Anti-prostate Cancer Agents Research Articles

O-Aminoalkyl-O-Trimethyl-2,3-Dehydrosilybins: Synthesis and In Vitro Effects Towards Prostate Cancer Cells.

As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl-2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using the WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silibinin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, representing a 17- to 52-fold improvement in potency compared to silibinin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents.

A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified.

Novel metabolites from Trichoderma atroviride against human prostate cancer cells and their inhibitory effect on Helicobacter pylori and Shigella toxin producing Escherichia coli

The present study aimed to purify and identify the metabolites from T. atroviride using high-performance liquid chromatography (HPLC) and 1H and 13C nuclear magnetic resonance spectrometer (NMR) followed by analyzing their toxicological, antibacterial and anticancer properties. This work identified two metabolites - TM1 and TM2. TM1 was in two forms: (i) 1, 3-dione-5, 5-dimethylcyclohexane; and, (ii) 2-enone-3hydroxy −5,5-dimethylcylohex, while TM2 was 4H-1,3-dioxin-4-one-2,3,6-trimethyl. These metabolites did not exhibit any irritant or allergic reaction as revealed by HET- CAM test. TM2 significantly inhibited the growth of H. pylori and Shigella toxin producing Escherichia coli (STEC) as evident by in vitro and microscopic observations of bacterial cell death. TM2 also induced the cell death and cytotoxicity, as revealed by cell viability test and western blot analysis. According to microscopic, flow cytometer and western blot analysis, TM2 treated cells displayed higher ROS, cell death, and apoptosis-related protein expression than TM1 and control. This study concluded that TM2 derived from T. atroviride was a potential therapeutic agent for anti-prostate cancer and antibiotic agent against MDR- H. pylori and STEC and it is also recommended to carry out further in vivo animal model experiments with improved stability of the metabolites for future pharmaceutical trails.

Structure-activity relationship of novel (benzoylaminophenoxy)phenol derivatives as anti-prostate cancer agents

The androgen receptor (AR) is a ligand-inducible transcription factor belonging to the nuclear receptor superfamily, and is a target molecule for development of drugs to treat prostate cancer. However, AR antagonists in clinical use, such as flutamide (3a) and bicalutamide (4), encounter resistance after several years of hormone therapy, predominantly due to mutations of AR. Thus, although some new-generation AR antagonists have been developed, novel types of AR antagonists are still required to treat drug-resistant prostate cancer. We previously reported a novel (benzoylaminophenoxy)phenol derivative 10a, which is structurally distinct from conventional AR antagonists. Here, we systematically examined the structure–activity relationship of (benzoylaminophenoxy)phenol derivatives on the inhibitory activity on the prostate cancer cell proliferations. We found that the 4-[4-(benzoylamino)phenoxy]phenol backbone is important for anti-prostate cancer activity. Introduction of a small substituent at the 2 position of the central benzene ring (B ring) increases the activity. Among the synthesized compounds, 19a and 19b exhibited the most potent inhibitory activity toward dihydrotestosterone-induced proliferation of several androgen-dependent cell lines, SC-3 (wild-type AR), LNCaP (T877A AR), and 22Rv1 (H874Y AR), but interestingly also inhibited proliferation of AR-independent PC-3 cells. These compounds, which have a different pharmacophore from conventional AR antagonists, are promising drug candidates for the treatment of prostate cancer.

Structure-activity relationship and pharmacokinetic studies of 3-O-substitutedflavonols as anti-prostate cancer agents

