The reaction of [Pt2Me4(μ-SMe2)2] with ligands 1-(Me2NCH2CH2NCH)C10H7 (2a) and 2-(Me2NCH2CH2NCH)C... more The reaction of [Pt2Me4(μ-SMe2)2] with ligands 1-(Me2NCH2CH2NCH)C10H7 (2a) and 2-(Me2NCH2CH2NCH)C10H7 (2b) carried out in acetone at room temperature produced compounds [PtMe2{1-(Me2NCH2CH2NCH)C10H7}] (3a) and [PtMe2{1-(Me2NCH2CH2NCH)C10H7}] (3b), respectively, in which the imines act as bidentate [N,N′] ligands. Cyclometallated [C,N,N′] compounds [PtMe{1-(Me2NCH2CH2NCH)C10H6}] (4a) and [PtMe{2-(Me2NCH2CH2NCH)C10H6}] (4b) were obtained by refluxing toluene solutions of compounds 3a or 3b. Reaction of [Pt2Me4(μ-SMe2)2] with ligands 1-(2′-ClC6H4CH2NCH)C10H7 (2c) and 2-(2′-ClC6H4CH2NCH)C10H7 (2d) produced straightforward metallation to yield [PtMe{1-(2′-ClC6H4CH2NCH)C10H6}SMe2] (5c) and [PtMe{2-(2′-ClC6H4CH2NCH)C10H6}SMe2] (5d) containing a [C,N] ligand. Triphenylphosphine derivatives [PtMe{1-(2′-ClC6H4CH2NCH)C10H6}PPh3] (6c) and [PtMe{2-(2′-ClC6H4CH2NCH)C10H6}PPh3] (6d) were also prepared. All compounds were characterised by NMR spectroscopies and 6c and 6d were also characterised cry...
The reaction of PhCHNCH2CH2NMe2 with [PtCl2S2] (S = SMe2 or dmso) produces [PtCl2(PhCHNCH2CH2NMe2... more The reaction of PhCHNCH2CH2NMe2 with [PtCl2S2] (S = SMe2 or dmso) produces [PtCl2(PhCHNCH2CH2NMe2)] (1) in which the imine acts as a bidentate [N,N′] ligand. The cyclometallated [C,N,N′] platinum(II) complex [PtCl(C6H4CHNCH2CH2NMe2)] (2) has been obtained by refluxing a methanol solution of complex 1 in the presence of base; both complexes 1 and 2 have been characterized crystallographically. The cyclometallation process has been studied kinetically at variable temperature and pressure as a function of the base added in methanol and ethanol solutions. In all cases, the actual C–H bond activation is preceded by the Z to E isomerization of the imine; detection of this species by proton NMR has also been achieved. The kinetic, thermal and baric activation parameters associated with the two processes are indicative of a different reaction mechanism operating for the reactions when the “external” base added (NaCH3CO2) can, in fact, react with the starting material to form a new acetato c...
Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide v... more 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.
New [C,N,N′]-cyclometallated platinum(ii) and platinum(iv) complexes are prepared and their emiss... more New [C,N,N′]-cyclometallated platinum(ii) and platinum(iv) complexes are prepared and their emission properties are reported.
Six novel cyclometallated platinum(iv) iodido complexes are prepared and their cytotoxic activity... more Six novel cyclometallated platinum(iv) iodido complexes are prepared and their cytotoxic activity against a panel of human adenocarcinoma is reported.
Synthesis and biological activity of cyclometallated platinum(iv) compounds containing a para-tol... more Synthesis and biological activity of cyclometallated platinum(iv) compounds containing a para-tolyl ligand are reported.
A series of cyclometallated platinum(IV) compounds (3a, 3a&am... more 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.
