Anti-prostate Cancer Activity Research Articles

Design, Synthesis, and Anti-Prostrate Cancer Potential of 2-(4-nitrobenzyl) malonates In Vitro and DAL Acute Oral Toxicity Assessment In Vivo.

New 4-nitrobenzyl derivatives were designed and synthesised by nucleophilic substitution reactions of 4-nitrobenzyl bromide with malonic acid and its derivatives. The synthesised molecules were characterised using mass analysis and spectroscopic techniques and tested for their antioxidant properties using various methods, such as nitric oxide, DPPH, and hydrogen peroxide radical scavenging methods. The anti-inflammatory activities of the molecules were assessed using RBC membrane stabilisation and albumin denaturation methods. We evaluated the compounds' potential anti-prostate cancer activity using the DU145 cell line. The MTT assay determined the cell viability, indicating good anti-proliferative activity. The molecule 3c exhibited the highest potency, with a CTC50 of 11.83 µg/mL. Molecular dynamics simulations were performed to study the stability of the ligand within the protein after docking and the resulting protein-ligand complex. The in vivo analysis of molecule 3c in the DAL xenograft model demonstrated promising results. The increase in life span, reduction in tumor volume, and comparable effects to standard drugs are encouraging features that suggest that molecule 3c may possess significant potential as an anti-cancer agent. The research also implies that these molecules might be potential lead compounds for developing new prostate cancer drugs.

Ilicicolin C suppresses the progression of prostate cancer by inhibiting PI3K/AKT/mTOR pathway.

Aberrant activation of the PI3K/AKT pathway is a driving factor in the development of prostate cancer. Therefore, inhibiting the function of the PI3K/AKT signaling pathway is a strategy for the treatment of prostate cancer. Ilicicolin C is an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501. Which has anti-inflammatory activity, but its activity against prostate cancer has not yet been elucidated. MTT assay, plate clone-formation assay, flow cytometry and real-time cell analysis technology were used to detect the effects of ilicicolin C on cell viability, proliferation, apoptosis and migration of prostate cancer cells. Molecular docking software and surface plasmon resonance technology were used to analyze the interaction between ilicicolin C and PI3K/AKT proteins. Western blot assay was performed to examine the changes in protein expression. Finally, QikProp software was used to simulate the process of ilicicolin C in vivo, and a zebrafish xenograft model was used to further verify the anti-prostate cancer activity of ilicicolin C in vivo. Ilicicolin C showed cytotoxic effects on prostate cancer cells, with the most significant effect on PC-3 cells. Ilicicolin C inhibited proliferation and migration of PC-3 cells. It could also block the cell cycle and induce apoptosis in PC-3 cells. In addition, ilicicolin C could bind to PI3K/AKT proteins. Furthermore, ilicicolin C inhibited the expression of PI3K, AKT and mTOR proteins and could also regulate the expression of downstream proteins in the PI3K/AKT/mTOR signaling pathway. Moreover, the calculations speculated that ilicicolin C was well absorbed orally, and the zebrafish xenograft model confirmed the in vivo anti-prostate cancer effect of ilicicolin C. Ilicicolin C emerges as a promising marine compound capable of inducing apoptosis of prostate cancer cells by counteracting the aberrant activation of PI3K/AKT/mTOR, suggesting that ilicicolin C may be a viable candidate for anti-prostate cancer drug development. These findings highlight the potential of ilicicolin C against prostate cancer and shed light on its mechanism of action.

Novel Metabolites from the Marine-Derived Fungus Peniophora sp. SCSIO41203 Show Promising In Vitro Antitumor Activity as Methuosis Inducers in PC-3 Cells.

Two new cytochalasin derivatives, peniotrinins A (1) and B (2), three new citrinin derivatives, peniotrinins C-E (4, 5, 7), and one new tetramic acid derivative, peniotrinin F (12), along with nine structurally related known compounds, were isolated from the solid culture of Peniophora sp. SCSIO41203. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis, quantum chemical calculations, and the calculated ECD. Interestingly, 1 is the first example of a rare 6/5/5/5/6/13 hexacyclic cytochalasin. We screened the above compounds for their anti-prostate cancer activity and found that compound 3 had a significant anti-prostate cancer cell proliferation effect, while compounds 1 and 2 showed weak activity at 10 μM. We then confirmed that compound 3 exerts its anti-prostate cancer effect by inducing methuosis through transmission electron microscopy and cellular immunostaining, which suggested that compound 3 might be first reported as a potential anti-prostate methuosis inducer.