Thirty-eight 3-O-substituted-3′,4′-dimethoxyflavonols and twenty-five 3-O-substituted-3′,4′,7-trimethoxyflavonols have been synthesized for systematic investigation on the structure-activity relationships of 3-O-substituted-3′,4′-dimethoxyflavonols in three human prostate cancer cell models. Our findings indicate that incorporation of an appropriate amino group to 3-OH of 3′,4′-dimethoxyflavonol and 3′,4′,7-trimethoxyflavonol through a 3- to 5-carbon linker can substantially improve the in vitro antiproliferative potency in three human prostate cancer cell models, but not in two non-neoplastic human epithelial cell models (MCF 10A and PWR-1E). 1-Methylpiperazine, pyrrolidine, and dibutylamine are optimal terminal amine groups that, in combination with a 3- to 5-carbon linker, are notably beneficial to the anti-proliferative potency of 3-O-substituted-3′,4′-dimethoxyflavonols. It is worth noting that 3-O-(4-methylpiperazin-1-yl)propyl-3′,4′,7-trimethoxyflavonol (76) induces PC-3 cell death in a completely different way from 3-O-pyrrolidinopentyl-3′,4′,7-trimethoxyflavonol (81) even though they belong to 3-O-substituted-3′,4′,7-trimethoxyflavonols and exhibit similar potency in inhibiting PC-3 cell proliferation, suggesting that the mechanism of action for each specific 3-O-substitutedflavonol varies with different amino moiety. 3-O-(N,N-Dibutylamino)propyl-3′,4′-dimethoxyflavonol (42) emerged as the most promising derivative due to its substantially improved potency in cell models, superior bioavailability in rats, and good selectivity of inhibiting prostate cancer cell proliferation over non-neoplastic human epithelial cell proliferation.

Design, synthesis and biological evaluation of ring A modified 11-keto-boswellic acid derivatives as Pin1 inhibitors with remarkable anti-prostate cancer activity

Pin1 (Protein interaction with never in mitosis A1) is a validated molecular target for anticancer drug discovery. Herein, we reported the design, synthesis, and structure-activity relationship study of novel ring A modified AKBA (3-acetyl-11-keto-boswellic acid) derivatives as Pin1 inhibitors. Most compounds showed superior Pin1 inhibitory activities to AKBA. One of the most promising compounds, 10a, potently inhibited Pin1 with IC50 value of 0.46 μM, while it displayed excellent anti-proliferative effect against prostate cancer cells PC-3 with GI50 value of 1.82 μM. Structure-activity relationship indicated that reasonable structural modifications in ring A had significant impact on improving activity. Further mechanism research revealed that 10a decreased the level of Cyclin D1 and caused cell cycle arrest at G0/G1 phase in PC-3 cancer cells. Thus, compound 10a may serve as potential anti-prostate cancer agent for further investigation through Pin1 inhibition.

Optimization of diarylpentadienones as chemotherapeutics for prostate cancer

Our earlier studies indicate that (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones and (1E,4E)-1,5-bis(1-alkyl-1H-benzo[d]imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2–10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1E,4E)-1,5-Bis(1H-imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N-aryl substitution to exclude the C–H bond on the carbon adjacent to the N1 position (α-H) may increase the metabolic stability. Consequently, seven (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones and three (1E,4E)-1,5-bis(1-aryl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1E,4E)-1,5-bis(1-aryl-1H-pyrrolo[3,2-b]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N-arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-imidazol-2-yl)penta-1,4-dien-3-one (17d) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth.

Degradation of Androgen Receptor through Small Molecules for Prostate Cancer.

Prostate cancer is the most common carcinoma among aged males in western countries and more aggressive and lethal castration resistant prostate cancer often occurs after androgen deprivation therapy. The high expression of androgens and androgen receptor is closely related to prostate cancer. Efficient androgen receptor antagonists, such as enzalutamide and ARN-509, could be employed as potent anti-prostate cancer agents. Nevertheless, recent studies have revealed that F876L mutation in androgen receptor converts the action of enzalutamide and ARN-509 from an antagonist to agonist, so that novel strategies are urgent to address this resistance mechanism. In this review, we focus on the discussion about some novel strategies, which targets androgen receptor mainly through the degrading pathway as potential treatments for prostate cancer.

A COMPARATIVE STUDY OF STEREOCHEMICAL EFFECTS OF ANTI-PROSTATE AGENTS BY MOLECULAR DOCKING

Objective: A comparative study of anti-prostate agents to investigate the stereochemical influences on binding affinity by molecular docking.Methods: Structures of enantiomers (R and S stereoisomers) for known anti-prostate cancer (PCa) agents were drawn using ChemBioDraw 2D software. Thereafter, they were converted to 3D structures using the ChemBioDraw 3D software in which they were subjected to energy minimization using the MM2 method and then saved as PDB extension files which can be accessed using the ADT interface. AutoDock Vina (ADT) 1.5.6 software version was used for molecular docking study.Results: A total of 12 different anti-PCa agents were selected and drawn including well-known drug R-bicalutamide. All molecules showed the binding affinity with respect to the nature of stereochemistry. R-stereoisomers showed better interaction as well as binding affinity toward 1z95 (mutated androgen receptor protein involved in the progression of PCa) whereas their S-stereoisomers were found inferior in comparison.Conclusion: This study showed that CB1-R and R-bicalutamide (with R-stereochemistry) were better in binding affinity comparative to their counterpart CB1-S and S-Bicalutamide (with S-stereochemistry). All the selected anti-PCa agents were showing the effect of stereochemical center; therefore, we must choose the right kind of stereochemistry while planning to develop the newer anti-PCa agents.

Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2-Thioxoimidazolidinones.

Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target. A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38). Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 - 186.9 and 24.6 - 147.5 µM respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 - 198.5 and 16.9 - 188.2 µM respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 µM respectively). 11c (IC50 = 22.7 and 29.2 µM) and 11f (IC50 = 28.7 and 16.9 µM) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38. The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.

Ophiopogonin D', a Natural Product From Radix Ophiopogonis, Induces in Vitro and in Vivo RIPK1-Dependent and Caspase-Independent Apoptotic Death in Androgen-Independent Human Prostate Cancer Cells.

Objective: The purpose of this study was to evaluate the anticancer effects of Ophiopogonin D′ (OPD′, a natural product extracted from a traditional Chinese medicine (Radix Ophiopogonis) against androgen-independent prostate cancer cells and to explore the underlying molecular mechanism(s) of action.Methods: The CCK-8 assay was used to assess the viability of prostate cancer cells. The cell morphology was examined by an ultrastructural analysis via transmission electron microscopy. Cells in apoptosis (early and late stages) were detected using an Annexin V-FITC/propidium iodide kit with a FACSCaliber flow cytometer. JC-1, a cationic lipophilic probe, was employed to measure the mitochondrial membrane potential (MMP) of PC3 cells. Changes in the protein expression of RIPK1, C-RIPK1, caspase 8, cleaved-caspase 8, Bim, Bid, caspase 10, and cleaved-caspase 10 were evaluated by Western blotting. The mRNA expression of Bim was examined by quantitative real-time reverse transcription polymerase chain reaction. Z-VAD-FMK (a caspase inhibitor) and necrostatin-1 (a specific inhibitor of RIPK1) were utilized to determine whether the cell death was mediated by RIPK1 or caspases. PC3 and DU145 xenograft models in BALB/c nude mice were used to evaluate the anticancer activity of OPD′ in vivo.Results: OPD′ was shown to exert potent anti-tumor activity against PC3 cells. It induced apoptosis via a RIPK1-related pathway, increased the protein expression levels of RIPK1 and Bim, and decreased the levels of cleaved-RIPK1, caspase 8, cleaved-caspase 8, Bid, caspase 10, and cleaved-caspase 10. OPD′ also increased the mRNA expression of Bim. The protein expression of Bim was decreased when cells were pre-treated with necrostatin-1. Treatment with OPD′ inhibited the growth of PC3 and DU145 xenograft tumors in BALB/c nude mice.Conclusion: OPD′ significantly inhibited the in vitro and in vivo growth of prostate cells via RIPK1, suggesting that OPD′ may be developed as a potential anti-prostate cancer agent.

Procyanidin from peanut skin induces antiproliferative effect in human prostate carcinoma cells DU145

In this study, the antiproliferative activity of peanut skin procyanidins (PSP) and six fractions (PSP-1∼6) isolated from PSP by several chromatographic steps on the human prostate cancer DU145 cells were evaluated. The results showed that PSP and PSP-1∼6 significantly inhibited the proliferation of DU145 cells. PSP-2 was the most effective fraction, which was identified as procyanidin B3 mainly and procyanidin dimer [(E)C-luteolin or keampferol] secondarily. Moreover, the mechanism of antiproliferative activity of PSP-2 was investigated. It was observed that PSP-2 induced apoptotic cell death and cell cycle arrest at S phase in DU145 cells. PSP-2 caused the increase of intracellular ROS level and the decrease of Bcl-2/Bax ratio, and triggered the activation of p53 and caspases-3 in DU145 cells. Our findings demonstrated that procyanidins from peanut skin have the potential to be developed as an anti-prostate cancer agent.

