Biomedical Division Technological Center

Barcelona, Spain

Biomedical Division Technological Center

Barcelona, Spain
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Albert J.,University of Barcelona | Granell J.,University of Barcelona | Duran J.A.,University of Barcelona | Lozano A.,University of Barcelona | And 8 more authors.
Journal of Organometallic Chemistry | Year: 2017

(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. © 2017 Elsevier B.V.


Albert J.,University of Barcelona | D'Andrea L.,University of Barcelona | Granell J.,University of Barcelona | Pla-Vilanova P.,University of Barcelona | And 8 more authors.
Journal of Inorganic Biochemistry | Year: 2014

The antitumor, antibacterial and antioxidant activity, DNA interaction and cathepsin B inhibition of cyclo-ortho-palladated and -platinated compounds [Pd(C,N)]2(μ-X)2 [X = OAc (1), X = Cl (2)] and trans-N,P-[M(C,N)X(PPh3)] [M = Pd, X = OAc (3), M = Pd, X = Cl (4), M = Pt, X = Cl (5)] are discussed [(C,N) = cyclo-ortho-metallated benzophenone imine]. The cytotoxicity of compound 5 has been evaluated towards human breast (MDA-MB-231 and MCF-7) and colon (HCT-116) cancer cell lines and that of compounds 1-4 towards the HCT-116 human colon cancer cell line. These cytotoxicities have been compared with those previously reported for compounds 1-4 towards MDA-MB-231 and MCF-7 cancer cell lines. Compound 3 and 4 were approximately four times more active than cisplatin against the MDA-MB-231 and MCF-7 cancer cell lines, and compound 5, was approximately four times more potent than cisplatin against the HCT-116 cancer cell line. The antibacterial activity of compounds 1-5 was in between the ranges of activity of the commercial antibiotic compounds cefixime and roxithromycin. Complexes 1-2 and 4-5 presented also antioxidant activity. Compounds 1-5 alter the DNA tertiary structure in a similar way to cisplatin, but at higher concentration, and do not present a high efficiency as cathepsin B inhibitors. Compound 5 has not been previously described, and its preparation, characterization, and X-ray crystal structure are reported. © 2014 Elsevier Inc.


Albert J.,University of Barcelona | Garcia S.,University of Barcelona | Granell J.,University of Barcelona | Llorca A.,University of Barcelona | And 10 more authors.
Journal of Organometallic Chemistry | Year: 2013

Treatment of benzophenone imine with the stoichiometric amount of Pd(OAc)2 in acetic acid at 60 °C produced the corresponding acetato-bridged five-membered ortho-cyclopalladated dimer [Pd{C 6H4CPhNH}(μ-OAc)]2 (1), which was isolated in pure form in a 79% yield. Reaction of 1 with an excess of LiCl in acetone gave rise to the corresponding chlorido-bridged cyclopalladated dimer [Pd{C 6H4CPhNH}(μ-Cl)]2 (2) in a 78% yield. Compounds 1-2 reacted with an excess of py-d5 or the stoichiometric amount of PPh3 to give the mononuclear compounds trans-N,L-[Pd{C 6H4CPhNH}(X)(L)] [3 (X = OAc, L = py-d5); 4 (X = Cl, L = py-d5); 5 (X = OAc, L = PPh3) and 6 (X = Cl, L = PPh3)]. Compounds 2-3 were prepared in CDCl3/py-d 5 solution and were studied by 1H NMR, but were not isolated. In contrast, compounds 5-6 were prepared in acetone and were isolated in pure form in 43 and 79% yields, respectively. Compounds 1, 2, 5 and 6 were characterized by elemental analyses, mass spectrometry, IR, NMR and electronic spectroscopy. Compounds 1, 2, 5 and 6 showed high antiproliferative activity against MDA-MB231 and MCF7 human breast cancer cell lines, especially, compounds 5-6. These two latter compounds presented greater antiproliferative activity than cisplatin and produced IC50 values in the range 1-5 μM. The interaction of compounds 1, 2, 5 and 6 with DNA was also studied by the DNA electrophoretic migration, DNA-ethidium bromide fluorescence quenching and viscometry techniques. © 2012 Elsevier B.V. All rights reserved.


Albert J.,University of Barcelona | Bosque R.,University of Barcelona | Cadena M.,University of Barcelona | D'Andrea L.,University of Barcelona | And 11 more authors.
Organometallics | Year: 2014

The cyclopalladation of a series of symmetric diimines with the formula (RC6H4CH=NZ)2, where Z = CH2 or (CH2)2OCH2 and R = p-Cl, p-OMe, p-NO 2, and o-Cl, is described. Optimal conditions to obtain the dimetalated compounds were found to be palladium(II) acetate, in toluene, at 60 °C and with a reaction time of 2-4 h. The reactivity of the dimetalated compounds with monodentate, bidentate, and bis(monodentate) Lewis bases was also studied. The cytotoxic activity of some selected compounds was evaluated against a panel of adenocarcinoma cell lines (colon HCT116 and breast MCF7 and MDA-MB231). Compounds containing the fragment NCH2CH 2OCH2CH2OCH2CH2N exhibited a remarkable cytotoxic activity in the three cancer cells assayed, but complexes containing the NCH2CH2N fragment showed no activity. It seems that the length and flexibility of the central saturated chain in the imine molecule, as well as its lipophilicity and hydrophilicity, explain the different cytotoxicity of the two series of coordination compounds here reported. © 2014 American Chemical Society.


Cortes R.,University of Barcelona | Crespo M.,University of Barcelona | Davin L.,University of Barcelona | Martin R.,University of Barcelona | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2012

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-C6H 4Me)2(μ-SEt2)]2 or cis-[Pt(C 6H5)2(SMe2)2] with imines 2-ClC6H4CHNCH2CH2NMe2 (b) or 2-F,6-ClC6H3CHNCH2CH2NMe 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. © 2012 Elsevier Masson SAS. All rights reserved.


Albert J.,University of Barcelona | Bosque R.,University of Barcelona | Crespo M.,University of Barcelona | Garcia G.,University of Barcelona | And 15 more authors.
European Journal of Medicinal Chemistry | Year: 2014

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). © 2014 Elsevier Masson SAS. All rights reserved.


Albert J.,University of Barcelona | Albert J.,University Of Barcelonabarcelona | Bosque R.,University of Barcelona | Bosque R.,University Of Barcelonabarcelona | And 22 more authors.
Dalton Transactions | Year: 2015

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. This journal is © The Royal Society of Chemistry.

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