Recent advances in flavonoid compounds for the treatment of prostate cancer.

Prostate cancer is a malignant epithelial tumor of the prostate gland and is the most common malignant tumor of the male genitourinary system. Pharmacological therapies, including chemotherapy and androgen deprivation therapy, play a key role in the treatment of prostate cancer. However, drug resistance and side effects limit the use of these drugs and so there is a need for new drug therapies for prostate cancer patients. Flavonoids, with their wide range of sources and diverse biological activities, have attracted much attention in the field of anti-tumor drug screening. In 2016, at least 58 flavonoids were reported to have anti-prostate cancer activity. In recent years, six additional flavonoid compounds have been found to have anti-prostate cancer potential. In this review, we have collected a large amount of evidence on the anti-prostate cancer effects of these six flavonoids, including a large number of cellular experiments and a small number of preclinical animal experiments. In addition, we predicted their drug-forming properties using Schrödinger's QikProp software and ADMETlab due to the lack of in vivo pharmacokinetic data for the six compounds. In conclusion, this review has fully confirmed the anti-prostate cancer effects of these six flavonoids, summarized their mechanisms of action and predicted their druggability. It provides a reference for the further development of these compounds into anti-prostate cancer drugs.

Assessment of Anti-Prostate Cancer Activity among Four Seaweeds, with Focus on Caulerpa lentillifera J.Agardh.

In response to a global shift towards health-conscious and environmentally sustainable food choices, seaweed has emerged as a focus for researchers due to its large-scale cultivation potential and the development of bioactive substances. This research explores the potential anticancer properties of seaweed extracts, focusing on analyzing the impact of four common edible seaweeds in Taiwan on prostate cancer (PCa) cells' activity. The study used bioassay-guided fractionation to extract Cl80 from various seaweeds with androgen receptor (AR)-inhibitory activity. Cl80 demonstrated effective suppression of 5α-dihydrotestosterone (DHT)-induced AR activity in 103E cells and attenuated the growth and prostate-specific antigen (PSA) protein expression in LNCaP and 22Rv1 cells. Additionally, Cl80 exhibited differential effects on various PCa cell lines. Concentrations above 5 μg/mL significantly inhibited LNCaP cell proliferation, while 22Rv1 cells were more resistant to Cl80. PC-3 cell proliferation was inhibited at 5 μg/mL but not completely at 50 μg/mL. A clonogenic assay showed that at a concentration of 0.5 μg/mL, the colony formation in LNCaP and PC-3 cells was significantly reduced, with a dose-dependent effect. Cl80 induced apoptosis in all PCa cell types, especially in LNCaP cells, with increased apoptotic cells observed at higher concentrations. Cl80 also decreased the mitochondrial membrane potential (ΔΨm) in a dose-dependent manner in all PCa cell lines. Furthermore, Cl80 suppressed the migration ability of PCa cells, with significant reductions observed in LNCaP, 22Rv1, and PC-3 cells at various concentrations. These compelling findings highlight the promising therapeutic potential of C. lentillifera J.Agardh and its isolated compound Cl80 in the treatment of PCa.

Molecular docking of phytochemical compounds in Cucurbita maxima with anti-prostate cancer activity

Molecular docking of phytochemical compounds in Cucurbita maxima with anti-prostate cancer activity

Exploring substituted 3,4-dihydropyrimidinone and thione derivatives as anti-prostate cancer agents: Computational screening, synthesis, characterization, and in vitro efficacy assessment

