•Synthesis of two structural isomers of a cyclopalladated imine.•Comparison of their pharmacological activities with those of the free imine.•Comparison of their pharmacological activities with those of a cyclopalladated amine.•Anticancer, antibacterial and antioxidant activities.(E)-N-([1,1'-biphenyl]-2-yl)-1-mesitylmethanimine (imine a) and two structural cyclopalladated isomers of imine a, which contained a six-membered metallacycle and an aliphatic and an aromatic metallated carbon of formula [Pd{CH2-3,5-Me2-6-(CH=N-C6H4-2′-C6H5)C6H2}Br(PPh3)] (3a-endo) and [Pd(C6H4-2-C6H4-2′-N=CH-2,4,6-C6H2Me3)Br(PPh3)] (3a-exo), were synthetized by condensation reaction (imine a) and subsequent cyclometallation, metathesis and splitting reactions (compounds 3a-endo and 3a-exo). Imine a was characterized by high resolution ESI-(+) mass spectrometry, IR, and 1H-NMR, and compounds 3a by elemental analysis, high resolution ESI-(+) mass spectrometry, IR, and 1H- and 31P{1H}-NMR. The structural isomer 3a-exo consisted of a mixture of Z and E geometrical isomers in relation to its carbon-nitrogen double bond. In vitro anticancer, antibacterial and antioxidant activities of structural isomers 3a were compared with those of imine a and those of the six membered cyclopalladated primary amine 3b of formula [Pd(C6H4-2-C6H4-2′-NH2)Br(PPh3)]. Compound 3b was prepared as reported. Compounds 3 cytotoxicity towards cancer and normal cells was very dependent on their structure. Compounds 3a-exo and 3b were more cytotoxic than imine a towards the assayed cancer cell lines. Interestingly, compound 3a-exo with an exo imine function to the palladacycle presented a cytotoxicity in the low micromolar range (5–20 μM) towards the assayed cancer cell lines and was at least seven times less cytotoxic than cisplatin against normal BJ human fibroblast cells. Compounds 3 and imine a presented a noticeable antibacterial and antioxidant activity. Notably, imine a produced an antioxidant activity similar to that of ascorbic acid. Finally, compounds 3 were not efficient for altering the DNA tertiary structure or as inhibitors of cathepsin B.The synthesis and characterization of the imine cyclopalladated structural isomers 3a are reported, and their anticancer, antibacterial and antioxidant activities are compared with those of the free imine and compound 3b. The interaction of compounds 3 with DNA and cathepsin B has also been studied.Download high-res image (227KB)Download full-size image

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).

•Cyclometallated Pt(IV) compounds with halido and aryl as axial ligands.•Based on very negative reduction potentials, high difficulty of the compounds for being reduced.•Low IC50 values in human A-549 lung, HCT-116 colon and MCF-7 breast cancer cells.•Antiproliferative activity in NSCL A-549 by cell cycle arrest, apoptosis and increased ROS.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 −1.570 V) 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.

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)-NH2CH(CH3)C10H6}(L)] [L = SOMe2 (1-R or 1-S), L = PPh3 (2-R or 2-S), L = P(4-FC6H4)3 (3-R), L = P(CH2)3N3(CH2)3 (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH2CH(CH3)C10H6}{L}]Cl [L = Ph2PCH2CH2PPh2 (5-R), L = (C6F5)2PCH2CH2P(C6F5)2 (6-R)] and the Pt(II) coordination compound trans-[PtCl2{(R)-NH2CH(CH3)C10H6}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 (IC50 = 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.

The new compound [Pt2(4-FC6H4)4(μ-SEt2)2] (A) was prepared and fully characterized. The reactions of compound A with ligands ArCH═NCH2CH2NMe2 (Ar = 2-BrC6H4, 1a; 2,6-Cl2C6H3, 1b; 4-ClC6H4, 1c; 2-Cl,6-FC6H3, 1d) were studied under different conditions and produced platinum(II) compounds [Pt(4-FC6H4)2(ArCH═NCH2CH2NMe2)] (2b–2d), containing a bidentate [N,N′] ligand, as well as cyclometalated platinum(IV) or platinum(II) compounds such as [PtBr(4-FC6H4)2(C6H4CH═NCH2CH2NMe2)] (4a) or [PtCl{(3-FC6H3)(2-XC6H3)CH═NCH2CH2NMe2}] (5b: X = Cl; 5d: X = F), containing a tridentate [C,N,N′] ligand and either a five (4a) or a seven (5b, 5d) membered metallacycle. These compounds exhibit a great antiproliferative activity against non-small lung cancer cells (A549), and the best result was obtained for compound 2c (IC50 = 0.3 ± 0.1 μM). While compounds 5 alter the mobility of plasmid DNA in a similar way to cisplatin, compound 4 was less efficient in removing the supercoils from DNA. In spite of the very low IC50 value obtained for compound 2c, this compound does not interact with DNA, and it is neither an intercalator nor a topoisomerase I inhibitor.

•Cytotoxic evaluation of Pt(II) complexes with (N,N′) or (C,N,E)− (E = N,S) ligands.•Remarkable antiproliferative activity in lung, breast and colon human cancer cells.•These compounds modify the DNA tertiary structure, in a similar way as cisplatin.•Structure–activity relationship and theoretical calculations analysis.The cytotoxic activity of two series of platinum(II) complexes containing the polyfunctional imines R1–CHN–R2 [R1 = phenyl or ferrocenyl unit and R2 = (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.

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-C6H4Me)2(μ-SEt2)]2 or cis-[Pt(C6H5)2(SMe2)2] with imines 2-ClC6H4CHNCH2CH2NMe2 (b) or 2-F,6-ClC6H3CHNCH2CH2NMe2 (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.Graphical abstractHighlights► Seven-membered cyclometallated Pt(II) compounds as a new class of potential anticancer drugs. ► Non-planar arrangement of these compounds deduced from molecular structures. ► Remarkable antiproliferative activity in the human lung carcinoma, breast and colon cancer cell lines. ► These compounds modify the DNA tertiary structure, in a similar way than cisplatin.

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)-NH2CH(CH3)C10H6}(L)] [L = SOMe2 (1-R or 1-S), L = PPh3 (2-R or 2-S), L = P(4-FC6H4)3 (3-R), L = P(CH2)3N3(CH2)3 (4-R)], cycloplatinated cationic complexes [Pt{(R)-NH2CH(CH3)C10H6}{L}]Cl [L = Ph2PCH2CH2PPh2 (5-R), L = (C6F5)2PCH2CH2P(C6F5)2 (6-R)] and the Pt(II) coordination compound trans-[PtCl2{(R)-NH2CH(CH3)C10H6}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 (IC50 = 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.