Synthesis, biological evaluation and SAR of naftopidil-based arylpiperazine derivatives

For the development of potential anti-prostate cancer agents, 24 kinds of novel naftopidil-based arylpiperazine derivatives have been synthesized and characterized by spectroscopic methods. Their antitumor activities were evaluated against several classical prostate cancer cell lines including PC-3, LNCaP, and DU145. Among all the compounds, 9, 13, 17, 21 and 27 showed strong cytotoxic activities against DU145 cells (IC50 < 1 μM). Further testing confirmed that compound 17 inhibited the growth of DU145 cells by inducing cell cycle arrest at G0/G1 phase. Besides, antagonistic activities of compounds (9, 13, 17, 21 and 27) towards a1-ARs (α1A, α1B, and α1D) were further evaluated using dual-luciferase reporter assays, and the compounds 13 and 17 exhibited better a1-ARs subtype selectivity. The structure–activity relationship (SAR) of these developed arylpiperazine derivatives was rationally discussed. Taken together, these results suggested that further development of such compounds may be of great interest.

Discovery of novel 5-methyl-1H-pyrazole derivatives as potential antiprostate cancer agents: Design, synthesis, molecular modeling, and biological evaluation.

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration-resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability compared with 10e in human liver microsomes.

Evaluation of pharmacokinetics/pharmacodynamics and efficacy of one-month depots of TAK-448 and TAK-683, investigational kisspeptin analogs, in male rats and an androgen-dependent prostate cancer model

TAK-448 and TAK-683 are kisspeptin agonist analogs with improved in vivo stability and activity. Previous studies showed that continuous subcutaneous administration of TAK-448 or TAK-683 caused rapid and profound reductions in plasma testosterone levels in various species, including male healthy volunteers, suggesting their therapeutic potential as anti-prostate cancer agents. For clinical drug development, one-month sustained-release depots of TAK-448 and TAK-683, TAK-448-SR(1M) and TAK-683-SR(1M), were designed to improve usability in clinical practice. In this study, the pharmacokinetics/pharmacodynamics (PK/PD) profiles of TAK-448-SR(1M) and TAK-683-SR(1M) were initially tested in male rats to ensure their eligibility as one-month depots. The therapeutic advantages of TAK-448-SR(1M) and TAK-683-SR(1M) over TAP-144-SR(1M) were then investigated in a JDCaP xenograft rat model. TAK-448-SR(1M) and TAK-683-SR(1M) maintained certain levels of plasma TAK-448 free form (TAK-448F) and plasma TAK-683 free form (TAK-683F) for at least 4 weeks, before clearance from the circulation. Accompanying their desirable PK profiles, TAK-448-SR(1M) and TAK-683-SR(1M) showed favorable PD responses as one-month depots and demonstrated better testosterone control than TAP-144-SR(1M). Both depots exerted rapid and profound suppression of plasma testosterone levels in male rats. These profound suppressive effects were maintained in dose-dependent manners, before recovery toward normal levels. In the JDCaP xenograft model, TAK-448-SR(1M) and TAK-683-SR(1M) both showed better prostate-specific antigen (PSA) control than TAP-144-SR(1M), although all treatment groups eventually experienced PSA recurrence and tumor regrowth. In conclusion, this study demonstrates that both TAK-448-SR(1M) and TAK-683-SR(1M) have desirable and better PK/PD profiles than TAP-144-SR(1M) in rats, which could potentially provide better clinical outcomes in androgen-dependent prostate cancer.

Design, Synthesis and Biological Evaluation of Novel 1, 3- thiazolidine-2, 4-diones as Anti-prostate Cancer Agents.

