Peripheral White Blood Cell Subsets in Metastatic Colorectal Cancer Patients Treated with Cetuximab: The Potential Clinical Relevance.

It was demonstrated that cetuximab-induced tumor regression is based on the effects exerted by immune cells included mainly in the innate immune response. Therefore, the focus of this study was to explore the alterations in the percentages of CD16+, and/or CD56+ lymphocytes, which are comprised of NK cells, and minority of CD56+CD3+ cells, in patients with metastatic colorectal cancer before or 2 months after the treatment with cetuximab-based regimens associated with the response to therapy. The changes in the percentages of lymphocytes and granulocytes in these patients were evaluated as well. We enrolled 50 patients with wild-type KRAS metastatic colorectal cancer. Disease progression was observed in 11/50 patients (non-responders), while other patients achieved partial response or stable disease (responders). Control groups included up to 72 healthy individuals. A significant decrease in the percentages of CD56+ and CD16+CD56+ lymphocytes together with a significant decrease in the percentage of lymphocytes and an increase in the ratio of granulocyte to lymphocyte percentages were observed in patients with metastatic colorectal cancer before therapy, compared with those in the healthy individuals. In contrast to those in the responders, the percentage of CD16+ lymphocytes in the overall white blood cell pool was shown to be significantly decreased in the non-responders, together with a significantly decreased percentage of lymphocytes, a significantly increased percentage of granulocytes, and an increased ratio of granulocyte to lymphocyte percentages before treatment compared with those in the healthy controls. Two months after the initiation of the treatment, significantly decreased percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes were observed in patients, compared with those determined in the healthy controls. The same changes in the amounts of circulating immune cells were also observed in the responder subgroup, but the percentages of CD16+, CD56+, and CD16+CD56+ lymphocytes 2 months after treatment in the non-responder group did not differ significantly in comparison with healthy individuals. Considerable alterations of immune cell percentages observed in patients with metastatic colorectal cancer with disease progression indicate that the assessment of peripheral white blood cell architecture before treatment initiation may be clinically relevant.

Steroid dimers-in vitro cytotoxic and antimicrobial activities.

The in vitro cytotoxic activity of previously synthesized steroid dimers with different spacer group (sulfide, trithiolane ring or phosphorotrithioate) and the substituent at C-17 position was tested for their possible effects against following human tumor cell lines: cervical adenocarcinoma (HeLa), chronic myelogenous leukemia (K562) and two human breast cancer cell lines (MDA-MB-361 and MDA-MB-453). These compounds, applied at micromolar concentrations, exhibited cytotoxic activity of different intensity (compared with cisplatin as a control), modality and selectivity in these malignant cell lines. The best activity against all four cell cancer lines was exhibited by dimer-sulfides. All screened compounds exerted concentration-dependent cytotoxic activity against leukemia K562 cells. The compounds which exerted the most pronounced cytotoxic action exhibited notably higher cytotoxic activities against K562, HeLa and MDA-MB-453 cells in comparison to resting and PHA-stimulated PBMC, pointing to a significant selectivity in their antitumor actions. Examination of the mechanisms of cytotoxicity on leukemia K562 cells revealed pro-apoptotic action of each of the investigated compounds applied at concentrations 2IC50. The most prominent pro-apoptotic action was exhibited by dimer-sulfide of cholest-4-en-3-one. Furthermore, almost all of the tested compounds at IC50 concentrations induced G1 phase cell cycle arrest in K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina, were evaluated. There was no antibacterial activity. The best antifungal activity was exhibited against Saccharomyces cerevisiae by dimers linked with trithiolane ring, indicating a selective activity of investigated compounds.

Cancer-suppressive potential of extracts of endemic plant Helichrysum zivojinii: effects on cell migration, invasion and angiogenesis.

