Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications.

Hypervalent aryliodoumiums are intensively investigated as arylating agents. They are excellent surrogates to aryl halides, and moreover they exhibit better reactivity, which allows the corresponding arylation reactions to be performed under mild conditions. In the past decades, acyclic aryliodoniums are widely explored as arylation agents. However, the unmet need for acyclic aryliodoniums is the improvement of their notoriously low reaction economy because the coproduced aryl iodides during the arylation are often wasted. Cyclic aryliodoniums have their intrinsic advantage in terms of reaction economy, and they have started to receive considerable attention due to their valuable synthetic applications to initiate cascade reactions, which can enable the construction of complex structures, including polycycles with potential pharmaceutical and functional properties. Here, we are summarizing the recent advances made in the research field of cyclic aryliodoniums, including the nascent design of aryliodonium species and their synthetic applications. First, the general preparation of typical diphenyl iodoniums is described, followed by the construction of heterocyclic iodoniums and monoaryl iodoniums. Then, the initiated arylations coupled with subsequent domino reactions are summarized to construct polycycles. Meanwhile, the advances in cyclic aryliodoniums for building biaryls including axial atropisomers are discussed in a systematic manner. Finally, a very recent advance of cyclic aryliodoniums employed as halogen-bonding organocatalysts is described.

Novel gold-based complex GC7 suppresses cancer cell proliferation via impacting energy metabolism mediated by mitochondria.

Due to their pivotal roles in regulating energy metabolism and apoptosis, mitochondria in cancer cells have been considered a vulnerable and feasible target. Many anticancer agents, e.g., metal-based compounds, are found to target and disturb mitochondria primarily, which may lead to the disturbance of energy metabolism and, more importantly, the initiation of apoptosis. In this work, a gold-based complex 7 (GC7) was synthesized and evaluated in a series of different cancer cell lines. The anticancer efficacies of GC7 on cell viability, apoptosis, and colony formation were determined. Cellular thioredoxin reductase (TrxR) activity, oxygen consumption rate (OCR), glucose uptake, and lactate production following GC7 treatment were evaluated and analyzed. The Jeko-1 and A549 xenograft models were used to assess GC7's tumor-suppressing effects. The results showed that GC7 possessed a broad-spectrum anticancer effect, with IC50 values ranging from 0.43 to 1.2 µM in multiple cancer cell lines, which was more potent than gold-based auranofin (∼2-6 folds). GC7 (0.3 and 1 µM) efficiently induced apoptosis of Jeko-1, A549, and HCT116 cells, and it suppressed the sphere formation of cancer stem cells GSC11 and GSC23 cells at 0.1 µM, and it completely eliminated colony at 0.3 µM. The preliminary mechanistic study showed that GC7 inhibited cellular TrxR activity, suppressed mitochondrial OCR, reduced mitochondrial membrane potential (MMP), decreased glucose uptake, and possibly suppressed glycolysis to reduce lactate production. GC7 was predicted to have a similar yet slightly different pharmacokinetic profile as auranofin. Finally, GC7 (20 mg/kg, oral, 5/week, or 3 mg/kg, IP, 3/week) significantly inhibited tumor growth. In conclusion, GC7 showed great potential in suppressing cancer cell proliferation, probably via inhibiting TrxR and impacting mitochondria-mediated energy metabolism.

Discovery of novel selective phosphodiesterase­1 inhibitors for the treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer.

BACKGROUND: Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and plays an oncogenic role in various cancers through catalysis-dependent or catalysis-independent pathways. However, the related mechanisms contributing to ovarian cancer (OC) are not well understood. METHODS: The levels of EZH2 and H3K27me3 were evaluated in 105 OC patients by immunohistochemistry (IHC) staining, and these patients were stratified based on these levels. Canonical and noncanonical binding sites of EZH2 were defined by chromatin immunoprecipitation sequencing (ChIP-Seq). The EZH2 solo targets were obtained by integrative analysis of ChIP-Seq and RNA sequencing data. In vitro and in vivo experiments were performed to determine the role of EZH2 in OC growth. RESULTS: We showed that a subgroup of OC patients with high EZH2 expression but low H3K27me3 exhibited the worst prognosis, with limited therapeutic options. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked OC cell proliferation and tumorigenicity in vitro and in vivo. Integrative analysis of genome-wide chromatin and transcriptome profiles revealed extensive EZH2 occupancy not only at genomic loci marked by H3K27me3 but also at promoters independent of PRC2, indicating a noncanonical role of EZH2 in OC. Mechanistically, EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing tricarboxylic acid cycle (TCA cycle) activity, which contributed to the growth of OC. CONCLUSIONS: These data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.

Recent progress in analytical strategies of arsenic-binding proteomes in living systems.