Androgen receptor is an attractive target for the treatment of prostate cancer. The 1,3- thiazolidine-2,4-diones possess a wide diversity of important biochemical effects and interesting pharmacological properties. The aim of the study is to find the experimental and computational methods to investigate the interference of 1,3-thiazolidine-2,4-diones with androgen receptor against prostate cancer. Structural modification and molecular docking-based virtual screening approaches were imposed to identify the novel 1,3-thiazolidine-2,4-diones by using Schrödinger (Maestro 9.5). The best fit molecules (3-12 & 23-31) were synthesized and characterized using spectroscopic techniques, then in vitro antioxidant and antiprostate cancer activities were evaluated. Further, the structure of the intermediate (18) was confirmed by single crystal XRD analysis. The mechanism studies were performed through the gene expression for the compounds, 29, 30, and 31, the standards, dihydrotestosterone and R-bicalutamide. The compounds, 29, 30 and 31 showed comparatively significant antioxidant activity and better antiproliferative activity against PC-3 and LNCaP cell lines. Also, very low cytotoxicity was observed in the noncancerous cell (3T3). The compounds, 29, 30 and 31 significantly decreased the mRNA expression of ARstimulated genes, PSA and TMPRSS2, which demonstrated their anti-prostate cancer activities. ADME/T properties prediction of the compounds (3-12 and23-31) showed the promising drug-likeness and pharmacokinetic parameters without toxicity. Moreover, DFT calculations apparently confirmed the stable conformer of the compound, 31. These findings may provide the essential information for the development of anti-prostate cancer agents.

Synthesis and biological evaluation of new steroidal pyridines as potential anti-prostate cancer agents

A series of new steroidal pyridines have been synthesized through the based-promoted three-component reaction and preliminarily evaluated for their antiproliferative activity against different types of cancer cell lines. SARs studies showed that the heterocyclic rings attached to the 4-position of the pyridine ring were preferred over the phenyl rings for the activity. Among these compounds, the most potent compound exhibited good growth inhibition against all the tested cancer cells, especially for PC-3 cells with an IC50 value of 1.55 μM. Further mechanistic studies revealed that the most potent compound inhibited colony formation, migration and evasion of PC-3 cells in a concentration-dependent manner as well as induced apoptosis of PC-3 cells possibly through the mitochondria-related apoptotic pathways. Caspase-3/-9 and PARP were activated, finally leading to the apoptosis of PC-3 cells. For the androgen-sensitive (AR+) prostate cancer cell line LNCaP, the most potent compound was less potent than abiraterone with the IC50 value of 8.48 and 3.29 μM, respectively. The most potent compound could be used as a starting point for the development of new steroidal heterocycles with improved anticancer potency and selectivity. The synthesized steroidal pyridines contain the functional -OEt and CN groups, which could be used for further modifications for the construction of the steroid library.

Anticancer potential of Moringa oleifera flower extract in human prostate cancer PC-3 cells via induction of apoptosis and downregulation of AKT pathway

Background: Moringa oleifera (MO), or the horseradish tree, is a pantropical species that is known by such regional names as benzolive, drumstick tree, kelor, marango, mlonge, mulangay, nebeday, saijhan, and sajna. Over the past two decades, many reports have appeared in mainstream scientific journals describing its anticancer properties of MO. While much of this recent enthusiasm indeed appears to be justified, it is critical to evaluate therapeutic activity of MO on prostate cancer to separate rigorous scientific evidence from anecdote. MO contained active polyphenols such as ellagic acid, gallate, methyl gallate, catechol, kaempferol quercetin, and their derivatives. Objective: It is the purpose of this series of brief reviews to critically assess the efficacy of MO flower extract as an antiprostate cancer agent. Materials and Methods: The cell viability of the extract was determined using MTT in different time point and cell cycle progression studies was analyzed by flow cytometry. Various markers of apoptosis were evaluated by immunoblotting. Results: We observed that prostate cancer cells treated with MO flower extract caused 50% inhibition at a dose of 22.61 μg/mL and 6.25 μg/mL in PC-3 cells at 24 and 48 h, respectively. MO flower extract induced the accumulation of G1 phase cell cycle arrest and apoptosis by annexin V staining. Further, immunoblot detection of PARP cleavage leads to increase the protein expression of caspase-3 activity and Bax indicates induction of apoptosis. Conclusion: Together, the results suggest for the first time that administration of MO flower extract inhibits prostate cancer progression in PC-3 cells by interfering AKT pathway. Abbreviation used: MO: Moringa oleifera; PARP: Poly (ADP-ribose) polymerase; BAD: Bcl-2-associated death promoter; FACS: Fluorescence-activated cell sorting.

Synthesis and Antitumor Activity of Novel Arylpiperazine Derivatives Containing the Saccharin Moiety.

Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC50) < 2 μM). The structure–activity relationship (SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data. This work provides a potential lead compound for anticancer agent development focusing on prostate cancer therapy.

Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents

Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.