Targeting telomerase utilizing zeolitic imidazole frameworks as non-viral gene delivery agents across different cancer cell types.

Telomerase, a ribonucleoprotein coded by the hTERT gene, plays an important role in cellular immortalization and carcinogenesis. hTERT is a suitable target for cancer therapeutics as its activity is highly upregulated in most of cancer cells but absent in normal somatic cells. Here, by employing the two Metal-Organic Frameworks (MOFs), viz. ZIF-C and ZIF-8, based biomineralization we encapsulate Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 plasmid system that targets hTERT gene (CrhTERT) in cancer cells. When comparing the two biocomposites, ZIF-C shows the better loading capacity and cell viability. The loaded plasmid in ZIF-C is highly protected against enzymatic degradation. CrhTERT@ZIF-C is efficiently endocytosed by cancer cells and the subcellular release of CrhTERT leads to telomerase knockdown. The resultant inhibition of hTERT expression decreases cellular proliferation and causing cancer cell death. Furthermore, hTERT knockdown shows a significant reduction in tumour metastasis and alters protein expression. Collectively we show the high potential of ZIF-C-based biocomposites as a promising general tool for gene therapy of different types of cancers.

Nanoformulations as a strategy to overcome the delivery limitations of cannabinoids.

Medical cannabis has received significant interest in recent years due to its promising benefits in the management of pain, anxiety, depression and neurological and movement disorders. Specifically, the major phytocannabinoids derived from the cannabis plant such as (-) trans-Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), have been shown to be responsible for the pharmacological and therapeutic properties. Recently, these phytocannabinoids have also attracted special attention in cancer treatment due to their well-known palliative benefits in chemotherapy-induced nausea, vomiting, pain and loss of appetite along with their anticancer activities. Despite the enormous pharmacological benefits, the low aqueous solubility, high instability (susceptibility to extensive first pass metabolism) and poor systemic bioavailability restrict their utilization at clinical perspective. Therefore, drug delivery strategies based on nanotechnology are emerging to improve pharmacokinetic profile and bioavailability of cannabinoids as well as enhance their targeted delivery. Here, we critically review the nano-formulation systems engineered for overcoming the delivery limitations of native phytocannabinoids including polymeric and lipid-based nanoparticles (lipid nano capsules (LNCs), nanostructured lipid carriers (NLCs), nanoemulsions (NE) and self-emulsifying drug delivery systems (SEDDS)), ethosomes and cyclodextrins as well as their therapeutic applications.

Malicious anchor node extraction using geodesic search for survivable underwater wireless sensor network.

Localization in underwater wireless sensor network (UWSN) faces an imminent threat when the triangulating anchor node starts to malfunction. Traditional geometric approaches are insufficient to cope with the survivability of UWSN topology. To address these issues, this paper presents a symplectic geometry for identification of the malicious anchor node. Consequently, a geodesic search algorithm (GSA) based Target localization is proposed which reduces the positioning error by exploiting the phase-space constancy of the underwater acoustic sensor network topology to effectively triangulate the target node despite its mobility. First, a malicious anchor node model is presented. The node movement is expressed in the form of "ripple region". GSA is then proposed which effectively frees the node metastasis from anchor node geometry, thereby making the underwater system more survivable and resilient. Simulation results evaluate the survivability of the geodesic formalism in terms of the reduced penalty incurred by node movement, as well as the reduced impact of anchor node malfunction. An improvement of 13.46% and 9.26% reveals the utility of the geodesic technique in aquamarine sensor deployments, which would be beneficial in underwater resource exploration and defense planning.

ZIF-C for targeted RNA interference and CRISPR/Cas9 based gene editing in prostate cancer.

Gene therapy is highly suited for prostate cancer (PC). Metal-organic-frameworks (MOFs) are potential gene delivery systems. Target-specific cytoplasmic and nuclear knockdown in host gene expression using ZIF-C is shown for the first time through RNAi and CRISPR/Cas9 based gene editing in PC cells. A green tea phytochemical coating enhances intracellular delivery.

Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect.

The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 µM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.

Pyrazolo-benzothiazole hybrids: Synthesis, anticancer properties and evaluation of antiangiogenic activity using in vitro VEGFR-2 kinase and in vivo transgenic zebrafish model.

A series of new pyrazolo-benzothiazole hybrids (7-26) were synthesised and screened for their cytotoxic activity towards several cancer cell lines [colon (HT-29), prostate (PC-3), lung (A549), glioblastoma (U87MG)] and normal human embryonic kidney cell line (Hek-293T). Compounds 8, 9, 13, 14, 18, 19, 23, and 24 displayed significant activity, with compound 14 being particularly potent towards all the tested cancer cell lines with IC50 values in the range 3.17-6.77 µM, even better than reference drug axitinib (4.88-21.7 µM). Compound 14 also showed the strongest growth inhibition in 3D multicellular spheroids of PC-3 and U87MG cells. The mechanism of cellular toxicity in PC-3 cells was found to be cell cycle arrest and apoptosis induction through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage. Further, compound 14 displayed significant in vitro (VEGFR-2 inhibition) and in vivo [transgenic zebrafish Tg(flila:EGFP) model] antiangiogenic properties. Overall, these results provide strong evidence that compound 14 could be considered for a lead candidate in anticancer and antiangiogenic drug discovery.

Potent and Selective Cytotoxic and Anti-inflammatory Gold(III) Compounds Containing Cyclometalated Phosphine Sulfide Ligands.

Four cycloaurated phosphine sulfide complexes, [Au{κ2 -2-C6 H4 P(S)Ph2 }2 ][AuX2 ] [X=Cl (2), Br (3), I (4)] and [Au{κ2 -2-C6 H4 P(S)Ph2 }2 ]PF6 (5), have been prepared and thoroughly characterized. The compounds were found to be stable under physiological-like conditions and showed excellent cytotoxicity against a broad range of cancer cell lines and remarkable cytotoxicity in 3D tumor spheroids. Mechanistic studies with cervical cancer (HeLa) cells indicated that the cytotoxic effects of the compounds involve the inhibition of thioredoxin reductase and induction of apoptosis through mitochondrial disruption. In vivo experiments in nude mice bearing HeLa xenografts showed that treatment with compounds 4 and 5 resulted in significant inhibition of tumor growth (35.8 and 46.9 %, respectively), better than that of cisplatin (29 %). The newly synthesized gold complexes were also evaluated for their in vitro and in vivo anti-inflammatory activity through the study of lipopolysaccharide (LPS)-activated macrophages and carrageenan-induced hind paw edema in rats, respectively.

Synthesis and in vitro cytotoxicity evaluation of ß-carboline-combretastatin carboxamides as apoptosis inducing agents: DNA intercalation and topoisomerase-II inhibition.

To explore a new set of cytotoxic agents, ß-carboline-combretastatin carboxamide conjugates were designed, synthesized and evaluated for their in vitro cytotoxicity potential, DNA binding affinity and Topoisomerase-II (topo-II) inhibition activity. Among the designed hybrids, 10v and 10af have shown significant cytotoxic effect against A549 (lung cancer) cell line having IC50 value 1.01 µM and 1.17 µM respectively. Further, it was speculated that treatment with compound 10v may induce apoptosis among A549 cells, which was supported by Hoechst staining, DCFDA, Annexin V-FITC and morphological assays. Flow cytometric analysis revealed that the hybrid 10v arrests A549 cells in G2/M phase of cell cycle in a dose dependent manner. Amongst the active hybrids, most potent hybrid 10v was tested for DNA topo-II inhibition activity. Moreover, to further support the biological activity and to infer the mode of interaction between ligands and DNA, spectroscopy and molecular docking studies were carried out. The docking and spectroscopy results showed that the ligands exhibited an intercalative mode of binding with DNA and could efficiently bind to DNA and form topo-II ternary complex. Based on these experiments, the hybrids 10v and 10af were identified as proficient new scaffolds which need to be developed as hit molecules for therapeutic interest.