Compound [PtMe2{1-(Me2NCH2CH2NCH)C10 H7}] (2a) gave upon reaction with methyl iodide platinum (IV... more Compound [PtMe2{1-(Me2NCH2CH2NCH)C10 H7}] (2a) gave upon reaction with methyl iodide platinum (IV) compound [PtMe3I{1-(Me2NCH2CH2NCH)C10H7}] (3a) as a single isomer which was characterised structurally. Upon standing in solution, two isomers of 3a were detected by 1H NMR. New chiral compounds [PtMe2(N,N′-chelate)] (N,N′=2-((S)-CHNCH(Me)C6H5)C9H6N (2b), 2-((R)-CHNCH(Me)C10H7)C5H4N (2c) and 2-((R)-CHNCH(Me)C10H7)C9H6N (2d)) were obtained from [Pt2Me4(μ-SMe2)2] and the corresponding diimines. The oxidative addition of methyl
... 3.1. Preparation of the conpounds The complex [PtaMe(IxSMe)] (1) was prepared by the method r... more ... 3.1. Preparation of the conpounds The complex [PtaMe(IxSMe)] (1) was prepared by the method reported in the literature [17]. 3. Experlmen SH and tP 'H NMR spectra were recorded using Van Gemini 200 (SH; 200 MHz). Broker ...
... 32-9. Reactivity and Mechanism in the Formation of ... Models show that 14 can undergo intram... more ... 32-9. Reactivity and Mechanism in the Formation of ... Models show that 14 can undergo intramolecular oxidative addition by the SN2 mechanism to give 15 (Scheme 111), and this reaction is clearly much faster than the rate of formation of 14. ...
Following our interest in cyclometallated platinum(II) and platinum(IV) complexes, containing ter... more Following our interest in cyclometallated platinum(II) and platinum(IV) complexes, containing terdentate [C,N,N′] [2, 3, 4] or bidentate [C,N] [5, 6] ligands, we now report the synthesis, reactivity and electrochemical properties of new compounds obtained by the reaction of [Pt 2 Me 4 ...
Dalton transactions (Cambridge, England : 2003), Jan 3, 2015
The synthesis and preliminary biological evaluation of neutral and cationic platinum derivatives ... more 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 ( or ), L = PPh3 ( or ), L = P(4-FC6H4)3 (), L = P(CH2)3N3(CH2)3 ()], cycloplatinated cationic complexes [Pt{(R)-NH2CH(CH3)C10H6}{L}]Cl [L = Ph2PCH2CH2PPh2 (), L = (C6F5)2PCH2CH2P(C6F5)2 ()] and the Pt(ii) coordination compound trans-[PtCl2{(R)-NH2CH(CH3)C10H6}2] (). The X-ray molecular structure of 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/...
The reaction of [Pt2Me4(μ-SMe2)2] with ligands 1-(Me2NCH2CH2NCH)C10H7 (2a) and 2-(Me2NCH2CH2NCH)C... more The reaction of [Pt2Me4(μ-SMe2)2] with ligands 1-(Me2NCH2CH2NCH)C10H7 (2a) and 2-(Me2NCH2CH2NCH)C10H7 (2b) carried out in acetone at room temperature produced compounds [PtMe2{1-(Me2NCH2CH2NCH)C10H7}] (3a) and [PtMe2{1-(Me2NCH2CH2NCH)C10H7}] (3b), respectively, in which the imines act as bidentate [N,N′] ligands. Cyclometallated [C,N,N′] compounds [PtMe{1-(Me2NCH2CH2NCH)C10H6}] (4a) and [PtMe{2-(Me2NCH2CH2NCH)C10H6}] (4b) were obtained by refluxing toluene solutions of compounds 3a or 3b. Reaction of [Pt2Me4(μ-SMe2)2] with ligands 1-(2′-ClC6H4CH2NCH)C10H7 (2c) and 2-(2′-ClC6H4CH2NCH)C10H7 (2d) produced straightforward metallation to yield [PtMe{1-(2′-ClC6H4CH2NCH)C10H6}SMe2] (5c) and [PtMe{2-(2′-ClC6H4CH2NCH)C10H6}SMe2] (5d) containing a [C,N] ligand. Triphenylphosphine derivatives [PtMe{1-(2′-ClC6H4CH2NCH)C10H6}PPh3] (6c) and [PtMe{2-(2′-ClC6H4CH2NCH)C10H6}PPh3] (6d) were also prepared. All compounds were characterised by NMR spectroscopies and 6c and 6d were also characterised cry...