Helichrysum zivojinii Cernjavski & Soska is an endemic plant species that grows in the National Park Galicica in Macedonia. Five extracts were isolated as fractions from the aerial parts of the plant: a n-hexane extract (1), a dichloromethane extract (2), an ethyl-acetate extract (3), a n-butanol extract (4) and a methanol extract (5). A dose-dependent cytotoxic activity of the extracts on MDA-MB-231 and EA.hy926 cells was observed. Extracts exhibited more pronounced cytotoxic actions on MDA-MB-231 cells than on EA.hy926 cells. The n-hexane extract (1), at a non-toxic concentration, exhibited an inhibitory effect on the migration as well the invasiveness of MDA-MB-231 cells. The dichloromethane extract (2), at a non-toxic concentration, demonstrated inhibition of MDA-MB-231 cells invasion. Each of the five extracts applied at non-toxic concentrations inhibited migration of EA.hy926 cells. The prominent inhibitory effect of the n-hexane extract on EA.hy926 cells migration was associated with a notable anti-angiogenic action of this extract. The other four tested extracts demonstrated mild anti-angiogenic activity. Our data highlight the prominent anticancer potential of n-hexane (1) and dichloromethane (2) extracts, which could be attributed to their very pronounced and selective cytotoxic activities as well as their anti-invasive and anti-angiogenic properties.

Dipeptidyl peptidase IV: serum activity and expression on lymphocytes in different hematological malignancies.

The aim of this research was to determine the serum dipeptidyl peptidase IV (DPPIV) activity as well as the percentages of CD26 + lymphocytes and CD26 + overall white blood cells in patients with hematological malignancies: non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), leukemia, plasmacytoma and multiple myeloma, and in healthy individuals. Data from our study showed significantly decreased serum DPPIV activity and a significant decrease in the percentage of: CD26 + lymphocytes, CD26 + overall white blood cells and lymphocytes in patients with NHL in comparison to healthy controls. Patients with leukemia had a statistically significant lower activity of DPPIV in serum and significant decrease in the percentage of CD26 + lymphocytes in relation to healthy controls. Furthermore, significantly decreased DPPIV serum activity associated with a significantly reduced percentage of CD26 + overall white blood cells and percentage of lymphocytes was found in patients with multiple myeloma when compared to the healthy control group. The obtained results indicate that immune disturbances that can occur in hematological malignancies might be related to the decreased expression and activity of CD26/DPPIV that we observed.

Bioreactor validation and biocompatibility of Ag/poly(N-vinyl-2-pyrrolidone) hydrogel nanocomposites.

Silver/poly(N-vinyl-2-pyrrolidone) (Ag/PVP) nanocomposites containing Ag nanoparticles at different concentrations were synthesized using γ-irradiation. Cytotoxicity of the obtained nanocomposites was determined by MTT assay in monolayer cultures of normal human immunocompetent peripheral blood mononuclear cells (PBMC) that were either non-stimulated or stimulated to proliferate by mitogen phytohemagglutinin (PHA), as well as in human cervix adenocarcinoma cell (HeLa) cultures. Silver release kinetics and mechanical properties of nanocomposites were investigated under bioreactor conditions in the simulated body fluid (SBF) at 37°C. The release of silver was monitored under static conditions, and in two types of bioreactors: perfusion bioreactors and a bioreactor with dynamic compression coupled with SBF perfusion simulating in vivo conditions in articular cartilage. Ag/PVP nanocomposites exhibited slight cytotoxic effects against PBMC at the estimated concentration of 0.4 µmol dm(-3), with negligible variations observed amongst different cell cultures investigated. Studies of the silver release kinetics indicated internal diffusion as the rate limiting step, determined by statistically comparable results obtained at all investigated conditions. However, silver release rate was slightly higher in the bioreactor with dynamic compression coupled with SBF perfusion as compared to the other two systems indicating the influence of dynamic compression. Modelling of silver release kinetics revealed potentials for optimization of Ag/PVP nanocomposites for particular applications as wound dressings or soft tissue implants.

In vitro antitumor actions of extracts from endemic plant Helichrysum zivojinii.

