Synthesis,characterization, in vitro antimicrobial and cytotoxic evaluation of Co(II), Ni(II), Cu(II) and Zn(II) complexes derived from bidentate hydrazones

Co(II), Ni(II), Cu(II) and Zn(II) complexes have been synthesized from hydrazone ligands (HL¹–HL⁴) obtained by condensation reaction of 6-chlorothiochroman-4-one with benz hydrazide/nicotinic hydrazide/isonicotinic hydrazide/p-toluic hydrazide. The synthesized compounds (1–20) were characterized by physicochemical procedures, i.e. (FTIR, ¹H NMR, ¹³C NMR, mass, ESR, UV–Vis), TGA/DTA, powder XRD, elemental analysis (CHN), magnetic susceptibility and molar conductance measurements. The various data suggested bidentate nature (NO) of hydrazones, which coordinate with central metal ions via nitrogen of azomethine (–C=N–) group and deprotonated carbonyl oxygen in the enolized form, resulting in octahedral complexes. Low values of molar conductance suggested their non-electrolytic nature. Thermal decomposition pattern of complexes confirms the metal oxides as end product. In vitro antimicrobial activity of hydrazones and their metal complexes were evaluated against two gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus); two gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli); and two fungal strains (Candida albicans and Aspergillus niger) by serial dilution method, and it was found that the metal complexes were highly active as compared to hydrazones. Among all the compounds, complexes 11, 13, 14 and 19 were found most efficient antimicrobial agent. The anticancer activity of (1–20) compounds was performed on human cancer cell lines A549 (lung), DU145 (prostate) and SW620 (colorectal) by MTT assay using paclitaxel as reference drug. The cytotoxicity results suggested compounds [Cu(L²)₂(H₂O)₂] 11 as most potent against A549, DU145 and SW620 cancer cell lines with IC₅₀ values of 3.46, 18.21 and 7.61 µM. Furthermore, compounds (9, 10, 11, 12) were also investigated on A549 cell line for their ROS generation and mitochondrial membrane potential loss and suggested that complex [Cu(L²)₂(H₂O)₂] 11 has highest ROS production and induction of apoptosis by mitochondrial depolarization in cancer cells.

Graphic abstract

The synthesized compounds (1–20) were screened for in vitro cytotoxicity against A549 (lung), DU145 (prostate), SW620 (colorectal) human cancer cell lines. Copper complex (11) was found to be the most active antitumor agent which enhance ROS production and MMP loss on A549 cells.

     

A Cyclometalated IrIII Complex Conjugated to a Coumarin Derivative Is a Potent Photodynamic Agent against Prostate Differentiated and Tumorigenic Cancer Stem Cells

A cyclometalated Ir^III complex conjugated to a far-red-emitting coumarin, Ir^III-COUPY ( 3 ), was recently shown as a very promising photosensitizer suitable for photodynamic therapy of cancer. Therefore, the primary goal of this work was to deepen knowledge on the mechanism of its photoactivated antitumor action so that this information could be used to propose a new class of compounds as drug candidates for curing very hardly treatable human tumors, such as androgen resistant prostatic tumors of metastatic origin. Conventional anticancer chemotherapies exhibit several disadvantages, such as limited efficiency to target cancer stem cells (CSCs), which are considered the main reason for chemotherapy resistance, relapse, and metastasis. Herein, we show, using DU145 tumor cells, taken as the model of hormone-refractory and aggressive prostate cancer cells resistant to conventional antineoplastic drugs, that the photoactivated conjugate 3 very efficiently eliminates both prostate bulk (differentiated) and prostate hardly treatable CSCs simultaneously and with a similar efficiency. Notably, the very low toxicity of Ir^III-COUPY conjugate in the prostate DU145 cells in the dark and its pronounced selectivity for tumor cells compared with noncancerous cells could result in low side effects and reduced damage of healthy cells during the photoactivated therapy by this agent. Moreover, the experiments performed with the 3D spheroids formed from DU145 CSCs showed that conjugate 3 can penetrate the inner layers of tumor spheres, which might markedly increase its therapeutic effect. Also interestingly, this conjugate induces apoptotic cell death in prostate cancer DU145 cells associated with calcium signaling flux in these cells and autophagy. To the best of our knowledge, this is the first study demonstrating that a photoactivatable metal-based compound is an efficient agent capable of killing even hardly treatable CSCs.     