Arsenic (As) is one of the most concerning elements due to its high exposure risks to organisms and ecosystems. The interaction between arsenicals and proteins plays a pivotal role in inducing their biological effects on living systems, e.g., arsenicosis. In this review article, the recent advances in analytical techniques and methods of As-binding proteomes were well summarized and discussed, including chromatographic separation and purification, biotin-streptavidin pull-down probes, in situ imaging using novel fluorescent probes, and protein identification. These analytical technologies could provide a growing body of knowledge regarding the composition, level, and distribution of As-binding proteomes in both cells and biological samples, even at the organellar level. The perspectives on analysis of As-binding proteomes are also proposed, e.g., isolation and identification of minor proteins, in vivo targeted protein degradation (TPD) technologies, and spatial As-binding proteomics. The application and development of sensitive, accurate, and high-throughput methodologies of As-binding proteomics would enable us to address the key molecular mechanisms underlying the adverse health effects of arsenicals.

Developing Bi-Gold Compound BGC2a to Target Mitochondria for the Elimination of Cancer Cells.

Reactive oxygen species (ROS) homeostasis and mitochondrial metabolism are critical for the survival of cancer cells, including cancer stem cells (CSCs), which often cause drug resistance and cancer relapse. Auranofin is a mono-gold anti-rheumatic drug, and it has been repurposed as an anticancer agent working by the induction of both ROS increase and mitochondrial dysfunction. Hypothetically, increasing auranofin's positive charges via incorporating more gold atoms to enhance its mitochondria-targeting capacity could enhance its anti-cancer efficacy. Hence, in this work, both mono-gold and bi-gold compounds were designed and evaluated to test our hypothesis. The results showed that bi-gold compounds generally suppressed cancer cells proliferation better than their mono-gold counterparts. The most potent compound, BGC2a, substantially inhibited the antioxidant enzyme TrxR and increased the cellular ROS. BGC2a induced cell apoptosis, which could not be reversed by the antioxidant agent vitamin C, implying that the ROS induced by TrxR inhibition might not be the decisive cause of cell death. As expected, a significant proportion of BGC2a accumulated within mitochondria, likely contributing to mitochondrial dysfunction, which was further confirmed by measuring oxygen consumption rate, mitochondrial membrane potential, and ATP production. Moreover, BGC2a inhibited colony formation and reduced stem-like side population (SP) cells of A549. Finally, the compound effectively suppressed the tumor growth of both A549 and PANC-1 xenografts. Our study showed that mitochondrial disturbance may be gold-based compounds' major lethal factor in eradicating cancer cells, providing a new approach to developing potent gold-based anti-cancer drugs by increasing mitochondria-targeting capacity.

Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug.

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system (CNS). Effective treatments remain limited. Therefore, novel chemotherapy drugs with high efficiency and few adverse effects are urgently needed. Histone deacetylase (HDAC) and serum and glucocorticoid-regulated protein kinase 1 (SGK1) are targets for the prevention and treatment of GBM. Rhein has antitumor and SGK1 suppression effects, although its biological activity is limited by poor bioavailability. To improve the drug-like properties of rhein, we constructed a novel rhein-hydroxyethyl hydroxamic acid derivative (SYSUP007), which combined rhein with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). In the present study, the human GBM cell lines, T98G, U87 and U251, were used to investigate the anticancer effects of SYSUP007 in vitro. We found that SYSUP007 was more effective in inhibiting glioma cell proliferation, invasion and migration in vitro compared with the effects of rhein and SAHA. We also confirmed that SYSUP007 increased the expression of Ac-K100 and NDRG1 (targets of HDAC and SGK1). The present study indicates the potential that SYSUP007, as a novel rhein and SAHA derivative, for development as an anti-cancer therapy.

New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: Design, synthesis and biological evaluation.

Lysine-specific demethylase 1 (LSD1) is frequently elevated in acute myeloid leukemia (AML) and often leads to tumorigenesis. In recent years, numerous LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have reached clinical trials. Most TCP derivatives were modified at the amino site of cyclopropane motif. Herein, we for the first time introduced a sulfonamide group in TCP benzene ring of series a compounds and performed a systematical study on structure and activity relationships by varying sulfonamide groups. The introduction of sulfonamide significantly increased the targeting capacity of TCP against LSD1. Moreover, we discovered that the Boc attached LSD1 inhibitors (labelled as series b compounds) substantially improved their anti-proliferation capacity towards AML cells. The intracellular thermal shift and LC-MS/MS results implied that Boc enhanced the drug lipophilicity and might be removed under the cancerous acidic environment to release the real pharmacophore, evidenced by the fact that a structurally similar but acidic inert pivaloyl to replace Boc dramatically dropped the cellular anti-proliferation effect. Finally, a benzyl group installed at the amino site to appropriately increase lipophilicity led to trans-4-(2-(benzylamino)-cyclopropyl)-N,N-diethylbenzenesulfonamide a10 that showed better anti-proliferation activity in AML cells and enzymatic inhibition against LSD1. Taken together, our work offers a novel TCP-based structure and provides a prodrug strategy for the discovery of potent LSD1 inhibitors by having appropriate lipophilicity.

