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The search is ongoing for new anticancer therapeutics that would overcome resistance to chemotherapy. This includes chronic myeloid leukemia, particularly suitable for the studies of novel anticancer compounds due to its homogenous and well-known genetic background. Here we show anticancer efficacy of novel dicarboximide denoted BK124.1 (C

Gold(I) complexes with phosphine ligands—[Au(TrippyPhos)Cl] (1) (TrippyPhos = 1-[2-[bis(tert-butyl)phosphino]phenyl]-3,5-diphenyl-1H-pyrazole), [Au(BippyPhos)Cl]0.5CH2Cl2 (2) (BippyPhos = 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole), and [Au(meCgPPh)Cl] (3) (meCgPPh = 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane—were investigated as types of bioactive gold metallodrugs. Complexes (1)–(3) were characterized using IR, 1H, 13C, 31P NMR spectroscopy, elemental analysis and mass spectrometry (FAB-MS). Complexes of (1) and (2) exhibited substantial in vitro cytotoxicity (IC50 = 0.5–7.0 μM) against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the A549 human lung carcinoma, K562 chronic myelogenous leukemia, and HeLa (human cervix carcinoma) cells. However, among the compounds studied, complex (2) showed the most promising biological properties: the highest stability in biologically relevant media, selectivity towards cancer cells over the non-cancer cells (HUVEC, human umbilical vein endothelial cells), and the highest inhibitory effect on cytosolic NADPH-dependent reductases in A2780 and A2780cis cells among the gold complexes under analysis.

Functionalized carbon nanotubes are interesting, promising and unique delivery systems for anticancer drugs, which are now in the spotlight of nanomedicine. Connecting nanotubes with anticancer drugs or new compounds with anticancer properties aims at improving their stability, efficiency and reduces the toxic side effects of cancer treatment. In our research, we are interested in connecting functionalized MWCNTs-NH2 with [InH][trans-RuCl4(In)2], (KP1019) which is one of the most promising anticancer ruthenium(iii) drug candidates, known mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers. As a result of the amidation of MWCNTs (1), MWCNTs-NH2 (2) were obtained. Then, they were modified with [InH][RuCl4(In)2] (4) and the nanosystem [MWCNT-NH3+][RuCl4(In)2-] (3) was obtained. The characterization of the resulting products was performed using IR, Raman spectroscopy, thermal gravimetric, XRD, STEM-EDX, ESI-MS, ICP-MS, and XPS analyses. The cytotoxic activity has been tested on human lung carcinoma (A549), chronic myelogenous leukemia (K562) and human cervix carcinoma (HeLa) cells which showed the higher toxicity of the nanosystem than the ruthenium complex.

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.

Functionalized carbon nanotubes are interesting, promising and unique delivery systems for anticancer drugs, which are now in the spotlight of nanomedicine. Connecting nanotubes with anticancer drugs or new compounds with anticancer properties aims at improving their stability, efficiency and reduces the toxic side effects of cancer treatment. In our research, we are interested in connecting functionalized MWCNTs-NH2 with [InH][trans-RuCl4(In)2], (KP1019) which is one of the most promising anticancer ruthenium(iii) drug candidates, known mainly as a cytotoxic agent for the treatment of platinum-resistant colorectal cancers. As a result of the amidation of MWCNTs (1), MWCNTs-NH2 (2) were obtained. Then, they were modified with [InH][RuCl4(In)2] (4) and the nanosystem [MWCNT-NH3+][RuCl4(In)2-] (3) was obtained. The characterization of the resulting products was performed using IR, Raman spectroscopy, thermal gravimetric, XRD, STEM-EDX, ESI-MS, ICP-MS, and XPS analyses. The cytotoxic activity has been tested on human lung carcinoma (A549), chronic myelogenous leukemia (K562) and human cervix carcinoma (HeLa) cells which showed the higher toxicity of the nanosystem than the ruthenium complex.