BACKGROUND: The aim of this research was to determine the intensity and mechanisms of the cytotoxic actions of five extracts isolated from the endemic plant species Helichrysum zivojinii Cernjavski & Soska (family Asteraceae) against specific cancer cell lines. In order to evaluate the sensitivity of normal immunocompetent cells implicated in the antitumor immune response, the cytotoxicity of extracts was also tested against healthy peripheral blood mononuclear cells (PBMC). METHODS: The aerial parts of the plants were air-dried, powdered, and successively extracted with solvents of increasing polarity to obtain hexane, dichloromethane, ethyl-acetate, n-butanol and methanol extracts. The cytotoxic activities of the extracts against human cervix adenocarcinoma HeLa, human melanoma Fem-x, human myelogenous leukemia K562, human breast adenocarcinoma MDA-MB-361 cells and PBMC were evaluated by the MTT test. The mode of HeLa cell death was investigated by morphological analysis. Changes in the cell cycle of HeLa cells treated with the extracts were analyzed by flow cytometry. The apoptotic mechanisms induced by the tested extracts were determined using specific caspase inhibitors. RESULTS: The investigated Helichrysum zivojinii extracts exerted selective dose-dependent cytotoxic actions against selected cancer cell lines and healthy immunocompetent PBMC stimulated to proliferate, while the cytotoxic actions exerted on unstimulated PBMC were less pronounced. The tested extracts exhibited considerably stronger cytotoxic activities towards HeLa, Fem-x and K562 cells in comparison to resting and stimulated PBMC. It is worth noting that the cytotoxicity of the extracts was weaker against unstimulated PBMC in comparison to stimulated PBMC. Furthermore, each of the five extracts induced apoptosis in HeLa cells, through the activation of both intrinsic and extrinsic signaling pathways. CONCLUSION: Extracts obtained from the endemic plant Helichrysum zivojinii may represent an important source of novel potential antitumor agents due to their pronounced and selective cytotoxic actions towards malignant cells.

Cinnamic acid derivatives induce cell cycle arrest in carcinoma cell lines.

Cinnamic acid derivatives can be found in plant material, and they possess a remarkable variety of biological effects. In the present study, we have investigated the cytotoxic effects of representative cinnamic acid esters and amides. The cytotoxicity was determined by MTT test on human cervix adenocarcinoma (HeLa), myelogenous leukemia (K562), malignant melanoma (Fem-x), and estrogen-receptor-positive breast cancer (MCF-7) cells, versus peripheral blood mononuclear cells (PBMCs) without or with the addition of the plant lectin phytohemaglutinin (PHA). The compounds tested showed significant cytotoxicity (IC50s between 42 and 166 µM) and furthermore selectivity of these cytotoxic effects on the malignant cell lines versus the PBMCs was also seen, especially when electron-withdrawing groups, such as a cyano group (compound 5), were present on the aromatic rings of the alcohol or amine parts of the cinnamic acid derivatives. The additional study on cell cycle phase distribution indicated that novel cinnamic acid derivatives inhibit cell growth by induction of cell death. Thus, cinnamic acids derivatives represent important lead compounds for further development of antineoplastic agents.

Serum activity of DPPIV and its expression on lymphocytes in patients with melanoma and in people with vitiligo.

BACKGROUND: Dipeptidyl peptidase IV, a multifunctional serine protease, is implicated in regulation of malignant transformation, promotion and further progression of cancer, exerting tumor-suppressing or even completely opposite - tumor-promoting activities. The aim of present research was to determine the serum DPPIV activity, as well as the percentages of CD26+ lymphocytes, CD26+ overall white blood cells and the mean fluorescence intensity of CD26 expression on lymphocytes in patients with melanoma, people with vitiligo and in healthy controls. METHODS: The activity of DPPIV in serum was determined by colorimetric test. Expression of DPPIV (as CD26) on immunocompetent peripheral white blood cells was done using flow cytometry analysis. RESULTS: Data from our study show for the first time statistically significant decrease: in the serum DPPIV activity, in the percentage of CD26+ overall white blood cells and in the percentage of lymphocytes in patients with melanoma in comparison to healthy control people. In addition, significantly lower serum DPPIV activity was found in the group of patients with melanoma in relation to people with vitiligo too. CONCLUSION: This study indicates the need for exploring the cause and the importance of the disturbances in the serum DPPIV activity and in the CD26 expression on immunocompetent cells in complex molecular mechanisms underlying the development and progression of melanoma.

New androst-4-en-17-spiro-1,3,2-oxathiaphospholanes. Synthesis, assignment of absolute configuration and in vitro cytotoxic and antimicrobial activities.

