Associations between serum biomarkers of cartilage metabolism and serum hyaluronic acid, with risk factors, pain categories, and disease severity in knee osteoarthritis: a pilot study.

BACKGROUND: Specific serum biomarkers of cartilage metabolism such as cartilage oligomeric matrix protein (sCOMP) and procollagen type II C-terminal propeptide (sPIICP) as well as hyaluronan (sHA), a biomarker of synovitis, have been implicated in the pathophysiology of knee osteoarthritis (OA). However, the associations of these biomarkers with the severity of the disease and OA risk factors, including age and obesity remain inconclusive. This analysis examines the associations between these serum biomarkers and the radiographic severity of OA and knee pain, as wells as obesity, the age and gender of the participants, and other OA risk factors. METHODS: From 44 patients with early knee OA and 130 patients with late knee OA we analyzed the radiographic severity of the disease using the Kellgren and Lawrence (KL) grading system. Moreover, 38 overweight healthy individuals were used as a control group. Specific information was collected from all participants during their recruitment. The levels of the three serum biomarkers were quantified using commercially available ELISA kits. Serum biomarkers were analyzed for associations with the average KL scores and pain in both knees, as well as with specific OA risk factors. RESULTS: The levels of sCOMP were elevated in patients with severe late OA and knee pain and correlated weakly with OA severity. A weakly correlation of sHA levels and OA severity OA was observed. We demonstrated that only sPIICP levels were markedly decreased in patients with late knee OA suggesting the alterations of cartilage metabolism in this arthritic disease. Moreover, we found that sPIICP has the strongest correlation with obesity and the severity of OA, as well as with the knee pain at rest and during walking regardless of the severity of the disease. ROC analysis showed that the area under the ROC curve (AUC) was 0.980 (95% CI: 0.945-0.995; p < 0.0001), suggesting high diagnostic accuracy of sPIICP. Interestingly, gender and age had also an effect on the levels of sPIICP. CONCLUSION: This study revealed the potential of serum PIICP to be used as a biomarker to monitor the progression of knee OA, however, further studies are warranted to elucidate its clinical implication.

p13CMFA: Parsimonious 13C metabolic flux analysis.

Deciphering the mechanisms of regulation of metabolic networks subjected to perturbations, including disease states and drug-induced stress, relies on tracing metabolic fluxes. One of the most informative data to predict metabolic fluxes are 13C based metabolomics, which provide information about how carbons are redistributed along central carbon metabolism. Such data can be integrated using 13C Metabolic Flux Analysis (13C MFA) to provide quantitative metabolic maps of flux distributions. However, 13C MFA might be unable to reduce the solution space towards a unique solution either in large metabolic networks or when small sets of measurements are integrated. Here we present parsimonious 13C MFA (p13CMFA), an approach that runs a secondary optimization in the 13C MFA solution space to identify the solution that minimizes the total reaction flux. Furthermore, flux minimization can be weighted by gene expression measurements allowing seamless integration of gene expression data with 13C data. As proof of concept, we demonstrate how p13CMFA can be used to estimate intracellular flux distributions from 13C measurements and transcriptomics data. We have implemented p13CMFA in Iso2Flux, our in-house developed isotopic steady-state 13C MFA software. The source code is freely available on GitHub (https://github.com/cfoguet/iso2flux/releases/tag/0.7.2).

A novel role for an RCAN3-derived peptide as a tumor suppressor in breast cancer.