This study was aimed towards the development of a novel microfluidic approach for the preparation of (co)polymeric and hybrid nanoparticles (NPs) composed of (co)polymers/tannic acid (TA) in the microfluidic flow-focusing glass-capillary device. The MiliQ water was used as water phase, whereas the organic phase was composed of poly(e-caprolactone) (PCL) and poly(trimethylene carbonate) (PTMC) homopolymers and (co)polymers with different proportion of comonomers which were prepared via enzymatic polymerization that allows avoiding the usage of potentially toxic catalyst. To prepare hybrid NPs, TA was additionally added to the organic phase. Subsequently, as a result of mixing between these distinct phases in microfluidic channels, the nanoprecipitation in the form of spherical NPs occurs. The size of NPs was tuned over the range of 140-230 nm by controlling phase flow rates and the composition of NPs. Moreover, the release studies of the encapsulated anticancer drug doxorubicin (DOX) demonstrated that the drug release is greatly influenced by the (co)polymers composition, their molecular weight, NPs size, and the presence of TA. The antitumor activities of the (co)polymeric and hybrid NPs toward breast cancer cells (MCF-7) were tested in vitro. Among all tested formulation, the NPs composed of PCL/TA most efficiently inhibit the cell proliferation of MCF-7 cells, most importantly, their efficiency was higher than free DOX. The proposed strategy may provide an efficient alternative for the construction of nanocarriers with great potential in anticancer therapy.

Two mononuclear ruthenium(iii) mer- and fac-isomers of the formula [RuCl3(PPh3)(dmpbt)] (where PPh3 = triphenylphosphine, dmpbt = 2-(3,5-dimethylpyrazoll-yl)benzothiazole) have been synthesised from the reaction of [RuCl3(PPh3)3] with a bidentate ligand - dmpbt. Appropriate reaction conditions allowed obtaining the two isomers separately without separation techniques. X-ray crystallography has determined the crystal and molecular structures of the new complexes. mer-Ru(iii) (1) crystallised in the monoclinic P2(1)/n group, and fac-Ru(iii) (2, 2') in the triclinic P1[combining macron] space group. The composition of the ruthenium coordination sphere was confirmed and characterised using spectroscopic techniques (FT-IR, UV-vis and EPR), elemental analysis and mass spectrometry (MS-FAB). The structures of the complexes obtained were analysed using X-ray and other spectroscopic methods (IR and UV-vis). The electrochemical properties of the ligand and the complex compound were identified using cyclic voltammetry, determining the potential and charge of faradaic processes. Both isomers are redox active and display quasi-reversible metal centered redox processes for the Ru(iii)/Ru(ii) pair. Moreover, preliminary tests of their biological activity were performed. The cytotoxicity of these compounds has been tested for human lung carcinoma (A549), chronic myelogenous leukemia (K562), human cervix carcinoma (HeLa) cells, acute lymphoblastic leukemia (MOLT-4), human breast adenocarcinoma cell line (MCF-7) and normal human umbilical vein endothelial cells (HUVEC). The ability to induce apoptosis has been demonstrated in caspase 3/7 activity assay. In addition, the lipophilicity of both isomers was described by a partition coefficient, log P, values of which were estimated by the shake-flask method. The interesting and promising preliminary results of the biological and chemical activities of the new octahedral mer/fac Ru(iii) complexes motivate further in vitro and in vivo studies.

A two new series of ferrocene containing quinolinones – 1-allyl-2-ferrocenyl-2,3-dihydroquinolin-4(1H)-ones and 1-allyl-2-ferrocenylquinolin-4(1H)-ones – were prepared and characterized by standard spectroscopic techniques and cyclic voltammetry. The in vitro antitumor activity of all synthesized compounds was investigated against Human Cervix Carcinoma (HeLa), Chronic Myelogenous Leukemia (K562) and normal endothelial (HUVEC) cell lines using the MTT method. Quinolone derivative 5c exhibited the highest cytotoxic activity in the cell growth inhibition of HeLa cell line while 5f was the most toxic against K562 cells.

Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2′‐deoxy‐5‐oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31 %). The synthetic outcomes were confirmed by X‐ray structure determination of dicobalt hexacarbonyl 2′‐deoxy‐5‐(4‐hydroxybut‐1‐yn‐1‐yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2′‐deoxy‐5‐alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80 μm for the HeLa cell line and 18 to 30 μm for the K562 cell line. Coordination of an acetyl‐substituted cobalt nucleoside was expanded by using the 1,1‐bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress.

