Zorica D. Juranić

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.

Cytotoxic studies of substituted titanocene and ansa-titanocene anticancer drugs

A variety of substituted titanocene and ansa-titanocene complexes have been synthesized and characterized using traditional methods. The cytotoxic activity of the different titanocene complexes was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x and normal immunocompetent cells, peripheral blood mononuclear cells PBMC. Alkenyl substitution, either on the cyclopentadienyl ring or on the silicon-atom ansa-bridge of the titanocene compounds [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(3){CMe(2)CH(2)CH(2)CHCH(2)})}Cl(2)] (8), [Ti{Me(CH(2)CH)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (9) and [Ti(eta(5)-C(5)H(4){CMe(2)CH(2)CH(2)CHCH(2)})(2)Cl(2)] (12) showed higher cytotoxic activities (IC(50) values from 24+/-3 to 151+/-10 microM) relative to complexes bearing an additional alkenyl-substituted silyl substituent on the silicon bridge [Ti{Me{(CH(2)CH)Me(2)SiCH(2)CH(2)}Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (10) and [Ti{Me{(CH(2)CH)(3)SiCH(2)CH(2)}Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (11) which causes a dramatic decrease of the cytotoxicity (IC(50) values from 155+/-9 to >200 microM). In addition, the synthesis of the analogous niobocene complex [Nb(eta(5)-C(5)H(4){CMe(2)CH(2)CH(2)CH=CH(2)})(2)Cl(2)] (13), is described. Structural studies based on DFT calculations of the most active complexes 8, 9 and 12 and the X-ray crystal structure of 13 are reported.

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.

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.

A novel lectin from the sponge Haliclona cratera: isolation, characterization and biological activity

A lectin from the Adriatic sponge Haliclona cratera was purified by ion-exchange and gel chromatography. The molecular mass of the lectin is approximately 29 kDa. Purified lectin is rich in hydrophobic and basic amino acids and has an isoelectric point at pH 8.6. H. cratera lectin is relatively heat- and pH-stable. It agglutinates native and trypsinized, papainized and neuraminidase-treated human A, B, O, AB and sheep erythrocytes, and the hemagglutinating activity is independent of Ca(2+), Mn(2+) and Mg(2+) ions; D-galactose and N-acetyl-D-galactosamine are found to be moderate inhibitors of the activity. H. cratera lectin displays cytotoxic effect on HeLa and FemX cells and weak mitogenic effect on human T-lymphocytes pretreated with phytohemagglutinin (PHA).

Study of the influence of the metal complex on the cytotoxic activity of titanocene-functionalized mesoporous materials

Four different titanocene complexes, [Ti(η5-C5H5)2Cl2] (1), [Ti(η5-C5H5)(η5-C5H4Pri)Cl2] (2), [Ti(η5-C5H5)(η5-C5H4But)Cl2] (3) and [Ti(η5-C5H5){η5-C5H3(SiMe3)2}Cl2] (4), have been grafted onto dehydroxylated MCM-41 to give the novel materials MCM-41/[Ti(η5-C5H5)2Cl2] (S1), MCM-41/[Ti(η5-C5H5)(η5-C5H4Pri)Cl2] (S2), MCM-41/[Ti(η5-C5H5)(η5-C5H4But)Cl2] (S3) and MCM-41/[Ti(η5-C5H5){η5-C5H3(SiMe3)2}Cl2] (S4), 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. The cytotoxicity of the non-functionalized MCM-41 and S1–S4 toward human cancer cell lines, such as adenocarcinoma HeLa, human myelogenous leukemia K562 and human malignant melanoma Fem-x, has been studied. Additional studies of the toxicity of these materials on stimulated and non-stimulated peripheral blood mononuclear cells (PBMC + PHA and PBMC − PHA; i.e. normal immunocompetent cells) have been also carried out. M50 values (quantity of material needed to inhibit normal cell growth by 50%) of the studied surfaces are reported observing that non-functionalized MCM-41 did not show notable antiproliferative activity, while the functionalized surfaces S1–S4 were active against all of the studied human cancer cells. The cytotoxic activities of surfaces S1–S3 were very similar on all the studied cancer cells, however, S4 showed M50 values that indicate the highest activity of all the analyzed materials on all the studied cells, being two to three times more cytotoxic than S1–S3. The same tendency in the cytotoxic activity of the metal complexes 1–3 compared with 4 was observed. Taking into account that all the studied surfaces had a very similar titanium content, the activity of these surfaces strongly depends on the grafted titanocene complex (1–4). This phenomenon indicates that, in contrast with that observed by other authors, the cytotoxicity of the studied materials may be due to action of the released metal complex and is probably not due to the particle action.