A novel bidentate ligand containing oxime,hydrazone and indole moieties and its BF2+ bridged transition metal complexes and their efficiency against prostate and breast cancer cells

In this study, a novel bidentate ligand containing oxime, hydrazone, and indole moieties and its BF₂⁺-bridged transition metal complexes [Ni(II), Cu(II), and Co(II)] were synthesized and their cytotoxic activities against prostate and breast cancer cells were investigated. The vic-dioxime ligand bearing indole–hydrazone side groups was synthesized by reacting antiglyoximehydrazine (GH₂) with 3-methoxy indole. The ligand forms mononuclear complexes with a metal-to-ligand ratio of 1:2 with M = Co(II)(H₂O)₂, Ni(II), and Cu(II). These metal complexes were then reacted with BF₃(C₂H₅)₂O to obtain BF₂⁺-bridged transition metal complexes. The Co(II) complex of the ligand is proposed to be octahedral with water molecules as axial ligands, whereas the Ni(II) and Cu(II) complexes are proposed to be square planar. Spectral studies showed that the ligand bonded to the metal ion in a neutral bidentate fashion through the azomethine nitrogen atom and the imine oxime group. Structural assignments are supported by a combination of ¹H nuclear magnetic resonance (NMR), ¹³C NMR, Fourier-transform infrared, LC/MS, elemental analyses, and magnetic susceptibility testing. For determining the cytotoxic effects of the novel anticancer products, cancer cells were cultured. The antiproliferative effects were determined using the MCF-7 breast cancer and PC-3 prostate cancer cell lines. The antiproliferative effects of the products were analyzed and their apoptotic or necrotic effects were determined with the Hoechst/propidium iodide double staining method in both cancer cell lines. Paclitaxel was used as the positive control (1 μm ). The results indicated that the newly synthesized compounds are effective on both cell lines between concentrations of 5 and 40 μm and show their effects by apoptotic mechanisms. Besides, these products were found to be more effective on the MCF-7 cell line. The cytotoxic efficiency of the newly synthesized products was more than that of paclitaxel (depending on concentration), which is a chemotherapeutic agent used in cancer therapy.     

2-Deoxy-d-glucose Promotes Buforin IIb-Induced Cytotoxicity in Prostate Cancer DU145 Cells and Xenograft Tumors

Inhibition of the glycolytic pathway is a critical strategy in anticancer therapy because of the role of aerobic glycolysis in cancer cells. The glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) has shown potential in combination with other anticancer agents. Buforin IIb is an effective antimicrobial peptide (AMP) with broad-spectrum anticancer activity and selectivity. The efficacy of combination treatment with 2-DG and buforin IIb in prostate cancer remains unknown. Here, we tested the efficacy of buforin IIb as a mitochondria-targeting AMP in the androgen-independent human prostate cancer cell line DU145. Combining 2-DG with buforin IIb had a synergistic toxic effect on DU145 cells and mouse xenograft tumors. Combination treatment with 2-DG and buforin IIb caused stronger proliferation inhibition, greater G1 cell cycle arrest, and higher apoptosis than either treatment alone. Combination treatment dramatically decreased L-lactate production and intracellular ATP levels, indicating severe inhibition of glycolysis and ATP production. Flow cytometry and confocal laser scanning microscopy results indicate that 2-DG may increase buforin IIb uptake by DU145 cells, thereby increasing the mitochondria-targeting capacity of buforin IIb. This may partly explain the effect of combination treatment on enhancing buforin IIb-induced apoptosis. Consistently, 2-DG increased mitochondrial dysfunction and upregulated Bax/Bcl-2, promoting cytochrome c release to initiate procaspase 3 cleavage induced by buforin IIb. These results suggest that 2-DG sensitizes prostate cancer DU145 cells to buforin IIb. Moreover, combination treatment caused minimal hemolysis and cytotoxicity to normal WPMY-1 cells. Collectively, the current study demonstrates that dual targeting of glycolysis and mitochondria by 2-DG and buforin IIb may be an effective anticancer strategy for the treatment of some advanced prostate cancer.     

Design,synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines

A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines(PC-3, LNCa P, and DU145) were evaluated by a CCK-8 assay. Compounds 8, 10, 13, 17 and 20 exhibited strong cytotoxic activities against the tested cancer cell lines(IC_(50)3 μmol/L). In addition, these compounds exhibited weak cytotoxic effects on human epithelial prostate normal cells WPMY-1. The structure–activity relationship(SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.     