Synthesis, anti-proliferative and apoptosis-inducing studies of palladacycles containing a diphosphine and a Sn,As-based chelate ligand.

Cleavage of the bromide bridges in [Pd2(µ-Br)2{κ2(Sn,As)-2-MeBrSnC6F4AsPh2}2] (1) by diphosphine ligands gave the mono- and dinuclear palladacycles [Pd(L)Br{κ2(Sn,As)-2-MeBrSnC6F4AsPh2}] [L = dppe (2) dppm (3), ortho-dppBz (4)] and [Pd2Br2(para-dppBz){κ2(Sn,As)-2-MeBrSnC6F4AsPh2}2] (5). The interactions of these complexes with DNA (CT-DNA) and proteins (human serum albumin) were studied by UV-Vis and fluorescence spectroscopy, respectively. The results confirmed the interaction of these palladium complexes with CT-DNA through groove binding, and their strong binding affinity to HSA. The anti-proliferative activities of complexes 1-5 were tested against four human cancer cell lines (HeLa, A549, PC-3, and HT1080) and normal keratinocytes (HaCaT). Among the series, the palladium(ii) complex containing the 1,2-bis(diphenylphosphino)benzene ligand (4) showed the highest cytotoxicity against HeLa, PC-3 and HT1080 cells, with IC50 values of 0.25 ± 0.08, 0.85 ± 0.11, and 0.66 ± 0.15 µM, respectively. Interestingly, compound 4 exhibited lower cytotoxic activity toward normal HaCaT cells (IC50 = 4.65 ± 0.16 µM). Additionally, this complex exhibited lower toxicity and better anti-cancer activity than cisplatin. Further mechanistic studies, including Hoechst staining and flow cytometry, confirmed that complex 4 induced G2/M phase cell cycle arrest and apoptotic cell death in HeLa cells.

Microwave-assisted one-pot synthesis of new phenanthrene fused-tetrahydrodibenzo-acridinones as potential cytotoxic and apoptosis inducing agents.

An expeditious microwave-assisted one-pot synthesis of new cytotoxic phenanthrene fused-tetrahydrodibenzo-acridinones has been successfully accomplished. This protocol offers wide substrate scope, catalyst-free synthesis, atom-economy, simple recrystallization, high yields, and ethanol was used as green solvent. These new compounds were tested for their in vitro cytotoxicity against cervical (HeLa), prostate (PC-3), fibrosarcoma (HT-1080), ovarian (SKOV-3) cancer cells, and were safer to normal (Hek-293T) kidney cell line. All the compounds have displayed significant cytotoxicity profile, among them 8m being the most potent compound with an IC50 0.24 ±â€¯0.05 µM against SKOV-3 ovarian cancer cells. Flow cytometry analysis revealed that cells were blocked at the G2/M phase of the cell cycle. The effect of 8m on F-actin polymerisation was also studied. Hoechst staining clearly showed the decreased number of viable cells and indicated apoptosis progression. Compound 8m caused the collapse of mitochondrial membrane potential as observed via JC-1 staining and also enhanced the generation of reactive oxygen species. The increase of caspase-3 activation by 3.7 folds supported the strong apoptosis induction. In addition, an in vitro 3D-spheroid progression assay was performed with 8m that significantly suppressed the tumor cells.

Synthesis of gold(I) phosphine complexes containing the 2-BrC6F4PPh2 ligand: Evaluation of anticancer activity in 2D and 3D spheroidal models of HeLa cancer cells.

