce complex 3a', the most prone to be reduced according its reduction potential, over a period of one week. These results suggest an intrinsic activity for the investigated platinum(IV) complexes (3a, 3a' and 3b'), which exhibit a remarkable cytotoxicity effectiveness (with IC50 values in the low micromolar range), even greater than that of cisplatin. The IC50 for A-549 lung cells and clog P values were found to follow the same trend: 3b'>3a'>3a. However, no correlation was observed between reduction potential and in vitro activity. As a representative example, cyclometallated platinum(IV) compound 3a', exercise its antiproliferative activity directly over non-microcytic A-549 lung cancer cells through a mixture of cell cycle arrest (13% arrest at G1 phase and 46% arrest at G2 phase) and apoptosis induction (increase of early apoptosis by 30 times with regard to control). To gain further insights into the mode of action of the investigated platinum(IV) complexes, drug uptake, cathepsin B inhibition and ROS generation were also evaluated. Interestingly an increased ROS generation could be related with the antiproliferative activity of the cyclometallated platinum(IV) series under study in the cisplatin-resistant A-549 lung and HCT-116 cancer cell lines.

A combined kinetico-mechanistic and computational study on the competitive formation of seven- versus five-membered platinacycles; the relevance of spectator halide ligands.

The metalation reactions between [Pt2(4-MeC6H4)4(µ-SEt2)2] and 2-X,6-FC6H3CH[double bond, length as m-dash]NCH2CH2NMe2 (X = Br, Cl) have been studied. In all cases, seven-membered platinacycles are formed in a process that involves an initial reductive elimination from cyclometallated Pt(IV) intermediate compounds, [PtX(4-CH3C6H4)2(ArCH[double bond, length as m-dash]NCH2CH2NMe2)] (X = Br, Cl), followed by isomerization of the resulting Pt(II) complexes and a final cyclometallation step. For the process with X = Br, the final seven-membered platinacycle and two intermediates, isolated under the conditions implemented from parallel kinetic studies, have been characterized by XRD. Contrary to previous results for the parent non-fluorinated imine 2-BrC6H4CH[double bond, length as m-dash]NCH2CH2NMe2 the presence of a fluoro substituent prevents the formation of the more stable five-membered platinacycle. Temperature and pressure dependent kinetico-mechanistic and DFT studies indicate that the final cyclometallation step is strongly influenced by the nature of the spectator halido ligand, the overall reaction being much faster for X = Cl. The same DFT study conducted on the previously studied systems with imine 2-BrC6H4CH[double bond, length as m-dash]NCH2CH2NMe2 indicates that, when possible, five-membered platinacycles are kinetically preferred for X = Br, while the presence of Cl as a spectator halido ligand leads to a preferential faster formation of seven-membered analogues.

Neutral and ionic platinum compounds containing a cyclometallated chiral primary amine: synthesis, antitumor activity, DNA interaction and topoisomerase I-cathepsin B inhibition.

The synthesis and preliminary biological evaluation of neutral and cationic platinum derivatives of chiral 1-(1-naphthyl)ethylamine are reported, namely cycloplatinated neutral complexes [PtCl{(R or S)-NH(2)CH(CH(3))C(10)H(6)}(L)] [L = SOMe(2) ( 1-R or 1-S ), L = PPh(3) (2-R or 2-S), L = P(4-FC(6)H(4))(3) (3-R), L = P(CH(2))(3)N(3)(CH(2))(3) (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH(2)CH(CH(3))C(10)H(6)}{L}]Cl [L = Ph(2)PCH(2)CH(2)PPh(2) (5-R), L = (C(6)F(5))(2)PCH(2)CH(2)P(C(6)F(5))(2) (6-R)] and the Pt(ii) coordination compound trans-[PtCl(2){(R)-NH(2)CH(CH(3))C(10)H(6)}(2)] (7-R). The X-ray molecular structure of 7-R is reported. The cytotoxic activity against a panel of human adenocarcinoma cell lines (A-549 lung, MDA-MB-231 and MCF-7 breast, and HCT-116 colon), cell cycle arrest and apoptosis, DNA interaction, topoisomerase I and cathepsin B inhibition, and Pt cell uptake of the studied compounds are presented. Remarkable cytotoxicity was observed for most of the synthesized Pt(ii) compounds regardless of (i) the absolute configuration R or S, and (ii) the coordinated/cyclometallated (neutral or cationic) nature of the complexes. The most potent compound 2-R (IC(50) = 270 nM) showed a 148-fold increase in potency with regard to cisplatin in HCT-116 colon cancer cells. Preliminary biological results point out to different biomolecular targets for the investigated compounds. Neutral cyclometallated complexes 1-R and 2-R, modify the DNA migration as cisplatin, cationic platinacycle 5-R was able to inhibit topoisomerase I-promoted DNA supercoiling, and Pt(ii) coordination compound 7-R turned out to be the most potent inhibitor of cathepsin B. Induction of G-1 phase ( 2-R and 5-R ), and S and G-2 phases (6-R) arrests are related to the antiproliferative activity of some representative compounds upon A-549 cells. Induction of apoptosis is also observed for 2-R and 6-R.