The reactions of 17α-hydroxyprogesterone with Lawesson's reagent (LR) in toluene, CH(2)Cl(2) and/or CCl(4) gave, depending on the duration of the reaction, two diastereoisomeric androst-4-en-17-spiro-1,3,2-oxathiaphospholane-2-sulfide pairs 2a,b and 3a,b in approximately 7:3 ratio, differing in configuration at the phosphorus atom. A parallel analysis of heteronuclear 2D (1)H-(13)C spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY) enabled complete (1)H and (13)C assignments of each isomer. Also, analysis of NOESY correlations provided evidence for the preferred conformation. X-ray analysis of 3a confirmed the structure and absolute configuration on phosphorus. A pathway for the formation of 1,3,2-oxathiaphospholane ring was proposed. Cytotoxic activity in vitro was tested against three tumor cell lines (human cervix carcinoma HeLa cells and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compound 3a and mixture 3a,b showed a moderate activity against HeLa and MDA-MB-453 cell lines while against MDA-MB-361 cell line all tested compounds exerted very weak cytotoxic effect. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, toxicity to brine shrimp Artemia salina, were evaluated. All tested compounds showed strong antifungal activity.

Serum DPPIV activity and CD26 expression on lymphocytes in patients with benign or malignant breast tumors.

The aim of this work was to determine serum DPPIV activity as well as the percentage of CD26+ white blood cells and of CD26+ lymphocytes and the mean fluorescence intensity (MFI) of CD26 expression on lymphocytes in groups of patients with benign or malignant breast tumors and in healthy control people. Serum DPPIV activity was determined by colorimetric test, while CD26+ cells were counted using flow cytometer. Results of this study show that there is no statistically significant difference in serum DPPIV activity between examined groups of patients and healthy controls. However, two times higher frequency of patients with breast cancers had the enhanced DPPIV enzymatic activity in comparison to controls. Significant decrease in the percentage of CD26+ total white blood cells was found in the group of breast cancer patients and in patients with benign breast tumors compared to that found for healthy people. Although there was decrease in the percentage of lymphocytes in patients with breast tumors it was not statistically significant. The MFI of CD26 expression on these cells was significantly lower for cancer patients in comparison to healthy controls. In conclusion, this work showed the enhanced frequency of breast cancer patients with higher serum DPPIV activity. Decreased percentage of CD26+ white blood cells and decreased CD26 expression on lymphocytes are also characteristics of this group of patients. Determination of the clinical outcome of analyzed patients, 1 and 2 years after the surgical resection of the tumor, would clarify potential prognostic values of examined parameters for breast cancer.

Synthesis, antitumor activity and QSAR studies of some 4-aminomethylidene derivatives of edaravone.

A series of aminomethylidene derivatives obtained from 4-formyledaravone were synthesized and characterized by IR, NMR and elemental analysis. All the compounds were screened for their antitumor activity. The compound containing 5-phenylpyrazole moiety (3q) exhibited remarkable antitumor activity in in vitro assays, especially against human breast cancer MDA-MB-361 and MDA-MB-453 cell lines. The most important whole-molecule descriptors for antitumor activity on MDA-MB-453 cells belong to the group of quantum-chemical descriptors.

An alignment independent 3D QSAR study of the antiproliferative activity of 1,2,4,5-tetraoxanes.

An alignment-free 3D QSAR study on antiproliferative activity of the thirty-three 1,2,4,5-tetraoxane derivatives toward two human dedifferentiated cell lines was reported. GRIND methodology, where descriptors are derived from GRID molecular interaction fields (MIF), were used. It was found that pharmacophoric pattern attributed to the most potent derivatives include amido NH of the primary or secondary amide, and the acetoxy fragments at positions 7 and 12 of steroid core which are, along with the tetraoxane ring, common for all studied compounds. Independently, simple multiple regression model obtained by using the whole-molecular properties, confirmed that the hydrophobicity and the H-bond donor properties are the main parameters influencing potency of compounds toward human cervix carcinoma (HeLa) and human malignant melanoma (FemX) cell lines. Corollary, similar structural motifs are found to be important for the potency toward both examined cell lines.