Five ruthenium(II) half-sandwich complexes containing arene and coumarin ligands with the general formula [Ru(arene)(L)Cl2] or [Ru(arene)(L2)Cl]Cl were synthesized. L: 3-aminocoumarin and 7-amino-4-methylcoumarin were used for the synthesis of complex compounds. The complexes were characterized by 1H NMR, IR, UV–Vis spectroscopy, electrospray mass spectrometry (ESI MS), elemental analysis and cyclic voltammetry measurement. X-ray crystallography found one molecular structure to be of pseudo-octahedral geometry. All compounds were also tested on Chronic Myelogenous Leukemia (K562), Human Cervix Carcinoma (HeLa), Human Pancreatic Carcinoma (CFPAC) cancer cell lines, and the viability of cells was evaluated by MTT assay.

A series of 3-benzylidenechrmanones 1, 3, 5, 7, 9 and their spiropyrazoline analogues 2, 4, 6, 8, 10 were synthesized. X-ray analysis confirms that compounds 2 and 8 crystallize in a monoclinic system in P21/n space groups with one and three molecules in each asymmetric unit. The crystal lattice of the analyzed compounds is enhanced by hydrogen bonds. The primary aim of the study was to evaluate the anti-proliferative potential of 3-benzylidenechromanones and their spiropyrazoline analogues towards four cancer cell lines. Our results indicate that parent compounds 1 and 9 with a phenyl ring at C2 have lower cytotoxic activity against cancer cell lines than their spiropyrazolines analogues. Analysis of IC50 values showed that the compounds 3 and 7 exhibited higher cytotoxic activity against cancer cells, being more active than the reference compound (4-chromanone or quercetin). The results of this study indicate that the incorporation of a pyrazoline ring into the 3-arylideneflavanone results in an improvement of the compounds&rsquo, activity and therefore it may be of use in the search of new anticancer agents. Further analysis allowed us to demonstrate the compounds to have a strong inhibitory effect on the cell cycle. For instance, compounds 2, 10 induced 60% of HL-60 cells to be arrested in G2/M phase. Using a DNA-cleavage protection assay we also demonstrated that tested compounds interact with DNA. All compounds at the concentrations corresponding to cytotoxic properties are not toxic towards red blood cells, and do not contribute to hemolysis of RBCs.

A large group of aminoalkyl and aminoalkanol derivatives of selected dicarboximides were synthesized and characterized by 1HNMR, 13CNMR and ESI MS spectra analysis. The thirty nine new compounds were tested for their cytotoxic properties in human chronic (K562), acute leukemia (HL-60), and cervical cancer cells (HeLa) as well as in normal endothelial cells (HUVEC). The most promising compounds are 4-[2-(dimethylamino)ethyl]-, (diethylamino) ethyl]-, 4-[2-(piperidin-1-yl)ethyl]-, 4-[3-(dimethylamino)propyl]- and 4-[2-hydroxy-3-(propan- 2-ylamino)propyl]- derivatives of 1,7-diethyl-8,9-diphenyl-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5,10-trione exhibiting high and selective cytotoxicity towards K562 and HL-60 cells (IC 50 in the range of 1-10 µM) while being non-toxic towards HUVEC and HeLa cells (IC 50 > 100 μM). Moreover, the preliminary studies have showed that 4-[2-(piperidin-1-yl)ethyl]- 1,7-diethyl-8,9-diphenyl-4-azatricyclo [5.2.1.0 2,6 ]dec-8-ene-3,5,10-trione induces programmed cell death (apoptosis) in leukemia cells.

A series of variously functionalized selenium-containing compounds were purposely synthesized and evaluated against a panel of cancer cell lines. Most of the compounds showed an interesting cytotoxicity profile with compound 5 showing a potent activity on MCF7 cells. The ethyl amino derivative 5 acts synergistically with cis-platin and inhibits the GST enzyme with a potency that well correlates with the cytotoxicity observed in MCF7 cells. A computational analysis suggests a possible binding mode on the GST enzyme. As the main outcome of the present study, the ethyl amino derivative 5 emerged as a valid lead compound for further, future developments.

