Pd(II) complexes with N-substituted pyrazoles as ligands. The influence of the R group [OMe versus NMe2] of [1-{R(CH2)2}-3,5-Ph2(C3HN2)] on their cytotoxic activity on breast cancer cell lines

The study of the reactivity of the novel pyrazole derivative [1-{MeOe(CH2)2e}-3,5-Ph2e(C3HN2)] (1) with Na2[PdCl4] or Pd(OAc)2 under different experimental conditions has allowed us to isolate and characterize the trans-isomers of [Pd{[1-{MeOe(CH2)2e}-3,5-Ph2e(C3HN2)]}2(X)2] [X ¼ Cl (2) or OAc (3)] and the di-m-ligand bridged cyclopalladated complexes [Pd{k2,C,N[1-{MeOe(CH2)2e}-3-(C6H4),5-Ph- (C3HN2)]}(m-X)]2 [X ¼ OAc (4) or Cl (5)]. Further treatment of compounds 4 or 5 with PPh3 in CH2Cl2 produced the bridge splitting and the formation of [Pd{k2,C,N[1-{MeOe(CH2)2e}-3-(C6H4),5-Ph- (C3HN2)]}X(PPh3)] [X ¼ OAc (6) or Cl (7)]. The cytotoxic assessment of the free ligand (1) and the Pd(II) complexes on the two breast cancer cell lines MCF7 and MDA-MB231 reveals that: a) compound 1 is less active than its analogue [1-{Me2Ne(CH2)2e}-3,5-Ph2e(C3HN2)] (Ic) and b) palladacycles 4e7 showed a remarkable cytotoxic activity in the MDA-MB231 cell line (with IC50 values in the range 9.1e14.4 mM)

Experimental and Theoretical Studies of the Factors Affecting the Cycloplatination of the Chiral Ferrocenylaldimine (SC)-[(η5-C5H5)Fe{(η5-C5H4) C(H)=N CH(Me)(C6H5)}]

The study of the reactivity of the enantiopure ferrocenyl Schiff base (SC)-[FcCH=N CH(Me)(C6H5)] (1) (Fc = (η5-C5H5)Fe(η5-C5H4)) with cis-[PtCl2(dmso)2] under different experimental conditions is reported. Four different types of chiral Pt(II) have been isolated and characterized. One of them is the enantiomerically pure trans-(SC)-[Pt{κ1-N[FcCH=N CH(Me)(C6H5)]}Cl2(dmso)] (2a) in which the imine acts as a neutral N-donor ligand; while the other three are the cycloplatinated complexes: [Pt{κ2-C,N [(C6H4) N=CHFc]}Cl(dmso)] (7a) and the two diastereomers {(Sp,SC) and (Rp,SC)} of [Pt{κ2-C,N[(η5-C5H3) CH=N {CH(Me)(C6H5)}]Fe(η5-C5H5)}Cl(dmso)] (8a and 9a, respectively). Isomers 7a-9a, differ in the nature of the metallated carbon atom [CPh (in 7a) or CFc (in 8a and 9a)] or the planar chirality of the 1,2-disubstituted ferrocenyl unit (8a and 9a). Reactions of 7a 9a with PPh3 gave [Pt{κ2-C,N[(C6H4) N=CHFc]}Cl(PPh3)] (in 7b) and the diastereomers (Sp,SC) and (Rp,SC) of [Pt{κ2-C,N[(η5-C5H3) CH=N {CH(Me)(C6H5)}] Fe(η5-C5H5)}Cl(PPh3)] (8b and 9b, respectively). Comparative studies of the electrochemical properties and cytotoxic activities on MCF7 and MDA-MB231 breast cancer cell lines of 2a and cycloplatinated complexes 7b-9b are also reported. Theoretical studies based on DFT calculations have also been carried out in order to rationalize the results obtained from the cycloplatination of 1, the stability of the Pt(II) complexes and their electrochemical properties

A study of the properties, reactivity and anticancer activity of novel N- methylated-3-thiazolyl or 3-thienyl carbazoles and their Pd(II) and Pt(II) complexes