Cytotoxic and cell cycle effects induced by two herbal extracts on human cervix carcinoma and human breast cancer cell lines.

In recent times interest has increased in the complementary medicine of cancer patients. Two herbal mixtures were prepared from 17 and 12 plants, respectively. The goal of this study was to examine the in vitro cytotoxic and cell cycle effects of the aqueous-ethanol extracts (Extract 1 and Extract 2) obtained by maceration of the mixtures. The two extracts investigated exhibited significant antiproliferative activity toward two human breast cancer cell lines (MDA-MB-361 and MDA-MB-453) and a human cervix carcinoma cell line (HeLa) with 50% inhibitory concentration (IC(50)) values ranging from 9.92 to 17.38 microL/mL. The extracts did not exert any significant cytotoxicity toward healthy human peripheral blood mononuclear cells. In vitro antitumor activities were accompanied by an important apoptotic fraction of all cell lines after treatment with the extracts. The amount of total phenols was similar in both extracts, whereas the concentration of total tannins was significantly higher in Extract 1. Extract 1 was also found to be a stronger free radical scavenger, with an IC(50) value of 13.4 microg/mL. Both extracts contained rosmarinic acid, while ursolic acid was identified in Extract 2.

Improvement of cytotoxicity of titanocene-functionalized mesoporous materials by the increase of the titanium content.

The reaction of [Ti(eta(5)-C(5)H(5))(2)Cl(2)] (1), with 3-mercaptopropyltrimethoxysilane or 3-mercaptopropyltriethoxysilane in the presence of triethylamine leads to the formation of the thiolate complexes [Ti(eta(5)-C(5)H(5))(2){SCH(2)CH(2)CH(2)Si(OMe)(3)}(2)] (2) and [Ti(eta(5)-C(5)H(5))(2){SCH(2)CH(2)CH(2)Si(OEt)(3)}(2)] (3), respectively. Complexes 2 and 3 have been characterized by traditional methods, in addition, structural studies based on DFT calculations are reported. 1-3 have been grafted onto dehydroxylated MCM-41 to give the novel materials MCM-41/[Ti(eta(5)-C(5)H(5))(2)Cl(2)] (S1), MCM-41/[Ti(eta(5)-C(5)H(5))(2){SCH(2)CH(2)CH(2)Si(OMe)(3)}(2)] (S2) and MCM-41/[Ti(eta(5)-C(5)H(5))(2){SCH(2)CH(2)CH(2)Si(OEt)(3)}(2)] (S3) which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, multinuclear MAS NMR spectroscopy, thermogravimetry, UV spectroscopy, SEM and TEM. Materials S2 and S3 present much higher values of Ti wt% (ca. 3%) than S1 (ca. 1%), indicating the higher functionalization rate induced by the substitution of the chloro ligands by the thiolato ligands in the starting titanocene derivatives. The cytotoxicity of the non-functionalized MCM-41 and S1-S3 toward human cancer cell lines such as adenocarcinoma HeLa, human myelogenous leukemia K562 and human malignant melanoma Fem-x has been studied. In addition the cytotoxicity of these materials on normal immunocompetent cells such as stimulated (PBMC+PHA) and non-stimulated (PBMC-PHA) peripheral blood mononuclear cells have been also studied. M(50) values (quantity of material needed to inhibit normal cell survival by 50%) of the studied surfaces show that non-functionalized MCM-41 was not active against any of the studied cells, while the functionalized surfaces S1-S3 were active against all the tested human cancer cells. The cytotoxic activity of surfaces S2 and S3 were very similar, however, S1 showed lower cytotoxic activity. This phenomenon indicates that the cytotoxicity of the titanocene-functionalized materials strongly depends on the titanium content.

Synthesis, characterization, electrochemical studies and antitumor activity of some new chalcone analogues containing ferrocenyl pyrazole moiety.