REV-ERBα Regulates CYP7A1 Through Repression of Liver Receptor Homolog-1.

Nuclear heme receptor reverse erythroblastosis virus (REV-ERB) α (a transcriptional repressor) is known to regulate cholesterol 7α-hydroxylase (CYP7A1) and bile acid synthesis. However, the mechanism for REV-ERBα regulation of CYP7A1 remains elusive. Here, we investigate the role of LRH-1 in REV-ERBα regulation of CYP7A1 and cholesterol metabolism. We first characterized the tertiary amine N-(4-chloro-2-methylbenzyl)-N-(4-chlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine (GSK2945) as a highly specific Rev-erbα/REV-ERBα antagonist using cell-based assays and confirmed expression of Rev-erbα in mouse liver. GSK2945 treatment increased hepatic mouse cholesterol 7α-hydroxylase (Cyp7a1) level and lowered plasma cholesterol in wild-type mice. Likewise, the compound increased the expression and microsomal activity of Cyp7a1 in hypercholesterolemic mice. This coincided with reduced plasma and liver cholesterol and enhanced production of bile acids. Increased levels of Cyp7a1/CYP7A1 were also found in mouse and human primary hepatocytes after GSK2945 treatment. In these experiments, we observed parallel increases in Lrh-1/LRH-1 (a known hepatic activator of Cyp7a1/CYP7A1) mRNA and protein. Luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Lrh-1/LRH-1 was a direct Rev-erbα/REV-ERBα target gene. Furthermore, conditional deletion of Lrh-1 in the liver abrogated the regulatory effects of Rev-erbα on Cyp7a1 and cholesterol metabolism in mice. In conclusion, Rev-erbα regulates Cyp7a1 and cholesterol metabolism through its repression of the Lrh-1 receptor. Targeting the REV-ERBα/LRH-1 axis may represent a novel approach for management of cholesterol-related diseases.

Regulation of stem-like cancer cells by glutamine through ß-catenin pathway mediated by redox signaling.

BACKGROUND: Cancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s). METHODS: Biochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo. RESULTS: We show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the ß-catenin pathway. CONCLUSION: Glutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by ß-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance.

New Mild and Simple Approach to Isothiocyanates: A Class of Potent Anticancer Agents.

In our current work, acetyl chloride-mediated synthesis of phenethyl isothiocyanate (PEITC) derivatives proves to be convenient and provides the expected products at good to excellent yields. Biological evaluation and structure-activity relationship analysis found that the novel compound 7 showed the best anticancer activity against human cancer cell line Panc1 and HGC27 compared with PEITC. Compounds 6 and 7 induced more apoptosis in pancreatic cancer cells but less toxicity in non-cancer cells. Further biological study demonstrated that 7 substantially increased intracellular reactive oxygen species (ROS) and depleted glutathione (GSH), leading to an oxidative stress to kill cancer cell.

Relayed Regioselective Alkynylation/Olefination of Unsymmetrical Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording Fluorescent Cytotoxic Benzoxazoles.

Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been known to pose a challenge. A regioselective relayed alkynylation and olefination of unsymmetrical cyclic diaryliodonium species has been achieved by installation of a directing amido group. These relayed transformations were delayed until an oxazole ring had formed, delivering a series of unique fluorescent benzoxazoles. Moreover, some of these synthetic benzoxazoles showed apparent inhibitory activity against malignant cancer cells. Further confocal visualization revealed that benzoxazoles targeted cell nuclei. These findings might provide a novel structural scaffold to develop desirable anticancer agents.

Pd catalyzed insertion of alkynes into cyclic diaryliodoniums: a direct access to multi-substituted phenanthrenes.

Cyclic diaryliodoniums remain unexplored compared to linear iodoniums. In our current work, internal alkynes were for the first time applied to react with cyclic iodoniums, catalyzed by Pd, resulting in a [4 + 2] benzannulation. Our work offers a new strategy to synthesize multi-substituted phenanthrene derivatives which are not easily accessed by conventional methods.

Berberine protects homocysteic acid-induced HT-22 cell death: involvement of Akt pathway.