A series of novel diosgenin (DSG) and tigogenin (TGG) derivatives with diosgenin or tigogenin steroid aglycons linked to levulinic and 3,4-dihydroxycinnamic acids, dipeptides and various amino acids by an ester bond at the C3-oxygen atom of the steroid skeleton has been synthesized. Diosgenyl esters have been prepared by an esterification reaction (DCC/DMAP) of diosgenin with the corresponding acids. All analogues have been evaluated in vitro for their antiproliferative profile against cancer cell lines (MCF-7, MDA-MB-231, PC-3) and human umbilical vein endothelial cells (HUVEC). Analogue2c (l-serine derivative of TGG), the best representative of the series showed IC50 of 1.5 μM (MCF-7), and induced apoptosis in MCF-7 by activating caspase-3/7. The immunomodulatory properties of six synthesized analogues have been determined by examining their effects on the expression of cytokine genes essential for the functioning of the human immune system (IL-1, IL-4, IL-10, IL-12 and TNF-α). Biological evaluation has revealed that new compounds 4c and 16a do not induce the expression of pro-inflammatory cytokines in THP-1 cells after the lipopolysaccharide (LPS) stimulation. They also stimulate the expression of anti-inflammatory IL-10 that acts stronger than diosgenin itself. An in silico ADME properties(absorption, distribution, metabolism, excretion) study was also performed to predict the pharmacokinetic profile of the synthesized compounds. To shed light on the molecular interactions between the synthesized compounds and the glucocorticoid receptor and the estrogen receptor, 2c, 4c and 16a compounds were docked into the active binding sites of these receptors. The in silico and in vitro data suggested that this new group of compounds might be considered as a promising scaffold for further modification of more potent and selective anticancer and immunomodulatory agents.

Background:Novel derivatives of benzo[b]furan were found to be highly toxic towards human chronic myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells.Objective:The objective was the characterization of the biological activity of novel benzofurans (influence on apoptosis, mitogen-activated protein kinases and on the cell cycle). Cellular protein(s) targeted by test benzofurans and mechanism of action were identified.Methods:The methods utilized in the study were chemical synthesis, fluorescence assays, flow cytometry, gene expression by DNA microarray and real-time RT-PCR, western blotting, cytotoxicity assays, pull-down assay, mass spectroscopy, in vitro polymerization of tubulin, molecular docking.Results:1,1'-[3-(bromomethyl)-5,6- dimethoxy-1-benzofuran-2,7-diyldiethanone (1) and methyl 4-bromo-6- (dibromoacetyl)-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate (2) induced apoptosis in K562 and MOLT-4 cells. The profiling of gene expression revealed that 1 and 2 increased the expression of proapoptotic genes involved in both receptor (TNFRSF 10A, TNFRSF 10B, CASP8) and mitochondrial (BAX, BID, NOXA, APAF1) pathways of apoptosis. Test benzo[b]furans activated c-Jun N-terminal kinase (JNK) and p38 kinase in K562 cells. Tubulin was identified as a protein target for benzo[b]furans in pull-down experiments with biotinylated 2. Test benzo[b]furans inhibited polymerization of tubulin monomers in vitro, decreased the level of cellular microtubules and arrested cells in a G2/M phase. Molecular docking suggests that benzo[b]furans 1 and 2 bind to tubulin via colchicine binding pocket and the complex is stabilized mainly by hydrophobic interactions.Conclusion:Novel benzo[b]furans with anti-microtubule activity were identified. They induce apoptosis in cancer cells and cause G2/M cell cycle arrest. Biological activity of 1 and 2 makes them potential lead compounds for development as anticancer drugs.