Newly synthesised mononuclear gold complexes containing the 2-BrC6F4PPh2 ligand have been fully characterised and their anticancer activity towards five human tumor [prostate (PC3), glioblastoma (U87MG), cervical (HeLa), fibrosarcoma (HT1080), ovarian (SKOV-3)] and normal human embryonic kidney (Hek-293T) cell lines investigated. Some of the synthesised gold complexes displayed higher cytotoxicity than cisplatin towards PC-3, HeLa and U87MG cells and inhibited the thioredoxin reductase (TrxR) enzyme, which is considered a potential target for new compounds in cancer treatment. The more physiologically relevant tumor spheroid assay demonstrated the superior potency of these gold phosphine complexes in inhibiting the growth of cervical carcinoma cell line HeLa (3D) spheroidal models. The mechanism of cell death was shown to be apoptotic cell death through cell cycle arrest, mitochondrial membrane depolarisation and increased ROS production.

4ß-amidotriazole linked podophyllotoxin congeners: DNA topoisomerase-IIα inhibition and potential anticancer agents for prostate cancer.

Topoisomerases (topo-I and topo-II) have occupied a significant role in DNA replication, transcription, and are a promising set of antitumor targets. In the present approach, a series of new 4ß-amidotriazole linked podophyllotoxin derivatives (10a-i and 11a-k) were designed, synthesized by employing the click chemistry and their biological activities were evaluated. The majority of derivatives showed promising antiproliferative activity with IC50 values ranging from 1 to 10 µM on the six human cancer cell lines; cervical (HeLa), breast (MCF-7), prostate (DU-145), lung (A549), liver (HepG2) and colon (HT-29). Among them, some of the congeners 10b, 10g and 10i have shown remarkable cytotoxicity with IC50 values of, < 1 µM against the tested cancer cell lines and found to be more active than etoposide. Topoisomerase-mediated DNA relaxation assay results showed that the derivatives could efficiently inhibit the activity of topoisomerase-II. In addition, flow cytometry analysis on DU-145 cells revealed that these compounds arrest G2/M phase of cell cycle. Further apoptotic studies were also performed on these DU-145 cells, which showed that this class of compounds could induce apoptosis effectively.

Conventional and microwave-assisted synthesis of new 1H-benzimidazole-thiazolidinedione derivatives: A potential anticancer scaffold.

A series of new benzimidazole bearing thiazolidinedione derivatives has been designed, synthesized by using conventional as well as microwave-assisted methods. Microwave-assisted synthesis caused a significant reduction in the reaction times and improvement in the yields of all the derivatives. All the new synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines of breast (MDAMB-231), prostate (PC-3), cervical (HeLa), lung (A549) and bone (HT1080) along with a normal kidney cells (HeK-293T). The compounds 17n, 17p and 17q were found to be potent cytotoxic with IC50 values in the range of 0.096-0.63 µM on PC-3, HeLa, A549 and HT1080 cancer cells. Most of the compounds have found to be safe on normal HeK-293T kidney cells in comparison to cancer cells. The treatment of cells with 17p and 17q showed the typical apoptotic morphological features like fragmentation and shrinkage of nuclei. Further, test compounds resulted in inhibition of cell migration through disruption of F-actin protein assembly. Hoechst, DCFH-DA staining, mitochondrial membrane and annexin binding assays revealed that the cancer cell proliferation was inhibited through induction of apoptosis in A549 cells.

Anti-cancer gold(I) phosphine complexes: Cyclic trimers and tetramers containing the P-Au-P moiety.

We report the application of cationic tri- and tetra-nuclear gold(I) phosphine complexes [Au3(µ-dppen)3]X3 and [Au4(µ-dppa)4]X4 (X=OTf, PF6) [OTf=trifluoromethanesulfonate, dppen=trans-1,2-bis(diphenylphosphino)ethene, dppa=bis(diphenylphosphino)acetylene] for cancer treatment. The results of cytotoxicity tests on four different cancer cells [prostate (DU145), cervical (HeLa), breast (MDAMB-231) and fibro sarcoma (HT1080)] indicate these complexes possess remarkable tumor cell growth inhibitory effects and high selectivity towards cancer cells. The anti-tumor mechanism of the tri- and tetra-nuclear gold(I) complexes has also been investigated.

Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors.

A series of thiazole linked indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 13d displayed cytotoxicity of IC50 = 93 nM towards DU145 cancer cell line. The most active compound 13d was also tested on RWPE-1 cells and was found to be safe compared to the DU145 cells. The target compounds were also evaluated for their inhibition activity of tubulin polymerization. Further, the treatment of compound 13d on DU145 cells led to the inhibition of cell migration ability. The detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 13d induced apoptosis in DU145 cells. The influence of the cytotoxic compound 13d on the cell cycle distribution was assessed on the DU145 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, the treatment with compound 13d caused collapse of mitochondrial membrane potential and elevated intracellular ROS levels in DU145 cells. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Thus, this new molecular scaffold could be a new lead for the development of anticancer agents that target tubulin.

Synthesis of 2,3,6,7-tetramethoxyphenanthren-9-amine: An efficient precursor to access new 4-aza-2,3-dihydropyridophenanthrenes as apoptosis inducing agents.

A new route for the synthesis of novel 2,3,6,7-tetramethoxy phenanthrene amine precursor has been successfully accomplished. Subsequently, this amine precursor has been directly utilized for the synthesis of a new series of 4-aza-2,3-dihydropyridophenanthrene derivatives via a three component reaction with tetronic acid and substituted aldehydes. These compounds were evaluated for their cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MDA-MB-231 and 4T1), gastric (HGC-27), colon (Caco-2) and cervical (HeLa) cancer cell lines. Compound 10l showed significant anticancer profile against DU145 cell line with an IC50 value of 2.6 ± 0.34 µM. Disruption of F-actin cytoskeleton structure and cell migration inhibition in DU145 cells clearly indicate that the tumor progression and metastasis are affected by this compound (10l). Cell cycle analysis revealed that it arrests the cells in G2/M phase. Acridine orange/ethidium bromide (AO/EB) staining, Hoechst staining and annexin-V binding assays showed that cell proliferation is inhibited through induction of apoptosis. Moreover, its treatment leads to collapse of the mitochondrial membrane potential (DΨm).

Synthesis of C5-tethered indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors.

A series of C5-tethered Indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 7f displayed cytotoxicity of IC50 = 140 nM towards DU145 cancer cell line. The treatment of DU145 cells with 7f led to inhibition of cell migration ability. Futher, the detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 7f induced apoptosis in DU145 cells. The influence of the cytotoxic compound 7f on the cell cycle distribution was assessed on the DU145 cell line, exhibiting a cell cycle arrest at the G2/M phase (hallmark of tubulin polymerization) and next inhibited tubulin polymerization with IC50 0.40 µM. Furthermore, the treatment with compound 7f caused collapse of mitochondrial membrane potential and elevated intracellular superoxide ROS levels in DU145 cells. Western blotting was performed to examine the levels of apoptotic proteins (Bcl-2 and Bax); the study confirmed that compound 7f induced apoptosis through apoptosis-related protein expression. Thus, these studies provided a new molecular scaffold for the further development of anticancer agents that target tubulin.

Design and synthesis of 4'-O-alkylamino-tethered-benzylideneindolin-2-ones as potent cytotoxic and apoptosis inducing agents.