Zinc(II) complexes of 2-acetyl pyridine 1-(4-fluorophenyl)-piperazinyl thiosemicarbazone: Synthesis, spectroscopic study and crystal structures – Potential anticancer drugs

2-Acetyl pyridine thiosemicarbazone containing an 1-(4-fluorophenyl)-piperazinyl ring incorporated at N(4)-position, HAcPipPheF (1) and the zinc(II) complexes [Zn(AcPipPheF)(2)] (2) and [Zn(OAc)(AcPipPheF)](2) (3) have been prepared and structurally characterized by means of vibrational and NMR ((1)H and (13)C) spectroscopy. The crystal structures of the compounds 1-3 have been determined by X-ray crystallography. The metal coordination geometry of [Zn(AcPipPheF)(2)] is described as distorted octahedral configuration in a trans-N-cis-N-cis-S configuration. In [Zn(OAc)(AcPipPheF)](2) one of the acetato group exhibits monoatomic bridge and the other bridges in a bidentate manner. The zinc(1) metal ion is coordinated in a distorted octahedral configuration while the metal coordination of Zn(2) is described as distorted square pyramidal. Biomedical studies revealed that, compounds 1-3 displayed potent anticancer activity. The antiproliferative activity of 1-3 was found to be considerably stronger than that of cis-platin. The IC(50) values range from 26 to 90nM, against all cell lines tested, while for cis-platin the IC(50) values range from 2 to 17microM and for the zinc salt, ZnCl(2), the IC(50) values range from 81 to 93microM. The complex 3 shows the highest activity against all four cancer cell lines and the highest selectivity against K562 and MDA-MB-453 cancer cell lines. The compounds inhibited tumor cell proliferation by arresting the cell cycle progression at the S phase.

In vitro cytotoxic and antioxidative activity of Cornus mas and Cotinus coggygria

Cytotoxicity and antioxidant properties of the methanol extracts of leaves and flowers of Cornus mas and Cotinus coggygria were studied, together with their chemical composition. Extracts of C. coggygria flowers and leaves showed better antioxidant activity in reaction with 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical as well as in inhibition of lipid peroxidation (LP) than C. mas extracts. Preliminary results showed that all extracts possessed potential cytotoxic activity towards HeLa and LS174 human cancer cell lines in vitro, with stronger inhibition against growth of HeLa cell growth than against LS174 cell growth. Cytotoxic activity of C. coggygria extracts showed good correlation with their antioxidative activity in vitro. In the brine shrimp lethality test, there were no significant changes in toxicity.

Chamomile and marigold tea: chemical characterization and evaluation of anticancer activity.

With the aim to evaluate the selectivity in the antitumor action, the cytotoxic activity of chamomile and marigold tea was tested against various malignant cell lines and against healthy immunocompetent peripheral blood mononuclear cells (PBMC). Chemical profiles of chamomile and marigold infusions and decoctions were analyzed by liquid chromatography/mass spectrometry; their total phenolic content and radical scavenging activity were determined, too. Results from present research demonstrate that chamomile and marigold tea exert selective dose‐dependent cytotoxic action against target cancer cells. It is noteworthy that cytotoxicity of tea prepared from Calendula officinalis is remarkably higher in comparison to that from Matricaria recutita tea. The cytotoxic effect of chamomile tea is very weak to healthy PBMC, while the effect of marigold tea on PBMC is more pronounced. Marigold tea exerts highly selective antitumor effect especially to melanoma Fem‐x cells in comparison to the action to normal healthy PBMC. Chemical analyses show that dominant phenolic compounds in examined infusions and decoctions are flavonoid glycosides and hydroxycinnamic acid derivatives. There are no considerable differences in total phenolic content and antioxidant activity between examined infusions. Antitumor potential of chamomile and marigold tea should be further investigated. Copyright

Synthesis and biological evaluation of some 17-picolyl and 17-picolinylidene androst-5-ene derivatives

Starting from dehydroepiandrosterone (1) 17-picolyl (2), 17-picolinylidene (7), 17-picolinylidene-16-one (10 and 11), and 17-picolyl-16-one (15) derivatives of androst-5-ene were synthesized in one, two, four and five steps respectively. By the Oppenauer oxidation or dehydration of 2, 7, 10, and 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the corresponding A and B ring modified derivatives 3, 5, 6, 8, 9, and 12-14 were obtained. The structure of 2 was unambiguously proved by the appropriate X-ray structural analysis. Compounds 3, 5, 9, 12-14 showed inhibitory activity against the enzyme aromatase. Antibacterial activity, toxicity to brine shrimp Artemia salina, antitumor activity against three tumor cell lines (human cervix carcinoma HeLa cells, human melanoma FemX cells, and human myelogenous leukemia K562 cells) and toxicity against peripheral blood mononuclear cells were evaluated. Three tested compounds, namely 11, 13, and 15, showed strong activity against all three cell lines, the IC(50) values being in the range of 4-10 microM.