This article presents the synthesis of three new 4-thiopyrimidine derivatives obtained from ethyl 4-methyl-2-phenyl-6-sulfanylpyrimidine-5-carboxylate as the starting material, namely, ethyl 4-[(4-chlorobenzyl)sulfanyl]-6-methyl-2-phenylpyrimidine-5-carboxylate, C21H19ClN2O2S, (2), {4-[(4-chlorobenzyl)sulfanyl]-6-methyl-2-phenylpyrimidin-5-yl}methanol, C19H17ClN2OS, (3), and 4-[(4-chlorobenzyl)sulfanyl]-5,6-dimethyl-2-phenylpyrimidine, C19H17ClN2S, (4), which vary in the substituent at the 5-position of the pyrimidine ring. The compounds were characterized by 1H NMR, 13C NMR, IR and mass spectroscopies, and also elemental analysis. The molecular structures were further studied by single-crystal X-ray diffraction. Compound (2) crystallizes in the space group P-1 with one molecule in the asymmetric unit, whereas compounds (3) and (4) crystallize in the space group P21/c with two and one molecule, respectively, in their asymmetric units. The conformation of each molecule is best defined by the dihedral angles formed between the pyrimidine ring and the planes of the two aryl substituents attached at the 2- and 4-positions. The only structural difference between the three compounds is the substituent at the 5-position of the pyrimidine ring, but they present significantly different features in the hydrogen-bond interactions. Compound (2) displays a one-dimensional chain formed by hydrogen bonds and the chains are further extended into a two-dimensional network. Molecules of (3) and (4) generate one-dimensional chains formed through intermolecular interactions. The study examines the cytotoxicity of compounds (3) and (4) against Human umbilical vein endothelial cells (HUVEC) and HeLa, K562 and CFPAC cancer cell lines. The presence of the hydroxymethyl and methyl groups in (3) and (4), respectively, offers an interesting new insight into the structures and behaviour of these derivatives. Compound (4) was found to be nontoxic against CFPAC and HUVEC; however, it shows weak activity against the HeLa and K563 cell lines. The presence of a hydroxy group in (3) significantly increases its cytotoxicity towards both, i.e. the cancer (HeLa, K562 and CFPAC) and normal (HUVEC) cell lines.

Copper(II), cobalt(II) and nickel (II) complexes (1–6) of 1-[amino(thioxo)methyl]-5-hydroxy-3-methyl-1H-pyrazole have been synthesized and characterized by IR, UV-Vis, NMR, ESI-MS and elemental analysis. Ligand and metal(II) complexes have been screened for their toxic effect on HeLa and K562 cancer cell lines, as well as on normal HUVEC cells. Cytotoxic effectiveness of copper(II) complexes (1 and 4) (IC50 2–5 μM after 48 h) was 4–50 times higher than that of other complexes and cisplatin. These complexes were non-toxic to primary human endothelial cells. For these complexes, induction of cell apoptosis by the caspase 3/7 assay has been measured. The interactions with DNA by the enzymatic method have also been investigated.

Hydrazone hesperetin Schiff base (HHSB) - N-[(±)-[5,7-dihydroxy-2-(3-hydroxy-4-methoxy-phenyl)chroman-4-ylidene]amino]benzamide has been synthesized and its crystal structure was determined. This compound was used for the formation of Cu(II) complexes in solid state and in solution which were characterized using different spectroscopic methods. The analyses of potentiometric titration curves revealed that monomeric and dimeric complexes of Cu(II) are formed above pH7. The ESI-MS (electrospray ionization-mass spectrometry) spectra confirmed their formation. The EPR and UV-visible spectra evidenced the involvement of oxygen and nitrogen atoms in Cu(II) coordination. Hydrazone hesperetin Schiff base can show keto-enol tautomerism and coordinate Cu(II) in the keto (O(-), N, Oket) and in the enolate form (O(-), N, O(-)enol). The semi-empirical molecular orbital method PM6 and DFT (density functional theory) calculations have revealed that the more stable form of the dimeric complex is that one in which the ligand is present in the enol form. The CuHHSB complex has shown high efficiency in the cleavage of plasmid DNA in aqueous solution, indicating its potential as chemical nuclease. Studies on DNA interactions, antimicrobial and cytotoxic activities have been undertaken to gain more information on the biological significance of HHSB and copper(II)-HHSB chelate species.

A series of 38 new derivatives of cyclic imides containing silicon in the structure was synthesized and characterized by 1H NMR, ESI-MS, and elemental analysis. Selected compounds (1l,m, 1g, 1o,p, 2l,m, and 2o,p) were tested for their cytotoxic properties in human chronic myelogenous leukemia (K562), human cervical cancer (HeLa), and normal endothelial cells (HUVEC). Seven compounds showed significant cytotoxicity. In addition, two compounds (1l and 2l) were tested toward affinity for 5-HT1A, 5-HT6, and 5-HT7 serotonin receptors, and all aryl/heteroarylopiperazino derivatives were tested for antimicrobial activity. The compounds tested toward affinity for selected serotonin receptors showed high and moderate affinity for 5-HT1A and 5-HT7, while the antimicrobial activity of tested compounds was not significant.