Berberine (BBR), one of the major constituents of Chinese herb Rhizoma coptidis, has been reported to exert beneficial effects to various diseases, including Alzheimer's disease (AD). In the present work, we aimed to investigate the effects of BBR on neuronal cell death induced by homocysteic acid (HCA), which was considered as a risk of AD. BBR significantly reduced HCA-induced reactive oxygen species (ROS) generation, lactate dehydrogenase release and subsequent cell death. LY294002, the PI3K inhibitor, blocked the protection as well as the up-regulation of Akt phosphorylation of BBR. Taken together, our results indicate that BBR protects HCA-induced HT-22 cell death partly via modulating Akt pathway, suggesting BBR may be a promising therapeutic agent for the treatment of HCA-related diseases, including AD.

Pantothenic acid biosynthesis in the parasite Toxoplasma gondii: a target for chemotherapy.

Toxoplasma gondii is a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B5) biosynthesis in T. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to coenzyme A were identified and are expressed in T. gondii. A panel of inhibitors developed to target Mycobacterium tuberculosis pantothenate synthetase were tested and found to exhibit a range of values for inhibition of T. gondii growth. Two inhibitors exhibited lower effective concentrations than the currently used toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway, as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence, T. gondii encodes and expresses the enzymes for pantothenate synthesis, and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target.

Carvedilol attenuates 6-hydroxydopamine-induced cell death in PC12 cells: involvement of Akt and Nrf2/ARE pathways.

Oxidative stress is closely related to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Carvedilol, a nonselective ß-adrenergic receptor blocker with pleiotropic activity has been shown to exert neuroprotective effect due to its antioxidant property. However, the neuroprotective mechanism of carvedilol is still not fully uncovered. The phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway plays key role in cell survival and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress. Here we investigated the effects of carvedilol on 6-hydroxydopamine (6-OHDA)-induced cell death as well as the Akt and Nrf2/ARE pathways in PC12 cells. We found that carvedilol significantly increased cell viability and decreased reactive oxygen species in PC12 cells exposed to 6-OHDA. Furthermore, carvedilol activated the Akt and Nrf2/ARE pathways in a concentration-dependent manner, and increased the protein levels of heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1(NQO-1), two downstream factors of the Nrf2/ARE pathway. In summary, our results indicate that carvedilol protects PC12 cells against 6-OHDA-induced neurotoxicity possibly through activating the Akt and Nrf2/ARE signaling pathways.

Palladium catalyzed dual C-H functionalization of indoles with cyclic diaryliodoniums, an approach to ring fused carbazole derivatives.

Palladium(II)-catalyzed dual C-H functionalization of indoles with cyclic diaryliodoniums was successfully achieved, providing a concise method to synthesize dibenzocarbazoles. In a single operation, two C-C bonds and one ring were formed. The reaction was ligand free and tolerated air and moisture conditions.

MOF@COF Nanocapsules Enhance Soft Tissue Sarcoma Treatment: Synergistic Effects of Photodynamic Therapy and PARP Inhibition on Tumor Growth Suppression and Immune Response Activation.

Soft tissue sarcomas (STS) are highly malignant tumors with limited treatment options owing to their heterogeneity and resistance to conventional therapies. Photodynamic therapy (PDT) and poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown potential for STS treatment, with PDT being effective for sarcomas located on the extremities and body surface and PARPi targeting defects in homologous recombination repair. To address the limitations of PDT and harness the potential of PARPi, herein, a novel therapeutic approach for STS treatment combining nanocapsules bearing integrated metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), i.e., MOF@COF, with PDT and PARPi is proposed. Nanocapsules are designed, referred to as ZTN@COF@poloxamer, which contain a Zr-based MOF and tetrakis (4-carbethoxyphenyl) porphyrin as a photosensitizer, are coated with a COF to improve the sensitizing properties, and are loaded with niraparib to inhibit DNA repair. Experiments demonstrate that this new nanocapsules treatment significantly inhibits STS growth, promotes tumor cell apoptosis, exhibits high antitumor activity with minimal side effects, activates the immune response of the tumor, and inhibits lung metastasis in vivo. Therefore, MOF@COF nanocapsules combined with PARPi offer a promising approach for STS treatment, with the potential to enhance the efficacy of PDT and prevent tumor recurrence.

Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

Design, Synthesis, and Biological Evaluation of Potent EZH2/LSD1 Dual Inhibitors for Prostate Cancer.

As histone modification enzymes, EZH2 mediates H3K27 trimethylation (H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and H3K9me1/2. Synergistic anticancer effects of combining inhibitors of these two enzymes are observed in leukemia and prostate cancer. Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized to evaluate their anticancer activity. After the structure-activity study, one of the best compounds, ML234, displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of ML234 was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by ML234 were verified by Western blot analysis. More importantly, the compound remarkably suppressed the tumor growth and enhanced the therapeutic efficacy of clinical drug enzalutamide in the 22RV1 xenograft mouse model, indicating that it may have potential as an anticancer agent in prostate cancer.