The members of the human regulators of calcineurin (RCAN) protein family are endogenous regulators of the calcineurin (CN)-cytosolic nuclear factor of activated T-cells (NFATc) pathway activation. This function is explained by the presence of a highly conserved calcipressin inhibitor of calcineurin (CIC) motif in RCAN proteins, which has been shown to compete with NFATc for the binding to CN and therefore are able to inhibit NFATc dephosphorylation and activation by CN. Very recently, emerging roles for NFATc proteins in transformation, tumor angiogenesis and metastasis have been described in different cancer cell types. In this work, we report that the overexpression of RCAN3 dramatically inhibits tumor growth and tumor angiogenesis in an orthotopic human breast cancer model. We suggest that RCAN3 exerts these effects in a CN-dependent manner, as mutation of the CIC motif in RCAN3 abolishes the tumor suppressor effect. Moreover, the expression of the EGFP-R3(178-210) peptide, spanning the CIC motif of RCAN3, is able to reproduce all the antitumor effects of RCAN3 full-length protein. Finally, we show that RCAN3 and the EGFP-R3(178-210) peptide inhibit the CN-NFATc signaling pathway and the induction of the NFATc-dependent gene cyclooxygenase-2. Our work suggests that the EGFP-R3(178-210) peptide possess potent tumor suppressor properties and therefore constitutes a novel lead for the development of potent and specific antitumoral agents. Moreover, we propose the targeting of the CN-NFATc pathway in the tumor cells constitutes an effective way to hamper tumor progression by impairing the paracrine network among tumor, endothelial and polymorphonucleated cells.

Postoperative peritoneal infection enhances migration and invasion capacities of tumor cells in vitro: an insight into the association between anastomotic leak and recurrence after surgery for colorectal cancer.

OBJECTIVE: The aim of this study was to investigate the effect of postoperative peritoneal infection on proliferation, migration, and invasion capacities of cancer cells lines in vitro after surgery for colorectal cancer. BACKGROUND: Anastomotic leakage is associated with higher rates of recurrence after surgery for colorectal cancer. However, the mechanisms responsible are unknown. We hypothesized that the infection-induced inflammatory response may enhance tumor progression features of residual cancer cells. METHODS: Prospective matched cohort study. Patients undergoing surgery for colorectal cancer with curative intent (January 2008-March 2012) were included. Patients who had an anastomotic leak or intra-abdominal abscess were included in the infection group (n=47). For each case patient, another patient with an uncomplicated postoperative course was selected for the control group (n=47).In vitro treatments on cancer cell lines (MDA-MB-231 and SW620) were performed using baseline and postoperative serum and peritoneal fluid samples to determine cell proliferation and cell migration/invasion activities. RESULTS: Postoperative peritoneal fluid from infected patients enhanced both cell migration (infection: 140±85 vs control: 94±30; P=0.016) and cell invasion (infection: 117±31 vs control: 103±16; P=0.024) capacities of cancer cell lines. With serum samples, these effects were only observed in cell migration assays (infection: 98±28 vs control: 87±17; P=0.005). Some minor activation of cell proliferation was observed by treatment with serum from infection group. Two-year cumulative disease-free survival was significantly lower in patients with postoperative peritoneal infection (infection: 77.6% vs control: 90.6%; P=0.032). CONCLUSIONS: Our results suggest that postoperative peritoneal infection enhances the invasive capacity of residual tumor cells after surgery, thus facilitating their growth to recurrent tumors.

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.

Novel multifunctional and multitarget homo- (Fe2) and heterobimetallic [(Fe,M) with M = Re or Mn] sulfonyl hydrazones.