The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 μM. Moreover, the C7-hydroxy derivative of NEPP11 displayed high cytotoxic selectivity between cancer cell lines and normal human cells. On the other hand, the J-type prostaglandin analogue of NEPP11 and its C13-hydroxy derivatives were much less toxic or nontoxic against the cancer and normal cells at concentrations up to 1 mM.

Biocompatible and biodegradable stereocomplexed micelles (SCMs) based on polylactides (PLAs) with β-cyclodextrin (β-CD) core were designed and used as efficient intracellular drug carriers. The micelles formation, stability and drug release behavior of enantiomeric and stereocomplexed micelles with β-CD core were systematically investigated in comparison to the micelles composed of PLAs with dipentaerythritol (DPE) core. The presence of β-CD core allows for the formation of inclusion complex with a model anticancer drug: doxorubicin (DOX), whereas stereocomplexation between PLLA and PDLA enhanced the stability of obtained micelles. By the utility of different supramolecular interactions, we were able to control the release of DOX from obtained micelles. The release tests of DOX from supramolecular nanocarriers showed that DOX release changes in the order of DPE core micelles >β-CD core micelles >SCMs. The antitumor activities of the enantiomeric and stereocomplexed micelles toward HeLa (cervical cancer) and K562 (chronic myelogenous leukemia) cells were tested in vitro. Our data demonstrated that the SCMs/DOX more effectively inhibited the cell proliferation than similar enantiomeric micelles and for the highest concentration of DOX inside the SCMs. Most importantly, micelles were more efficient than free DOX. In summary, the supramolecular interactions can provide a favourable tool to construct a drug delivery system with controlled drug release and efficient tumor cell suppression which is beneficial for cancer therapy.

In the search for new antimicrobial and anticancer agents, a series of (aryl/heteroaryl-piperazino-alkyl)-substituted derivatives of benzo[b]furans were prepared. All compounds were characterized by 1H NMR, 13C NMR, ESI-MS spectra and elemental analyses. Most of the investigated compounds had no antimicrobial activity (MIC > 512 mg/L) except for 2l, 2m and 2o, which showed activity against Candida albicans. None of the tested compounds showed significant anticancer activity in K562 and HeLa cells.

In the search for biological agents, a series of new N-substituted ethyl 11-ethyl-7-methyl-3,5,10-trioxo-4-azatricyclo[5.2.2.02,6]undecane-8-carboxylates 3, 9-methyl-3,5,8-trioxo-4-azatricyclo[5.2.1.02,6]dec-1-yl acetates 6 and 1,3-dioxo-4,5,6,7-tetraphenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-4-carboxylic acids 9 were prepared. All compounds were characterized by 1H NMR, ESI-MS, and elemental analyses. Moreover, for intermediate products 2, 5, and 8, X-ray structural analyses were conducted. Compounds 3a–e, 6a, 6b, 9a–e were tested for their cytotoxic properties in K562 and HeLa cells.

Aim The antioxidative and antinitrative activities of (1→3)-β- d -glucan (1–4 μg/ml) from the yeast cell walls of Saccharomyces cerevisiae in human plasma treated with strong oxidants – peroxynitrite (ONOO − ) (0.1 mM) and hydrogen peroxide (H 2 O 2 ) (2 mM) were studied in vitro. The main purpose of this study was to assess if (1→3)-β- d -glucan, a well known strong immunostimulatory agent, possesses a protective function against dual mechanism of ONOO − stroke associated with nitrative and oxidative damages to human plasma biomolecules. Scope The protein changes were determined in vitro by estimating the level of oxidative stress markers – carbonyl groups, and nitrative products – 3-nitrotyrosine residues. The plasma lipid peroxidation was also investigated. The obtained results show that (1→3)-β- d -glucan inhibits in vitro ONOO − -induced oxidation and nitration of plasma proteins, even by 50% and 30%, respectively. The antioxidative activity of (1→3)-β- d -glucan was confirmed by its inhibitory effect on plasma lipids peroxidation induced by ONOO − or by H 2 O 2 . Conclusions The obtained results demonstrate that (1→3)-β- d -glucan from S. cerevisiae protects plasma components against toxic effects of ONOO − and H 2 O 2 due to its antioxidative and antinitrative activities. Therefore (1→3)-β- d -glucan supplementation during inflammatory may be beneficial not only regard for its ability to stimulate the immune system but also by antioxidative properties.