A series of new 4'-O-alkylamino-tethered-benzylideneindolin-2-one derivatives has been synthesized and evaluated for their anti-proliferative activity against selected human cancer cell lines of lung (A549), prostate (DU-145), breast (BT549 and MDA-MB-231) and normal breast epithelial cells (MCF-10A). Gratifyingly, the compounds 5j, 5o and 5r exhibited potent cytotoxicity against breast cancer cell lines (BT549 and MDA-MB-231) with IC50 values in the range of 1.26-2.77µM, and are found to be safer with lesser cytotoxicity on normal breast epithelial cells (MCF-10A). Further, experiments were conducted with these compounds 5j, 5o and 5r on MDA-MB-231 cancer cells to study the mechanism of growth inhibition and apoptosis inducing effect. Treatment of MDA-MB-231 cells with test compounds resulted in inhibition of cell migration through disorganization and disruption of F-actin capping protein. The flow-cytometry analysis results showed that the compound 5o arrested MDA-MB-231 cells in G0/G1 phase of cell cycle in a dose dependent manner. Hoechst staining study revealed that the test compounds inhibited tumor cell proliferation through induction of apoptosis. In addition, the mitochondrial membrane potential (DΨm) was affected and the increased level of reactive oxygen species (ROS) was noted in MDA-MB-231 cells.

New (E)-1-alkyl-1H-benzo[d]imidazol-2-yl)methylene)indolin-2-ones: Synthesis, in vitro cytotoxicity evaluation and apoptosis inducing studies.

A new series of (E)-benzo[d]imidazol-2-yl)methylene)indolin-2-one derivatives has been synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines of prostate (PC-3 and DU-145) and breast (BT-549, MDA-MB-231, MCF-7, 4T1), non-small lung (A549) and gastric (HGC) cancer cells along with normal breast epithelial cells (MCF10A). Among the tested compounds, 8l showed significant cytotoxic activity against MDA-MB-231 and 4T1 cancer cells with IC50 values of 3.26 ± 0.24 µM and 5.96 ± 0.67 µM respectively. The compounds 8f, 8i, 8l and 8o were also screened on normal human breast epithelial cells (MCF10A) and found to be safer with lesser cytotoxicity. The treatment of MDA-MB-231 cells with 8l led to inhibition of cell migration ability through disruption of F-actin protein assembly. The flow-cytometry analysis reveals that the cells arrested in G0/G1 phase of the cell cycle. Further, the compound 8l induced apoptosis of MDA-MB-231 cells was characterized by different staining techniques such as Acridine Orange/Ethidium Bromide (AO/EB), DAPI, annexin V-FITC/PI, Rhodamine-123 and MitoSOX red assay. Western blot studies demonstrated that the compound 8l treatment led to activation of caspase-3, increased expression of cleaved PARP, increased expression of pro-apoptotic Bax and decreased expression of anti-apoptotic Bcl-2 in MDA-MB-231 cancer cells.

Design, synthesis and apoptosis inducing effect of novel (Z)-3-(3'-methoxy-4'-(2-amino-2-oxoethoxy)-benzylidene)indolin-2-ones as potential antitumour agents.

A series of new (Z)-3-(3'-methoxy-4'-(2-amino-2-oxoethoxy)benzylidene)indolin-2-one derivatives has been synthesized and evaluated for their cytotoxic activity against selected human cancer cell lines of prostate (PC-3 and DU-145), breast (BT-549 and MDA-MB-231) and non-tumorigenic prostate epithelial cells (RWPE-1). Among the tested, one of the compounds 4p exhibited potent cytotoxicity selectively on prostate cancer cell lines (PC-3 and DU-145; IC50: 1.89 ± 0.6 and 1.94 ± 0.2 µM, respectively). Further experiments were conducted with 4p on PC-3 cancer cells to study the mechanisms of growth inhibition and apoptosis inducing effect. Treatment of PC-3 cells with test compound 4p resulted in inhibition of cell migration through disorganization of F-actin protein. The flow-cytometry analysis results showed that the compound arrested PC-3 cancer cells in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining and annexin-V binding assay revealed that the compound 4p inhibited tumor cell proliferation through induction of apoptosis. Western blot studies demonstrated that the compound 4p treatment led to activation of caspase-3, increased expression of pro-apoptotic Bax and significantly decreased expression of anti-apoptotic Bcl-2 in human prostate cancer PC-3 cells. In addition, the mitochondrial membrane potential (ΔΨm) was also affected and the levels of intracellular Ca(2+) were raised.