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 (1)H 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).

Cyclopalladated primary amines: a preliminary study of antiproliferative activity through apoptosis induction.

Twelve cyclometallated palladium(II) complexes containing primary aromatic amines [benzylamine (a), (R)-1-(1-naphthyl)ethylamine (b) and 2-phenylaniline (c)] as anionic bidentate (C,N)(-) ligands have been evaluated against a panel of human adenocarcinoma cell lines (A549 lung, MDA-MB231 and MCF7 breast, and the cisplatin resistant HCT116 colon). The results revealed a remarkable antiproliferative activity of the triphenylphosphane mononuclear compounds 3-4 (series a, b, c) and the best inhibition was provided for 3c and 4c with the 2-phenylaniline ligand and a six membered chelate ring. Interestingly, 3c and 4c were 14 and 19 times more potent than cisplatin for the inhibition of the cisplatin resistant HCT116 human adenocarcinoma cell line, respectively. Cyclopalladated complexes 3c and 4c exercise their antiproliferative activity over A549 cells mainly through the induction of apoptosis (38 and 31-fold increase in early apoptotic cells, respectively).

Pt(II) complexes with (N,N') or (C,N,E)(-) (E=N,S) ligands: cytotoxic studies, effect on DNA tertiary structure and structure-activity relationships.

The cytotoxic activity of two series of platinum(II) complexes containing the polyfunctional imines R(1)-CHN-R(2) [R(1)=phenyl or ferrocenyl unit and R(2)=(CH2)n-CH2-NMe2 where n=1 or 2) (1 and 2) or C6H4-2-SMe (3)] acting as a bidentate (N,N') (4-7) or terdentate [C(phenyl or ferrocenyl),N,N'](-) (8-10) or [C(ferrocenyl),N,S](-) ligand (11) in front of A549 lung, MDA-MB231 breast and HCT116 colon human adenocarcinoma cell lines is reported. The results reveal that most of the platinum(II) complexes are active against the three assayed lines and compounds 6, 7 and the platinacycles 10 and 11 exhibit a remarkable antiproliferative activity, even greater than cisplatin itself, in the cisplatin resistant HCT116 human cancer cell line. Electrophoretic DNA migration studies showed that most of them modify the DNA tertiary structure in a similar way as the reference cisplatin. Solution studies of a selection of the most relevant complexes have also been performed in order to test: (a) their stability in the aqueous biological medium and/or the formation of biologically active species and (b) their proclivity to react with 9-methylguanine (9-MeG), as a model nucleobase. Computational studies at DFT level have also been performed in order to explain the different solution behaviour of the complexes and their proclivity to react with the nucleobase.

New insights in the formation of five- versus seven-membered platinacycles: a kinetico-mechanistic study.

The reaction of Pt(IV) organometallic cyclometalated complexes of type [PtXAr(2)(Ar'CHNCH(2)CH(2)NMe(2))] to produce 5- and 7-membered Pt(II) metalacycles by a formal C-C reductive elimination/C-H oxidative addition/Ar-H reductive elimination sequence has been studied from a preparative and kinetico-mechanistic perspective. The detection and characterization of key intermediates has also been achieved via the careful selection of reaction conditions, including time, extracted from the kinetic studies. From the data collected, it is clear that a fine-tuning of the reactivity is possible with respect to the formation of the alternative 5- and 7-membered cyclometalated complexes (i.e., [PtX(Ar-Ar'CH═NCH(2)CH(2)NMe(2))] and [PtX(Ar-Ar'CH═NCH(2)CH(2)NMe(2))]). In all cases a common reductive elimination reaction occurs to form a non cyclometalated intermediate compound of type [PtX(Ar)(Ar-Ar'CH═NCH(2)CH(2)NMe(2))], which leads to the selective formation of the above-mentioned complexes by the actuation of an unexpected equilibrium between its cis-(X,NMe(2)) and trans-(X,NMe(2)) isomers. While the cis-(X,NMe(2)) isomer produces the 7-membered metallacycle, the trans-(X,NMe(2)) form leads exclusively to the 5-membered analogue. The isomerization process is dominated by the steric hindrance existing between the Ar-Pt and Ar-Ar'CHN-Pt moieties in the cis-(X,NMe(2)) isomer that forces a Z conformation of the imine, thus leading exclusively to the 7-membered ring formation only for the less hindered X = Cl systems.

Seven-membered cycloplatinated complexes as a new family of anticancer agents. X-ray characterization and preliminary biological studies.