The reaction of PhCHNCH2CH2NMe2 with [PtCl2S2] (S = SMe2 or dmso) produces [PtCl2(PhCHNCH2CH2NMe2... more The reaction of PhCHNCH2CH2NMe2 with [PtCl2S2] (S = SMe2 or dmso) produces [PtCl2(PhCHNCH2CH2NMe2)] (1) in which the imine acts as a bidentate [N,N′] ligand. The cyclometallated [C,N,N′] platinum(II) complex [PtCl(C6H4CHNCH2CH2NMe2)] (2) has been obtained by refluxing a methanol solution of complex 1 in the presence of base; both complexes 1 and 2 have been characterized crystallographically. The cyclometallation process has been studied kinetically at variable temperature and pressure as a function of the base added in methanol and ethanol solutions. In all cases, the actual C–H bond activation is preceded by the Z to E isomerization of the imine; detection of this species by proton NMR has also been achieved. The kinetic, thermal and baric activation parameters associated with the two processes are indicative of a different reaction mechanism operating for the reactions when the “external” base added (NaCH3CO2) can, in fact, react with the starting material to form a new acetato c...
Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide v... more 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.
New [C,N,N′]-cyclometallated platinum(ii) and platinum(iv) complexes are prepared and their emiss... more New [C,N,N′]-cyclometallated platinum(ii) and platinum(iv) complexes are prepared and their emission properties are reported.
Six novel cyclometallated platinum(iv) iodido complexes are prepared and their cytotoxic activity... more Six novel cyclometallated platinum(iv) iodido complexes are prepared and their cytotoxic activity against a panel of human adenocarcinoma is reported.
Synthesis and biological activity of cyclometallated platinum(iv) compounds containing a para-tol... more Synthesis and biological activity of cyclometallated platinum(iv) compounds containing a para-tolyl ligand are reported.
A series of cyclometallated platinum(IV) compounds (3a, 3a&am... more 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.
Compound [PtMe2{1-(Me2NCH2CH2NCH)C10 H7}] (2a) gave upon reaction with methyl iodide platinum (IV... more Compound [PtMe2{1-(Me2NCH2CH2NCH)C10 H7}] (2a) gave upon reaction with methyl iodide platinum (IV) compound [PtMe3I{1-(Me2NCH2CH2NCH)C10H7}] (3a) as a single isomer which was characterised structurally. Upon standing in solution, two isomers of 3a were detected by 1H NMR. New chiral compounds [PtMe2(N,N′-chelate)] (N,N′=2-((S)-CHNCH(Me)C6H5)C9H6N (2b), 2-((R)-CHNCH(Me)C10H7)C5H4N (2c) and 2-((R)-CHNCH(Me)C10H7)C9H6N (2d)) were obtained from [Pt2Me4(μ-SMe2)2] and the corresponding diimines. The oxidative addition of methyl
... 3.1. Preparation of the conpounds The complex [PtaMe(IxSMe)] (1) was prepared by the method r... more ... 3.1. Preparation of the conpounds The complex [PtaMe(IxSMe)] (1) was prepared by the method reported in the literature [17]. 3. Experlmen SH and tP 'H NMR spectra were recorded using Van Gemini 200 (SH; 200 MHz). Broker ...
... 32-9. Reactivity and Mechanism in the Formation of ... Models show that 14 can undergo intram... more ... 32-9. Reactivity and Mechanism in the Formation of ... Models show that 14 can undergo intramolecular oxidative addition by the SN2 mechanism to give 15 (Scheme 111), and this reaction is clearly much faster than the rate of formation of 14. ...
Following our interest in cyclometallated platinum(II) and platinum(IV) complexes, containing ter... more Following our interest in cyclometallated platinum(II) and platinum(IV) complexes, containing terdentate [C,N,N′] [2, 3, 4] or bidentate [C,N] [5, 6] ligands, we now report the synthesis, reactivity and electrochemical properties of new compounds obtained by the reaction of [Pt 2 Me 4 ...
Dalton transactions (Cambridge, England : 2003), Jan 3, 2015
The synthesis and preliminary biological evaluation of neutral and cationic platinum derivatives ... more 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 ( or ), L = PPh3 ( or ), L = P(4-FC6H4)3 (), L = P(CH2)3N3(CH2)3 ()], cycloplatinated cationic complexes [Pt{(R)-NH2CH(CH3)C10H6}{L}]Cl [L = Ph2PCH2CH2PPh2 (), L = (C6F5)2PCH2CH2P(C6F5)2 ()] and the Pt(ii) coordination compound trans-[PtCl2{(R)-NH2CH(CH3)C10H6}2] (). The X-ray molecular structure of 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/...
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