The synthesis and characterization of the novel ferrocenyl sulfonyl hydrazide [Fe(η5-C5H5){(η5-C5H4)-S(O)2-NH-NH2}] (2) is reported. Additional studies on its reactivity using acetone or the ferrocenyl-, cyrhetrenyl- or cymantrenyl-aldehydes have allowed us to isolate and characterize [Fe(η5-C5H5){(η5-C5H4)-S(O)2-NH-N[double bond, length as m-dash]CMe2}] (3), the bis(ferrocenyl) derivative [Fe(η5-C5H5){[(η5-C5H4)-S(O)2-NH-N[double bond, length as m-dash]CH-(η5-C5H4)]Fe(η5-C5H5)}] (4) and the heterodimetallic compounds [Fe(η5-C5H5){[(η5-C5H4)-S(O)2-NH-N[double bond, length as m-dash]CH-(η5-C5H4)]M(CO)3}] with M = Re (5a) or Mn (5b). The X-ray crystal structures of compounds 3, 5a and 5b are also reported. A comparative study of their electrochemical and spectroscopic properties is also described. Additional computational calculations based on the DFT methodology have allowed us to elucidate the effect produced by the replacement of the terminal -NH2 (in 2) by the -N[double bond, length as m-dash]CMe2 (in 3) and -N[double bond, length as m-dash]CHR (in 4, 5a and 5b) moieties on the electronic distribution and to explain the differences detected in their electrochemical properties and absorption spectra. In vitro cytotoxicity studies of compounds 2, 4, 5a and 5b on the HCT-116 (colon), MCF7 and MDA-MB231 (breast) cancer cell lines reveal that compound 2 has no significant activity (IC50 > 100 µM), while its derivatives 4, 5a and 5b proved to be active in the three cancer cell lines selected in this study. The growth inhibition potency of compounds 5a and 5b against the triple negative MDA-MB231 breast cancer cell line is similar (or slightly) greater than that of cisplatin. Moreover, compounds 2, 4, 5a and 5b are less toxic than cisplatin in the normal and non-tumoral BJ fibroblasts, and the heterodimetallic complexes 5a and 5b with selective index >2.1 show an outstanding selective toxicity towards the MDA-MB231 cancer cells.

Characterization of the metabolic changes underlying growth factor angiogenic activation: identification of new potential therapeutic targets.

Angiogenesis is a fundamental process to normal and abnormal tissue growth and repair, which consists of recruiting endothelial cells toward an angiogenic stimulus. The cells subsequently proliferate and differentiate to form endothelial tubes and capillary-like structures. Little is known about the metabolic adaptation of endothelial cells through such a transformation. We studied the metabolic changes of endothelial cell activation by growth factors using human umbilical vein endothelial cells (HUVECs), [1,2-(13)C(2)]-glucose and mass isotopomer distribution analysis. The metabolism of [1,2-(13)C(2)]-glucose by HUVEC allows us to trace many of the main glucose metabolic pathways, including glycogen synthesis, the pentose cycle and the glycolytic pathways. So we established that these pathways were crucial to endothelial cell proliferation under vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) stimulation. A specific VEGF receptor-2 inhibitor demonstrated the importance of glycogen metabolism and pentose cycle pathway. Furthermore, we showed that glycogen was depleted in a low glucose medium, but conserved under hypoxic conditions. Finally, we demonstrated that direct inhibition of key enzymes to glycogen metabolism and pentose phosphate pathways reduced HUVEC viability and migration. In this regard, inhibitors of these pathways have been shown to be effective antitumoral agents. To sum up, our data suggest that the inhibition of metabolic pathways offers a novel and powerful therapeutic approach, which simultaneously inhibits tumor cell proliferation and tumor-induced angiogenesis.

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 antichagasic activities of the first examples of 2-substituted 2,4-dihydro-1H-3,1-benzoxazines with half-sandwich organometallic arrays, [M(η5-C5H4)(CO)3] (M = Re or Mn), at position-2 are described. Experimental and computational studies based on DFT calculations on the open forms [Schiff bases of general formulae R-CH[double bond, length as m-dash]N-C6H4-2-CH2OH] (5), with R = ferrocenyl (a), phenyl (b), cyrhetrenyl (c) or cymantrenyl (d), and their tautomeric forms (2-substituted 2,4-dihydro-1H-3,1 benzoxazines) have allowed us to establish the influence of substituents a-d and solvents on: (a) the extent of tautomeric equilibria (5a-5d) ↔ (6a-6d) and (b) their electrochemical properties and the electronic distribution on the open and closed forms. Despite the formal similarity between 6c and 6d, their anticancer and antiparasitic activities are markedly different. Compound 6d is inactive in the HCT116, MDA-MB231 and MCF7 cancer cell lines, but 6c shows moderate activity in the latter cell line, while the Mn(i) complex (6d) is a more potent anti-Trypanosoma cruzi agent than its Re(i) analogue (6c).