A series of seven-membered cyclometallated Pt(II) complexes containing a terdentate [C,N,N'] ligand (1a-1c and 2a-2c) have been developed as potential monofunctional DNA binding agents. By reactions of cis-[Pt(4-C(6)H(4)Me)(2)(µ-SEt(2))](2) or cis-[Pt(C(6)H(5))(2)(SMe(2))(2)] with imines 2-ClC(6)H(4)CHNCH(2)CH(2)NMe(2) (b) or 2-F,6-ClC(6)H(3)CH=NCH(2)CH(2)NMe(2) (c) the new compounds 1b, 1c and 2c were synthesized and characterized. Complex 1b and 1c were further characterized by X-ray crystallography. The cytotoxicity assessment of the seven-membered platinacycles 1 (1a-1c) and 2 (2a-2c) against a panel of human cancer cell lines (A549 lung, HCT116 colon, and MDA MB231 breast adenocarcinomas) revealed that the six cycloplatinated complexes exhibit a remarkable antiproliferative activity, even greater than cisplatin in the three human cancer cell lines. From a pharmacological point of view, platinacycles 1 (1a-1c) and 2 (2a-2c) may represent compounds for a new class of antitumor drugs. Electrophoretic DNA migration studies showed that all of them modify the DNA tertiary structure. Induction of S-G2/M arrest and apoptosis were also observed for one of the representative compounds (1c) of the series.

Biaryl formation in the synthesis of endo and exo-platinacycles.

The reactions of cis-[Pt(2)(4-MeC(6)H(4))(4)(µ-SEt(2))(2)] with bifunctional ligands ArCH=NCH(2)(2-XC(6)H(4)) containing a C-X bond at the ortho positions of the benzyl ring (Ar = 4-ClC(6)H(4), X = Br (1d); Ar = 2,4,6-(CH(3))(3)C(6)H(2), X = Br (1e); Ar = 2,4,6-(CH(3))(3)C(6)H(2), X = Cl (1f); Ar = 2-CH(3)C(6)H(4), X = Br (1h); Ar = 2,6-F(2)C(6)H(3), 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(sp(2)) bond (2d, 2h), ii) endo-six-membered with a Pt-C(sp(3)) bond (2e, 2f), and iii) exo-five membered with a Pt-C(sp(2)) 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 PPh(3) produced the corresponding phosphine derivatives, some of which (3d, 3e, 3h and 3i) were characterised crystallographically. In addition, compound [PtBr{2-CH(3)C(6)H(3)C(6)H(4)CH=NCH(2)(2-C(6)H(4)Br)}SEt(2)] (2c) containing a seven-membered endo-metallacycle was also obtained and characterised crystallographically.

Platinum-mediated aryl-aryl bond formation and sp(3) C-H bond activation.

A novel process is described in which intramolecular oxidative addition is followed by aryl-aryl bond formation and sp(3) C-H bond activation leading to a six-membered platinacycle.

A comparative study of the structures and reactivity of cyclometallated platinum compounds of N-benzylidenebenzylamines and cycloplatination of a primary amine.

The reaction of cis-[PtCl(2)(dmso)2] with ligands 4-ClC(6)H(4)CHNCH(2)C(6)H(5) (1a) and 4-ClC(6)H(4)CHNCH(2)(4-ClC(6)H(4)) (1b) in the presence of sodium acetate and using either methanol or toluene as solvent produced the corresponding five-membered endo-metallacycles [PtCl{(4-ClC(6)H(3))CHNCH(2)C(6)H(5)}{SOMe(2)}] (2a) and [PtCl{(4-ClC(6)H(3))CHNCH(2)(4'-ClC(6)H(4))}{SOMe(2)}] (2b). An analogous reaction for ligands 2,6-Cl(2)C(6)H(3)CHNCH(2)C(6)H(5) (1c) and 2,6-Cl(2)C(6)H(3)CHNCH(2)(4-ClC(6)H(4)) (1d) produced five-membered exo-metallacycles [PtCl{(2,6-Cl(2)C(6)H(3))CHNCH(2)C(6)H(4)}{SOMe(2)}] (2c) and [PtCl{(2,6-Cl(2)C(6)H(3))CHNCH(2)(4'-ClC(6)H(3))}{SOMe(2)}] (2d) when the reaction was carried out in methanol and seven-membered endo-platinacycles [PtCl{(MeC(6)H(3))ClC(6)H(3)CHNCH(2)C(6)H(4)}{SOMe(2)}] (3c) and [PtCl{(MeC(6)H(3))ClC(6)H(3)CHNCH(2)(4'-ClC(6)H(3))}{SOMe(2)}] (3d) when toluene was used as a solvent. The reaction of 2,4,6-(CH(3))(3)C(6)H(2)CHNCH(2)(4-ClC(6)H(4)) (1e) produced in both solvents an exo-platinacycle [PtCl{(2,4,6-(CH(3))(3)C(6)H(2))CHNCH(2)(4'-ClC(6)H(3))}{SO(CH(3))(2)}] (2e). Cyclometallation of 4-chlorobenzylamine was also achieved to produce compound [PtCl{(4-ClC(6)H(3))CH(2)NH(2)}{SOMe(2)}] (2g). The reactions of endo- and exo-metallacycles with phosphines evidenced the higher lability of the Pt-N bond in exo-metallacycles while a comparative analysis of the crystal structures points out a certain degree of aromaticity in the endo-metallacycle.

Unprecedented intermolecular C-H bond activation of a solvent toluene molecule leading to a seven-membered platinacycle.

A novel platinum-mediated process involving intermolecular activation of a C(aryl)-H bond of toluene, intramolecular activation of an imine C(aryl)-Cl bond and formation of a C-C bond is reported.