Synthesis,crystal structures,and urease inhibition studies of two new Schiff-base copper complexes derived from n-butylamine

Two Schiff-base copper(II) complexes, bis(N-n-butyl-5-chlorosalicylaldiminato) copper(II) (1) and bis(N-n-butyl-4-methoxysalicylaldiminato) copper(II) (2), were synthesized and their solid-state structures were determined by X-ray crystallography. Complex 1 displays a distorted square-planar geometry, while 2 possesses square-planar geometry. Copper(II) complexes 1 and 2 showed strong inhibitory activity against jack bean urease (IC₅₀?=?2.7, 3.5?µmol?L^?1), compared with acetohydroxamic acid (IC₅₀?=?63.00?µmol?L^?1). A molecular modeling study was carried out via the DOCK program to gain understanding of the potent inhibitory activity of these copper species against jack bean urease.     

人血清白蛋白与Cu(II)配合物的生物活性研究

Cu(II)配合物很有可能成为下一代的抗肿瘤药物。本文以2-氨基-5-氯苯酚和2-喹啉甲醛合成的席夫碱作为配体,与Cu(II)络合形成配合物1。分别对配合物1和其与人血清白蛋白(HSA)的复合物HSA-1进行体外抗肿瘤测试,发现HSA能提高配合物1的抗肿瘤活性,并降低了对正常细胞的毒性。通过线粒体膜电位等实验,可以推断出配合物1是通过线粒体通路诱导癌细胞凋亡。     

Synthesis,spectral characterization,and anticancer activity of 6-methylpyridine-2-carbaldehdyethiosemicarbazone and its complexes; crystal structure and DFT calculations of [Pd(mpyptsc)Cl]·DMSO

Synthesis and characterization of new complexes of 6-methylpyridine-2-carbaldehydethiosemicarbazone (Hmpytsc) and 6-methylpyridine-2-carbaldehyde-N(4)-phenylthiosemicarbazone (Hmpyptsc) with [VO₂L], [Zn(HL)Cl₂], [Ru(PPh₃)₂L₂], and [MLCl] (M(II)?=?Pd, Pt; HL?=?Hmpytsc, Hmpyptsc) are reported. Their structures are discussed on the basis of IR, Raman, UV–vis, NMR (¹H, ¹³C, and ³¹P), and mass spectroscopic data, as well as elemental analysis and molar conductivity. In the X-ray crystal structure of the square-planar [Pd(mpyptsc)Cl]·DMSO, mpyptsc^? is coordinated to Pd(II) in a tridentate manner through pyridyl N, azomethine N, and thiol S, and the fourth coordination site is occupied by a chloride. A theoretical study on [Pd(mpyptsc)Cl]·DMSO was undertaken through DFT conformational analysis. The in vitro cytotoxic activity has been evaluated against human colon cancer (HCT116) and prostate cancer (DU145) cell lines. Hmpyptsc and [Zn(Hmpyptsc)Cl₂] were most active with mean IC₅₀ values of 3.32 and 2.60 (HCT116), and 3.60 and 3.10 (DU145)?μM, respectively.     

Nano-TiO2-Induced Apoptosis by Oxidative Stress-Mediated DNA Damage and Activation of p53 in Human Embryonic Kidney Cells

The aim of the present study is to explore the mechanism of cytotoxic and genotoxic effects of TiO₂ nanoparticles on human embryonic kidney (HEK-293) cells. Toxicity was evaluated using changes in various cellular parameters of HEK-293 cells like morphology, viability, metabolic activity, oxidative stress and apoptosis. Oxidative stress was measured by the level of reactive oxygen species (ROS), lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase. Apoptosis induced by nano-TiO₂ was characterized by PI staining and DNA ladder assay. Furthermore, apoptotic proteins such as p53 and Bax were analysed by western blot. Our results indicate that nano-TiO₂ induces cytotoxicity in a time- and dose-dependent manner. Oxidative stress and apoptosis were induced by exposure to nano-TiO₂. Moreover, the expression of p53, Bax and caspase-3 were increased in a dose-dependent pattern. In conclusion, ROS-mediated oxidative stress, the activation of p53, Bax, caspase-3 and oxidative DNA damage are involved in the mechanistic pathways of nano-TiO₂-induced apoptosis in HEK-293 cells.     