The effects of the beta-D-glucan, a polysaccharide derived from the yeast cell walls of species such as Saccharomyces cerevisiae, on blood platelets activation induced by physiological agonists (thrombin, ADP, collagen) in vitro were studied. The aim of our study was to assess in vitro if beta-glucan, a naturally strong biological response modifier, may modify platelet activation, i.e. platelet aggregation and degranulation (release of proteins and adenine nucleotides) induced by thrombin, ADP and collagen. Cytochrome c reduction method was used to test the ability of beta-glucan to change superoxide anion generation in platelets. Moreover, we determined also its effect on enzymatic arachidonic acid cascade. The obtained results indicate that beta-glucan has the inhibitory effects on platelet aggregation and secretion. beta-glucan distinctly reduced the arachidonic acid pathway and superoxide anion radical generation in platelets stimulated by biological agonists. The results of the present study suggest that beta-glucan from Saccharomyces cerevisiae has antiplatelet and antioxidative activities, and therefore may be beneficial in the prevention of the excessive blood platelet activation-related diseases, such as cardiovascular or inflammatory diseases.

Gemcitabine (dFdC) is a cytidine analog remarkably active against a wide range of solid tumors. Inside a cell, gemcitabine is phosphorylated by deoxycytidine kinase to yield gemcitabine monophosphate, further converted to gemcitabine di- and triphosphate. The most frequent form of acquired resistance to gemcitabine in vitro is the deoxycytidine kinase deficiency. Thus, proper prodrugs carrying the 5'-pdFdC moiety may help to overcome this problem. A series of new derivatives of gemcitabine possessing N-acyl(thio)phosphoramidate moieties were prepared and their cytotoxic properties were determined. N-Acyl-phosphoramidate derivatives of gemcitabine have similar cytotoxicity as gemcitabine itself, and have been found accessible to the cellular enzymes. The nicotinic carboxamide derivative of gemcitabine 5'-O-phosphorothioate occurred to be the best inhibitor of bacterial DNA polymerase I and human DNA polymerase α.

In the search for novel biological agents, a series of new derivatives N-substituted 1,3-benzoxazol-2(3H)-one, 5-chloro-1,3-benzoxazol-2(3H)-one, 6-bromo-1,3-benzoxazol-2(3H)-one were prepared. All of the compounds were characterized by 1H NMR, 13C NMR and ESI MS spectra. Moreover, for compound 1 an Xray structure was determined. All derivatives were tested for antimicrobial activity against a selection of Gram-positive, Gram-negative bacteria and yeasts. The selected compounds (2-8, 10) were tested for their cytotoxic properties in K562, HeLa and normal cells.

Three new calcium(II) complexes with heterocyclic alcohol (2-hydroxymethylpyridine), aldehyde (4- methyl-5-carbaldehydeimidazole) and carboxylate (picolinate, obtained in situ ) moieties were synthes- ised and characterised using elemental analysis, X-ray, IR (Raman), 1 H, and 13 C NMR methods. In addition, we compared the X-ray results obtained for calcium(II) complexes with the structures of previously described cadmium compounds, which from the chemical point of view (HSAB and Lewis acids and bases theories) can give some information for the ability of Cd 2+ to mimic Ca 2+ ions in biological systems too. The studied ligands, calcium compounds ( 1 – 3 ) and cadmium analogues were tested for their cytotoxicity against HeLa (cervical carcinoma), K562 (leukaemia) and normal cells (HUVEC) using a 3-(4,5-dimethyl- thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.

A new approach to the synthesis of 5-arylisoxazolidine-3-phosphonates (III) (10 examples) utilizing 1,3-dipolar cycloaddition of nitrone (I) to styrenes is accomplished.