Despite decades of research, anticancer medication therapy is still largely constrained to prevent growth and limit the spread of tumour cells. To speed up the process of finding anticancer drugs, exploring novel therapeutic macromolecules and identifying the right small molecules using an integration of computational and experimental approaches is a recent tactic adopted by investigators. In the present study, we designed and created a library of 200 ligands with 3,4-dihydropyrimidinones or their thiones linked with imidazolidinones through amide linkage and explored the extent of their in vitro anticancer activity towards human topoisomerase IIalpha (TOP2α or TOP2A) using DU-145 and PC-3 prostate cancer cell lines using the SRB assay method. This was accomplished by the molecular docking and synthesis of the titled compounds using a series of organic nucleophilic addition reactions, including the Biginelli one-pot condensation reaction. The preliminary physical character evaluation was employed for the synthesized compounds, and the structural parameters were analyzed using FTIR, proton NMR, 13C NMR, and LC-MS/MS. The anti-prostate cancer activity of the prepared Biginelli analogues was evaluated against cancer cell lines and mild-to-moderate reduction in the viability of cell lines was observed with compounds 5, 6, 9, 14, 15, 16, 17, and 19. Among them, compounds 5, 14, 15, and 16 exhibited significant potent activity against TOP2α or TOP2A. This result indicated that the derivatives of Biginelli (3,4-dihydropyrimidinones/thiones) could be promising anti-prostate cancer drug candidates.

UPLC-Q-TOF-MS profiling of Viola stocksii Boiss. and evaluation of aphrodisiac potential and risk factors associated with erectile dysfunction

Ethnopharmacological relevanceViola stocksii Boiss. locally known as makhni or makhanr booti, is an important medicinal food plant with multiple therapeutic applications, including erectile dysfunction (ED). It is mixed with butter and used for boosting energy and sexual health in the subcontinent. Aims of the studyThis study was designed to evaluate the chemical composition, aphrodisiac potential and effect of V. stocksii on the risk factors associated with ED. MethodologyThe hydroethanolic extract of V. stocksii (HEEVS) was prepared through the microwave-assisted extraction (MAE) technique. The chemical composition was evaluated using preliminary phytochemical screening and UPLC-Q-TOF-MS analysis. Metals and minerals analysis was performed by an atomic absorption spectrophotometer. The aphrodisiac activity of HEEVS was evaluated using an in vivo aphrodisiac model established in male albino rats and the effect on various sexual parameters such as mount, intromission, ejaculation frequencies and mount, intromission, ejaculation latencies, postejaculatory interval, penile reflexes and serum hormone concentration were analyzed. The effect of HEEVS on various risk factors associated with ED, including prostate cancer (PC), bacterial infections, diabetes and obesity, was evaluated using various in vitro assays. Moreover, four compounds were selected from the UPLC-Q-TOF-MS profile and evaluated for in silico computational analysis against phosphodiesterase-5 (PDE-5) for possible interaction. FindingsThe phytochemical screening revealed the presence of various secondary metabolites in HEEVS, while 58 compounds were tentatively identified in the UPLC-Q-TOF-MS analysis. Various important minerals and metals such as zinc, calcium, cadmium and magnesium were detected in the atomic absorption spectrometry analysis. The in vivo aphrodisiac evaluation showed a significant (p < 0.05) increase in the mount, intromission and ejaculation frequencies and a decrease in the mount, intromission latencies and post-ejaculatory intervals at a dose of 300 mg/kg. A marked (p < 0.05) increase was observed in the concentration of serum testosterone and luteinizing hormones in HEEVS treated animals with a significant increase in total penile reflexes. The extract displayed significant anti-prostate cancer activity and a potential antibacterial spectrum against E. coli and S. aureus, with MIC50 values of 215.72 μg/mL and 139.05 μg/mL, respectively. Similarly, HEEVS was found active towards pancreatic lipase (67.34 ± 1.03%), α-glucosidase (3.87 ± 0.54 mmol ACAE/g d.w.) and α-amylase (6.98 ± 1.63 mmol ACAE/g d.w.). The in silico docking study presented a potential interaction between the selected compounds and residues of the active site of PDE-5. ConclusionThis report highlights the aphrodisiac potential of V. stocksii and provides experimental support for its traditional use in ED with an attenuative effect on the risk factors associated with ED. Moreover, the chemical composition displayed the presence of functional phytoconstituents and minerals in HEEVS and paves the way for the isolation of compounds with potent aphrodisiac activity.