Isomeric and hybrid ferrocenyl/cyrhetrenyl aldimines: a new family of multifunctional compounds.

The synthesis and characterization of two novel and isomeric hybrid ferrocenyl/cyrhetrenyl aldimines [(η5-C5H5)Fe{(η5-C5H4)-CH[double bond, length as m-dash]N-(η5-C5H4)}Re(CO)3] (1) and [(η5-C5H5)Fe{(η5-C5H4)-N[double bond, length as m-dash]CH-(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.

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.

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-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.

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).

Diastereomerically pure platinum(II) complexes as antitumoral agents.: The influence of the mode of binding {(N), (N,O)- or (C,N)}- of (1S,2R)[(η5-C5H5)Fe{(η5-C5H4)CHNCH(Me)CH(OH)C6H5}] and the arrangement of the auxiliary ligands.

The study of the reactivity of (1S,2R) [(η(5)-C(5)H(5))Fe{[(η(5)-C(5)H(4)) CHNCH(Me)CH(OH)C(6)H(5)}] (1a) with cis-[PtCl(2)(DMSO)(2)] under different experimental conditions has allowed to isolate and characterize three pairs of isomeric and diastereomerically pure platinum(II) complexes. Two of the pairs are the trans- and cis- isomers of (1S,2R)[Pt{(η(5)-C(5)H(5))Fe[(η(5)-C(5)H(4))CHNCH(Me)CH(OH)C(6)H(5)]}Cl(2)(DMSO)] [trans-(2a) and cis-(3a), respectively], and of (1S,2R) [Pt{(κ(2)-N,O)(η(5)-C(5)H(5))Fe[(η(5)-C(5)H(4))CHNCH(Me)CH(O)C(6)H(5)]}Cl(DMSO)], {trans-(Cl, N) in (4a)} or a cis-(Cl, N) {in (5a)}; while the third one is formed by platinacycles: [Pt{(κ(2)-C,N[(η(5)-C(5)H(3))]CHN-CH(Me)CH(OH)C(6)H(5)]Fe(η(5)-C(5)H(5))}Cl(DMSO)] with different planar chirality [S(p) (in 6a) or R(p) (in 7a)]. The crystal structures of compounds 2a, 3a, 5a and 6a are also reported. The cytotoxic assessment of 1a-7a on lung (A549), breast (MDA-MB-231) and colon (HCT-116) cancer cell lines is also reported and reveals that the potency of the complexes is strongly dependent on the mode of binding of the iminoalcohol {(N) in 2a and 3a, (N,O)(-) in 4a and 5a or (C,N)(-) in 6a and 7a}, the relative arrangement of the monodentate ligands (in 2a-5a), and the planar chirality of the 1,2-ferrocenylunit in (6a and 7a). Among the new products (2a-7a), compounds 4a and 5a exhibit the highest potency with IC(50) values smaller than cisplatin in the three cancer cell lines assayed. Electrophoretic DNA migration studies in the presence of 2a-7a have been performed in order to get further insights into their mechanism of action. A comparative study of the solution behaviour of all the complexes in DMSO-d(6) or in DMSO-d(6):D(2)O (1:1) mixtures at 298 K is also reported.

Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody.

S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.

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.

Platinum(II) and palladium(II) complexes with (N,N') and (C,N,N')- ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities.

The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH(2))(2)NMe(2)}-3,5-R(2)-pzol] {where pzol represents pyrazole and R=H (1a), Me (1b) or Ph (1c)} with [MCl(2)(DMSO)(2)] (M=Pt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{κ(2)-N,N'-{[1-(CH(2))(2)NMe(2)}-3,5-R(2)-pzol])}Cl(2)] {MM=PtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{κ(3)-C,N,N'-{[1-(CH(2))(2)NMe(2)}-3-(C(5)H(4))-5-Ph-pzol])}Cl] {M=Pt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC(50)=3 µM) versus breast cancer cell lines (IC(50)>20 µM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action.