The synthesis and characterization of two hybrid N-methylated carbazole derivatives containing a thiazolyl or a thienyl ring is reported. The thiazolyl derivative has been also characterised by X-ray diffraction analysis. The study of its reactivity in front of [MCl2(dmso)(2)] (M = Pd or Pt) or Na-2[PdCl4] in methanol has allowed us to isolate and characterize its complexes. However, for the thienyl analogue, the formation of any Pd(II) or Pt(II) complex was not detected, indicating that it is less prone to bind to the M(II) ions than its thiazolyl analogue. Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT) calculations have also been carried out in order to rationalize the influence of the nature of the thiazolyl or thienyl group on the electronic delocalization. Molecular mechanics calculations show that the free rotation of the thiazolyl in relation to the carbazole requires a greater energy income than for its thienyl analogue. Studies of the cytotoxic activity of the new compounds on colon (HCT116) and breast (MDA-MB231 and MCF7) cancer cell lines show that the thiazolyl carbazole ligand and its Pt(II) complex are the most active agents of the series and in the MCF7 line their potency is higher than that of cisplatin. In the non-tumoral human skin fibroblast BJ cell line, all the compounds were less toxic than cisplatin. Their potential ability to modify the electrophoretic mobility of pBluescript SK+ plasmid DNA and to act as inhibitors of Topoisomerases I and II alpha or cathepsin B has also been investigated

A novel type of organometallic 2-R-2,4-dihydro- 1H-3,1-benzoxazine with R = [M(η5-C5H4)(CO)3] (M = Re or Mn) units. Experimental and computational studies of the effect of substituent R on ring-chain tautomerism

The syntheses, characterization, X-ray crystal structures, electrochemical properties and anticancer and 35 antichagasic activities of the first examples of 2-substituted 2,4-dihydro-1H-3,1-benzoxazines with 36 halfsandwich organometallic arrays, [M(η5-C5H4)(CO)3] (M = Re or Mn), at position-2 are described. 37 Experimental and computational studies based on DFT calculations on the open forms [Schiff bases of 38 general formulae R-CHvN-C6H4-2-CH2OH] (5), with R = ferrocenyl (a), phenyl (b), cyrhetrenyl (c) or 39 cymantrenyl (d), and their tautomeric forms (2-substituted 2,4-dihydro-1H-3,1 benzoxazines) 40 haveallowed us to establish the influence of substituents a-d and solvents on: (a) the extent of 41 tautomeric equilibria (5a-5d) ↔ (6a-6d) and (b) their electrochemical properties and the electronic 42 distribution on the open and closed forms. Despite the formal similarity between 6c and 6d, their 43 anticancer and antiparasitic activities are markedly different. Compound 6d is inactive in the HCT116, 44 MDA-MB231 and MCF7 cancer cell lines, but 6c shows moderate activity in the latter cell line, while 45 the Mn(I) complex (6d) is a more potent anti-Trypanosoma cruzi agent than its Re(I) analogue (6c)

Isomeric and hybrid ferrocenyl/cyrhetrenylaldimines: a new family of multifunctional compounds

The synthesis and characterization of two novel and isomeric hybrid ferrocenyl/cyrhetrenyl aldimines [(η5-C5H5)Fe{(η5-C5H4)-CHvN-(η5-C5H4)}Re(CO)3] (1) and [(η5-C5H5)Fe{(η5-C5H4)-NvCH-(η5-C5H4)}Re (CO)3] (2) are reported. Their X-ray crystal structures reveal that both adopt the E form. However, molecules of 1 and 2 differ in the relative arrangement of the 'Fe(η5-C5H5)' and 'Re(CO)3' units (anti in 1 and syn in 2). This affects the type of intermolecular interactions, the assembly of the molecules and therefore their crystal architecture. Comparative studies of their electrochemical, spectroscopic and photo-physical properties have allowed us to clarify the effect produced by the location of the organometallic arrays (ferrocenyl or cyrhetrenyl) on electronic delocalization, the proclivity of the metals to undergo oxidation and their emissive properties. Theoretical studies based on Density Functional Theory (DFT) calculations on the two compounds have also been carried out in order to rationalize the experimental results and to assign the bands detected in their electronic spectra. The cytotoxic activities of compounds 1 and 2 against human adenocarcinoma cell lines [breast (MCF7 and MDA-MB-231) and colon (HCT-116)] reveal that imine 2 has a greater inhibitory growth effect than 1 and it is ca. 1.8 times more potent than cisplatin in the triple negative MDA-MB 231 and in the cisplatin resistant HCT-116 cell lines. A comparative study of their effect on the normal and non-tumour human skin fibroblast BJ cell lines is also reported