Production of Terretonin N and Butyrolactone I by Thermophilic Aspergillus terreus TM8 Promoted Apoptosis and Cell Death in Human Prostate and Ovarian Cancer Cells

The anticancer activity of terretonin N (1) and butyrolactone I (2), obtained from the thermophilic fungus Aspergillus terreus TM8, was intensively studied against prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines. According to this study, both compounds showed potent cytotoxicity towards ovarian adenocarcinoma cells (SKOV3) with IC₅₀ 1.2 and 0.6 μg/mL, respectively. With respect to metastatic prostate cells (PC-3), the two compounds 1 and 2 showed a significantly promising cytotoxicity effect with IC₅₀ of 7.4 and 4.5 μg/mL, respectively. The tested fungal metabolites showed higher rates of early and late apoptosis with little or no necrotic apoptotic pathway in all treated prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines, respectively. The results reported in this study confirmed the promising biological properties of terretonin N (1) and butyrolactone I (2) as anticancer agents via the induction of cellular apoptosis. However, further studies are needed to elucidate the molecular mechanism by which cellular apoptosis is induced in cancer cells.     

Cytotoxicity of syringin and 4-methoxycinnamyl alcohol isolated from Foeniculum vulgare on selected human cell lines

This study was carried out to determine the cytotoxic effect of seven plant extracts and the isolated compounds – syringin and 4-methoxycinnamyl alcohol – on cancerous and non-cancerous cells. The ethanol extract of Foeniculum vulgare was found to exhibit the most significant toxicity with an IC₅₀ value of 19.97 μg/mL on HeLa cells. Bioassay-guided fractionation led to the isolation of two compounds, syringin (1) and 4-methoxycinnamyl alcohol (2). Both compounds showed toxicity against MCF-7, HeLa and DU145 cancer cell line. The results showed that compound 2 showed high toxicity against all the cancer cell lines with IC₅₀ values of 14.24, 7.82 and 22.10 μg/mL, respectively. 4-Methoxycinnamyl alcohol also showed no apoptotic effect in cell cycle analysis after 48 h at a concentration of 10 μg/mL. However, DNA fragmentation study revealed that necrosis took place at a concentration of 10 μg/mL after 48 h exposure.     

Copper binding agents acting as copper ionophores lead to caspase inhibition and paraptotic cell death in human cancer cells

We report a quantitative structure-activity relationship study of a new class of pyrazole-pyridine copper complexes that establishes a clear correlation between the ability to promote copper accumulation and cytotoxicity. Intracellular metal accumulation is maximized when ligand lipophilicity allows the complex to rapidly cross the membrane. Copper and ligand follow different uptake kinetics and reach different intracellular equilibrium concentrations. These results support a model in which the ligand acts as an ionophore for the metal ion, cycling between intra- and extracellular compartments as dissociated or complexed entities. When treating cancer cells with structurally unrelated disulfiram and pyrazole-pyridine copper complexes, as well as with inorganic copper, the same morphological and molecular changes were reproduced, indicating that copper overload is responsible for the cytotoxic effects. Copper-based treatments drive sensitive cancer cells toward paraptotic cell death, a process hallmarked by endoplasmic reticulum stress and massive vacuolization in the absence of apoptotic features. A lack of caspase activation, as observed in copper-treated dying cells, is a consequence of metal-mediated inhibition of caspase-3. Thus, copper acts simultaneously as an endoplasmic reticulum (ER) stress inducer and a caspase-3 inhibitor, forcing the cell into caspase-independent paraptotic death. The establishment of a mechanism of action common to different copper binding agents provides a rationale for the exploitation of copper toxicity as an anticancer tool.     

Design, synthesis, and antitumor activities of some novel substituted 1,2,3-benzotriazines

A series of novel substituted 1,2,3-benzotriazines based on the structures of vatalanib succinate (PTK787) and vandetanib (ZD6474) were designed and synthesized. The antiproliferative effects of these compounds were tested on microvascular endothelial cells (MVECs) using the MTT assay. Introduction of a methoxy and a 3-chloropropoxy group into the 1,2,3-benzotriazines increased the antiproliferative effects. 4-(3-Chloro-4- fluoroanilino)-7-(3-chloropropoxy)-6-methoxy-1,2,3-benzotriazine (8m) was the most effective compound. It was 4-10 fold more potent than PTK787 in inhibiting the growth of T47D breast cancer cells, DU145 and PC-3 prostate cancer cells, LL/2 murine Lewis lung cancer cells and B16F0 melanoma cells.     

Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents.     

Synthesis,spectroscopic characterization,biological screening and in vitro cytotoxic studies of 4‐methyl‐3‐thiosemicarbazone derived Schiff bases and their Co (II), Ni (II), Cu (II) and Zn (II) complexes

A series of twenty compounds inclusive of bidentate Schiff bases derived from condensation of 4‐methyl‐3‐thiosemicarbazide with substituted derivatives of napthaldehyde/benzaldehyde/salicylaldehyde and their mononuclear Co (II), Ni (II), Cu (II) and Zn (II) complexes in molar ratio (1:1) were synthesized and characterized. The coordination behavior, modes of bonding and overall geometry of the compounds was known from the elemental analysis, spectral techniques (IR, UV–Vis, ¹H NMR, ¹³C NMR, ESR and ESI‐mass), magnetic moment measurements, molar conductance, thermal and powder XRD studies. The studies revealed octahedral geometry for all the complexes where ligands coordinated in a neutral bidentate manner (NS) via nitrogen atom of azomethine group and sulphur atom of thione group with the metal centre. In vitro biological effects of the compounds were tested against four bacterial species and two fungal strains. The results indicated that the metal complexes showed a marked enhancement in biocidal activity in comparable with the parent Schiff bases. In vitro anticancer activity against the malignant tumor cell lines; human alveolar adenocarcinoma epithelial cell line (A549), human breast adenocarcinoma cell line (MCF7), human prostate cancer cell line (DU145) and human normal lung cell line (MRC‐5) using MTT assay, exposed compound 16 as a leading member with lowest IC₅₀ value of 10.6 ± 0.14 μM against (A549) cell line.     

Excelsanone,a new isoflavonoid from Erythrina excelsa (Fabaceae), with in vitro antioxidant and in vitro cytotoxic effects on prostate cancer cells lines

Abstract

A new isoflavonoid, excelsanone (2), was isolated from the ethyl acetate extract of Erythrina excelsa stem bark, together with three known compounds namely 6,8-diprenylgenistein (3), β-sitosterol (1) and sitosteryl-β-D-glucopyranoside (4). Their structures were elucidated using spectroscopic methods (HR-ESI-MS, NMR and IR) and by comparison with some literature data. The antioxidant activity of crude extracts and two isolated compounds was evaluated using free radical scavenging (DPPH) and Ferric Reducing Ability Power (FRAP) methods with catechin as standard. The results of the radical scavenging activity showed that excelsanone (2) has a moderate potential with an IC₅₀ of 1.31?mg/ml. The cytotoxicity of compounds 2 and 3 as well as the ethyl acetate extract was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in two prostate cancer cell lines (DU145 and PC3). Excelsanone (2) induced a greater cytotoxicity in all tested cell lines, with a significant inhibition of DU145 cells growth in a concentration-dependent manner.     

Bioactive Tryptophan-Based Copper Complex with Auxiliary β-Carboline Spectacle Potential on Human Breast Cancer Cells: In Vitro and In Vivo Studies

Biocompatible tryptophan-derived copper (1) and zinc (2) complexes with norharmane (β-carboline) were designed, synthesized, characterized, and evaluated for the potential anticancer activity in vitro and in vivo. The in vitro cytotoxicity of both complexes 1 and 2 were assessed against two cancerous cells: (human breast cancer) MCF7 and (liver hepatocellular cancer) HepG2 cells with a non-tumorigenic: (human embryonic kidney) HEK293 cells. The results exhibited a potentially decent selectivity of 1 against MCF7 cells with an IC₅₀ value of 7.8 ± 0.4 μM compared to 2 (less active, IC₅₀ ~ 20 μM). Furthermore, we analyzed the level of glutathione, lipid peroxidation, and visualized ROS generation to get an insight into the mechanistic pathway and witnessed oxidative stress. These in vitro results were ascertained by in vivo experiments, which also supported the free radical-mediated oxidative stress. The comet assay confirmed the oxidative stress that leads to DNA damage. The histopathology of the liver also ascertained the low toxicity of 1.     