A series of new alpha,beta-unsaturated conjugated ketones containing ferrocenyl pyrazole unit were synthesized and fully characterized by IR and NMR spectroscopy. Electrochemical characterization of subject compounds was performed by means of cyclic voltametry. The in vitro cytotoxic activity of all the synthesized compounds was studied against cervix adenocarcinoma HeLa, melanoma Fem-x and myelogenous leukemia K562 cell lines by the MTT method. Derivative 1l containing 3-pyridyl moiety exhibited a better cytotoxic activity in the cell growth inhibition of K562 cell lines in comparison with cisplatin as a reference compound.

Some patients with NHL possessed immunoreactivity to gliadin and to cow's milk proteins.

Non-Hodgkin lymphoma (NHL) represents heterogeneous group of diseases either B, or T cell origin. In order to assess whether food antigens contribute to the imbalance of immune response, the aim of this work was screening the sera of patients with (mostly) B cell NHL, and of people with non-malignant health disorders (NMD), as well as of healthy people for their immunoreactivity to food constituent gliadin, and to cow's milk proteins. Data obtained by ELISA tests show the existence of the enhanced immunoreactivity to food antigens in some NHL patients, as well as in some people with NMD. The high degree of coincidence in the presence of enhanced levels of immune complexes in circulation (CIC) and of immunoreactivity with gliadin in immunofixation (after the serum protein electrophoresis in agarose gel in veronal buffer, at pH 8.6) especially in NHL patients points that some antigliadin immunoreactivity unrevealed in ELISA tests could be hidden in CIC. This, only in the presence of malignant genotype, as well as the enhanced levels of CIC in some of NHL patients could both, at least partially contribute to the persistent non-specific support of disease. They call for the new research of the clinical importance of both, the elevated humoral immunity to food antigens (gluten, cow's milk proteins) for the course of this very severe hematological disease.

A new generation of anticancer drugs: mesoporous materials modified with titanocene complexes.

Dehydroxylated MCM-41 and SBA-15 surfaces were modified by the grafting of two different titanocene complexes ([Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] and [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)]) to give new materials, which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, MAS-NMR spectroscopy, thermogravimetry, SEM, and TEM. The toxicity of the resulting materials toward human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, and normal immunocompetent cells, such as peripheral blood mononuclear cells PBMC has been studied. Estimation of the number of particles per gram of material led to the calculation of Q(50) values for these samples, which is the number of particles required to inhibit normal cell growth by 50%. In addition, M(50) values (quantity of material needed to inhibit normal cell growth by 50%) of the studied surfaces is also reported. Nonfunctionalized MCM-41 and SBA-15 did not show notable antiproliferative activity, whereas functionalization of these materials with different titanocene based anticancer drugs led to very promising antitumoral activity. The best Q(50) values correspond to titanocene functionalized MCM-41 surfaces (MCM-41/[Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] (1) and MCM-41/[Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (2)) with Q(50) values between 3.8+/-0.6x10(8) and 24.5+/-3.0x10(8) particles. Titanocene functionalized SBA-15 surfaces (SBA-15/[Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] (3) and SBA-15/[Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (4)) gave higher Q(50) values, showing lower activity from 73.2+/-9.9x10(8) to 362+/-7x10(8) particles. The best response of the studied materials in terms of M(50) values was observed against Fem-x (309+/-42 microg for 4) and K562 (338+/-18 microg for 2), whereas moderate activities were observed in HeLa cells (from 508+/-63 microg of 2 to 912+/-10 microg of 1). In addition, the analyzed surfaces presented only marginal activity against unstimulated and stimulated PBMC, showing a slight selectivity on human cancer cells. Comparison of the in vitro cytotoxicity in solution of the titanocene complexes [Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] and [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] and the corresponding titanocene functionalized materials is also described.

Palladium(II) complexes with R2edda-derived ligands. Part II. Synthesis, characterization and in vitro antitumoral studies of R2eddip esters and palladium(II) complexes.