Cyclopalladated Benzophenone Imines: Synthesis, Antitumor Activity, Cell Accumulation, DNA Interaction, and Cathepsin B Inhibition.

The synthesis of the endo five-membered cyclo-ortho-palladated benzophenone imines [Pd{C6H4(Ph)C═NR}]2(μ-X)2 [1 (X = OAc), 2 (X = Cl), a (R = phenyl), b (R = 1-naphthyl), c (R = benzyl), d (R = α-methylbenzyl)], and trans-N,P-[Pd{C6H4(Ph)C═NR}X(PPh3)] [3 (X = OAc), 4 (X = Cl), a (R = phenyl), b (R = 1-naphthyl), c (R = benzyl), d (R = α-methylbenzyl)] and the X-ray molecular structure of 1a, 1c, 1d, 4a, 4b, and 4c are reported. The antitumor activity, DNA interaction, and cathepsin B inhibition of palladium compounds a-d were studied and compared with those previously reported for palladium compounds e with R = H and compound 4f analogous to 4e but with a platinum(II) center. The IC50 values against a panel of human cancer cell lines allowed the establishment of a qualitative relationship between their structure and antitumor activity. Compounds 3e, 4e, and 4f were the most active ones in relation to their in vitro anticancer activity. Compounds 3e and 4e were about 4 times more active than cisplatin against the MDA-MB-231 and MCF-7 breast human cancer lines, and compound 4f was about 4 times more active than cisplatin against the cisplatin-resistant HCT-116 colon human cancer cell line. In addition, compound 3e was 3 times less cytotoxic than cisplatin toward the quiescent HUVEC cells. Accumulation of palladium compounds e and b in the MDA-MB-231 cell line was considerably greater than that of cisplatin in the same cell line, but palladium compounds b were noncytotoxic. Some of these complexes altered the DNA tertiary structure in a similar way to cisplatin but at higher concentration, and most cytotoxic ones did not present a high efficiency as cathepsin B inhibitors

A New Family of Doubly Cyclopalladated Diimines. A Remarkable Effect of the Linker between the Metalated Units on Their Cytotoxicity

The cyclopalladation of a series of symmetric diimines with the formula (RC6H4CHNZ)2, where Z = CH2 or (CH2)2OCH2 and R = p-Cl, p-OMe, p-NO2, 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 NCH2CH2OCH2CH2OCH2CH2N 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

Cyclopalladated and cycloplatinated benzophenone imines: antitumor, antibacterial and antioxidant activities, DNA interaction and cathepsin B inhibition

The antitumor, antibacterial and antioxidant activity, DNA interaction and cathepsin B inhibition of cyclo-orthopalladated 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-orthometallated 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 andMCF-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

Corrigendum to 'Cyclopalladated and cycloplatinated benzophenone imines: Antitumor, antibacterial and antioxidant activities, DNA interaction and cathepsin B inhibition' [J. Inorg. Biochem. 140 (2014) 80-88]

The magnitudes of MIC for the antibacterial activity and of the IC50 for the antioxidant activity reported in μM are really mM. Thus, in page 84: 0.18-0.34 μM is 0.18-0.34 mM; in Tables 2 and 3: μM is mM; in page 85: 0.12 and 0.14 μM is 0.12 and 0.14 mM; and in page 87: 0.12-0.14 μM is 0.12-0.14 mM. The authors apologize for any inconvenience caused

Neutral and ionic platinum compounds containing a cyclometalated 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