The cycloaddition reaction between nitrone (I) and chalcones (II) leads to isolated major isoxazolidines (III).

A new series of isomeric isoxazolidin-3-yl-3-phosphonates were synthesised from N -methyl- C -diethoxyphosphorylnitrone and substituted chalcones. The respective isoxazolidin-3-yl-3-phosphonic acids were obtained from phosphonates via dealkylation procedure using trimethylsilyl bromide. Selected phosphonates and their respective phosphonic acids were screened for their cytotoxic activity to HeLa and K562 cells with IC 50 in the 0.1–0.3 mM range.

5-Arylisoxazolidin-3-yl-3-diethoxyphosphonates have been synthesized from N-methyl-C-diethoxyphosphorylnitrone and vinyl aryls in good yields and their transformation into the respective phosphonic acids has been accomplished via dealkylation procedure using trimethylsilyl bromide. Phosphonates having 1- and 2-naphthyl substituents at C5 in the isoxazolidine ring as well as the respective phosphonic acids have been found cytotoxic to HeLa and K562 cells with IC(50) in the 0.1-0.3 mM range. Preliminary studies on mechanism of action imply that intercalation to DNA is not responsible for their cytotoxic properties.

Blood platelets in addition to their haemostatic role can function as inflammatory cells. The aim of our study was to assess if beta-D-glucan, the natural, very strong biological response modifier, may protect platelet proteins and lipids against oxidative/nitrative damages. The antioxidative activity of the beta-D-glucan, a known immunomodulator derived from the yeast cell walls of species such as Saccharomyces cerevisiae, on blood platelets treated with oxidants-peroxynitrite and hydroperoxide-was studied in vitro. The levels of different specific markers of oxidative stress, thiobarbituric acid reactive substances (TBARS), carbonyl groups and 3-nitrotyrosine (3-NT) were measured. Our studies showed that beta-glucan possesses significant defence properties against peroxynitrite or hydroperoxide induced lipid peroxidation. The level of TBARS was decreased by 80% at the highest dose of beta-glucan. In the presence of beta-glucan the distinct reduction of platelet protein oxidation was observed; the level of carbonyl groups was decreased by 50%. The results indicate that beta-glucan may also be effective in the protection against the nitrative action of peroxynitrite on platelet proteins, as in the presence of beta-glucan the level of 3-nitrotyrosine, measured by a competition-ELISA method, was diminished. The obtained in vitro results demonstrate that antiplatelet activity of beta-glucan from Saccharomyces cerevisiae is dependent on its antioxidative properties, and therefore beta-glucan supplementation may be beneficial in the prevention of excessive blood platelet activation-related diseases, such as cardiovascular or inflammatory diseases.

A series of seven derivatives of 1,1'-(5,6-dimethoxy-3-methyl-1-benzofuran-2,7-diyl)diethanone was synthesized and characterized by (1)HNMR and ESI MS spectra and elemental analyses. The obtained new compounds and three halogen derivatives of benzofuran, reported in our earlier work, were tested for their cytotoxic properties in human chronic (K562) and acute (HL60) leukemia cells, human cervical cancer (HeLa), and normal endothelial cells (HUVEC). Four compounds (2, 3, 4, 5), which contain halogens in their structure showed significant anticancer activity. The most promising was 1,1'-[3- (bromomethyl)-5,6-dimethoxy-1-benzofuran-2,7-diyl]diethanone (2), which was highly and selectively toxic for K562 cells (IC50 of 5µM) and HL60 cells (IC50 of 0.1µM), which showed no cytotoxicity toward HeLa and HUVEC cells. Moreover, the observed remarkable cytotoxicity of this compound toward K562 cells resulted from cells apoptosis.

A series of variously functionalized selenium-containing compounds were purposely synthesized and evaluated against a panel of cancer cell lines. Most of the compounds showed an interesting cytotoxicity profile with compound 5 showing a potent activity on MCF7 cells. The ethyl amino derivative 5 acts synergistically with cis-platin and inhibits the GST enzyme with a potency that well correlates with the cytotoxicity observed in MCF7 cells. A computational analysis suggests a possible binding mode on the GST enzyme. As the main outcome of the present study, the ethyl amino derivative 5 emerged as a valid lead compound for further, future developments.