New R(2)eddip-type esters (R = cyclopentyl, L3 x 2 HCl 1.5 H(2)O; cyclohexyl, L4 x 2 HCl x H(2)O) and corresponding palladium(II) complexes, [PdCl(2)L3] (3) and [PdCl(2)L4] x H(2)O (4), as well as [PdCl(2)L2] (2; L2 diisobutyl ester of eddip) were synthesized and characterized by IR, (1)H and (13)C NMR spectroscopies and elemental analysis. The crystal structure of L3 x 2 HCl x 2 CHCl(3) was resolved and is given herein. The NMR spectroscopy confirmed the presence of two isomers (from three possible) for each palladium(II) complex. DFT calculations support the formation of two diastereoisomers. In addition, antitumoral investigations were performed and these investigations also included the diisopropyl ester of eddip (L1) and corresponding palladium(II) complex, [PdCl(2)L1] (1). In vitro antiproliferative activity was determined against several tumor cell lines HeLa, Fem-x, K562 and rested and stimulated normal immunocompetent cells (human peripheral blood mononuclear cells--PBMCs) using MTT test.

Study of the cytotoxic activity of di and triphenyltin(IV) carboxylate complexes.

The reaction of 3-methoxyphenylacetic acid (3-MPAH), 4-methoxyphenylacetic acid (4-MPAH), 2,5-dimethyl-3-furoic acid (DMFUH) or 1,4-benzodioxane-6-carboxylic acid (BZDOH) with triphenyltin(IV) chloride (1:1) or diphenyltin(IV) dichloride (2:1) in the presence of triethylamine yielded the compounds [SnPh3(3-MPA)] (1), [SnPh3(4-MPA)] (2), [SnPh3(DMFU)] (3), [SnPh3(BZDO)] (4), [SnPh2(3-MPA)2] (5), [SnPh2(4-MPA)2] (6), [SnPh2(DMFU)2] (7) and [SnPh2(BZDO)2] (8), respectively. The tetranuclear complex [{Me2(DMFU)SnOSn(DMFU)Me2}2] (9) was prepared by the reaction of dimethyltin(IV) oxide and 2,5-dimethyl-3-furoic acid (DMFUH). The molecular structures of 3, 4 and 9, were determined by X-ray diffraction studies. The cytotoxic activity of the carboxylic acids (3-MPAH, 4-MPAH, BZDOH and DMFUH) and di (5-8) and triphenyltin(IV) complexes (2-4) was tested against tumor cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x and normal immunocompetent cells, peripheral blood mononuclear cells PBMC. Triphenyltin(IV) complexes show higher activities than the diphenyltin(IV) derivatives. The most active compound is [SnPh3(DMFU)] (3) with IC50 value of 0.15+/-0.01, 0.051+/-0.004, 0.074+/-0.004, 0.20+/-0.01, 0.15+/-0.02 on HeLa, K562, Fem-x, rested and stimulated PBMC, respectively, while the most selective are [SnPh2(3-MPA)2] (5), [SnPh(2)(DMFU)2] (7) and [SnPh((BZDO)2] (8). Compounds 3, 5, 7 and 8 present higher activities than cisplatin in all the tested cells and relative high selectivity especially on K562 cells.

Docking studies and anti-inflammatory activity of beta-hydroxy-beta-arylpropanoic acids.

The article describes a two-step synthesis of diastereomeric 3-hydroxy-2-methyl-3-(4-biphenylyl)butanoic acids. In the first step an intermediate alpha-bromo propanoic acid 1-ethoxyethyl ester was synthesized. The second step is a new modified Reformatsky reaction in presence of Zn in tetrahydrofuran (THF) at -5 to 10 degrees C between the previously synthesized intermediate and 4-acetylbiphenyl. Synthesis of the other studied beta-hydroxy-beta-arylpropanoic acids has already been reported. These beta-hydroxy-beta-arylpropanoic acids belong to the arylpropanoic acid class of compounds, structurally similar to the NSAIDs such as ibuprofen. The anti-inflammatory activity and gastric tolerability of the synthesized compounds were evaluated. Molecular docking experiments were carried out to identify potential COX-2 inhibitors among the beta-hydroxy-beta-aryl-alkanoic acids class. The results indicate that all compounds possess significant anti-inflammatory activity after oral administration and that the compounds 2-(9-(9-hydroxy-fluorenyl))-2-methylpropanoic acid (5) and 3-hydroxy-3,3-diphenyl-propanoic acid (3) possess the strongest anti-inflammatory activity, comparable to that of ibuprofen, a standard NSAID,and that none of tested substances or ibuprofen produced any significant gastric lesions.