In Vitro Effects of Papaverine on Cell Proliferation,Reactive Oxygen Species,and Cell Cycle Progression in Cancer Cells

Papaverine (PPV) is an alkaloid isolated from the Papaver somniferum. Research has shown that PPV inhibits proliferation. However, several questions remain regarding the effects of PPV in tumorigenic cells. In this study, the influence of PPV was investigated on the proliferation (spectrophotometry), morphology (light microscopy), oxidative stress (fluorescent microscopy), and cell cycle progression (flow cytometry) in MDA-MB-231, A549, and DU145 cell lines. Exposure to 150 μM PPV resulted in time- and dose-dependent antiproliferative activity with reduced cell growth to 56%, 53%, and 64% in the MDA-MB-231, A549, and DU145 cell lines, respectively. Light microscopy revealed that PPV exposure increased cellular protrusions in MDA-MB-231 and A549 cells to 34% and 23%. Hydrogen peroxide production increased to 1.04-, 1.02-, and 1.44-fold in PPV-treated MDA-MB-231, A549, and DU145 cells, respectively, compared to cells propagated in growth medium. Furthermore, exposure to PPV resulted in an increase of cells in the sub-G₁ phase by 46% and endoreduplication by 10% compared to cells propagated in growth medium that presented with 2.8% cells in the sub-G₁ phase and less than 1% in endoreduplication. The results of this study contribute to understanding of effects of PPV on cancer cell lines.     

Anticancer metallopharmaceutical agents based on mixed‐ligand palladium(II) complexes with dithiocarbamates and tertiary organophosphine ligands

Mixed‐ligand palladium(II) complexes of the type [(DT)Pd(PR₃)Cl], where DT = diethyldithiocarbamate (1), dibutyldithiocarbamate (2,3), dipropyldithiocarbamate (4,5), bis(2‐methoxyethyl)dithiocarbamate; PR₃ = benzyldiphenylphosphine (1,4), diphenyl‐o‐tolylphosphine (2), diphenyl‐t‐butylphosphine (3), P‐chlorodiphenylphosphine (5) and triphenylphosphine (6), have been synthesized and characterized by elemental analyses and FT‐IR, Raman and multinuclear NMR spectroscopy. The structures of compounds 1 and 2 were determined by single‐crystal X‐ray diffraction (XRD) measurements and these analyses showed that the complexes have pseudo square‐planar geometry around the Pd(II) and that the dithiocarbamate ligand is bound in a bidentate fashion, while the remaining two positions are occupied by a tertiary organophosphine and a chloride ligand. The anticancer studies showed that the Pd(II) complexes are highly active against cisplatin‐resistant DU145 human prostate carcinoma (HTB‐81) cells with the highest activity shown by compound 6 (IC₅₀ = 2.12 µm ). The redox behavior and ds‐DNA‐denaturing ability of the complexes were studied by cyclic voltammetry and two reduction and one oxidation waves were observed. The decrease in the reduction peak currents illustrated the consumption of the mixed‐ligand drug by the DNA molecule. Copyright © 2013 John Wiley & Sons, Ltd.     

In vitro antitumor activity,ADME-Tox and 3D-QSAR of synthesized and selected natural styryl lactones

Prostate cancer is a common cause of death in men and a novel treating methods should be developed. In order to find a new drug for prostate cancer, a series of novel conformationally constrained analogues of (+)-goniofufurone and 7-epi-(+)-goniofufurone, as well as the newly synthesized styryl lactones containing the cinnamic acid ester groups were evaluated for in vitro cytotoxicity against prostate cancer cell (PC-3). Furthermore, prediction of physicochemical characteristics and drugability as well as in silico ADME-Tox tests of investigated compounds were performed. The 3D-QSAR model was established using the comparative molecular field analysis method. According to obtained results, the tricyclic compounds 9 and 10 had the highest potency with IC₅₀ < 20 μM. Evaluation of structural features through 3D-QSAR model identified steric field feature on the cinnamic acid ester groups at C-7 as a crucial for the cytotoxic activity. This research suggests that most of the analysed compounds have desirable properties for drug candidates and high potential in drug development, which recommend them for further research in treatment of prostate cancer. Furthermore, obtained 3D-QSAR model is able to successfully identify styryl lactones that have significant cytotoxic activity and provide information for screening and design of novel inhibitors against PC-3 cell line that could be used as drugs in treatment of the prostate cancer.