Synthesis, characterization of a new series of thiohydantoin derivatives and study their biological activity against prostate cancer and microbes.

Prostate cancer is one of the most common malignant diseases in men, and the design of new chemical compounds against prostate cancer is one of the challenges faced by modern medicine. In this study, we prepared and characterized a new series of thiohydantoin derivatives by reacting maleimide derivatives (1C-4) with cyclohexyl isothiocyanate.The prepared compounds were diagnosed using (FT-IR ,1H-NMR ,13C-NMR ).MTT assay was used to determine the activity of the prepared compounds against prostate cancer cell lines, as the data indicated, based on IC50 values, that the prepared compounds do not have anti-prostate cancer activity. The prepared compounds were also studied against selected types of bacteria and fungi, as the data indicated that some of the prepared series compounds had anti-bacterial and anti-fungal activity under study, as the compound 4C showed a high anti-staph activity.

Anti-prostate cancer components of black ginseng based on the "nine steaming and nine sun-drying" process

This study was to identify the main active components of black ginseng responsible for prostate cancer treatment. HPLC fingerprints of 10 batches of processed ginseng from the "nine steaming and nine sun-drying" procedure were established. MTT test was performed to evaluate the inhibitory activity of black ginseng on human prostate cancer (DU145) cells. The spectrum-effect relationship analysis was assessed by correlation coefficient and grey relational analysis, and the active ginsenosides were further validated by bioactivity assay. Results indicated the anti-prostate cancer activity of black ginseng increased until the 7th cycle times of steaming and sun-drying, and the primary anti-prostate cancer ingredients of black ginseng were disclosed to be ginsenosides Rg5, F4, Rh4, Rk1, R-Rg3, and S-Rg3, of which Rk3, Rg5, and F4 exerted the highest effects. It is for the first time that a spectrum-effect relationship based on the ingredient changes of the "Nine Steaming and Nine Sun-drying" process was used to identify the active anticancer constituents of ginseng systemically and could further the stronger anticancer activity of black ginseng as well as provide a theoretical basis for the quality evaluation of black ginseng.

Unveiling poly(rC)-binding protein 2 as the target protein for curcusone C against prostate cancer: mechanism validation through click chemistry-activity based proteomics profiling approach

BackgroundProstate cancer is a disease that seriously troubles men. However, there are some inevitable limitations in interventional therapy for prostate cancer patients at present, most of which are caused by low selectivity and high toxic side effects due to unclear drug targets. In this study, we identified the target protein of Curcusone C with anti-prostate cancer potential activity and verified its target and mechanism of action.MethodsClick chemistry-activity based proteomics profiling (CC-ABPP) method was used to find target protein of Curcusone C against prostate cancer. Competitive CC-ABPP, drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR) methods were used to verifying the target protein. Moreover, potential mechanism was validated by western blot in vitro and by hematoxylin-eosin (HE) staining, detection of apoptosis in tumor tissue (TUNEL), and immunohistochemical (IHC) in vivo.ResultsWe found that poly(rC)-binding protein 2 (PCBP2) was the target protein of Curcusone C. In addition, Curcusone C might disrupt the Bax/Bcl-2 balance in PC-3 cells by inhibiting the expression of the target protein PCBP2, thereby inducing mitochondrial damage and activation of the mitochondrial apoptosis pathway, and ultimately inducing apoptosis of prostate cancer cells.ConclusionsCurcusone C is a potential compound with anti-prostate cancer activity, and this effect occurs by targeting the PCBP2 protein, which in turn may affect the TGF/Smad signaling pathway and Bax/Bcl-2 balance. Our results laid a material and theoretical foundation for Curcusone C, to be widely used in anti-prostate cancer.

Hirsutinolide-type sesquiterpenoids with anti-prostate cancer activity from Cyanthillium cinereum

Four previously undescribed hirsutinolide-type sesquiterpenoids, cyanolides A-D (1–4), along with twelve known analogues (5–16), were isolated from the aerial parts of Cyanthillium cinereum. Their structures were determined by comprehensive analysis of NMR, HRESIMS, and ECD spectra. Compound 1 is a rarely occurring hirsutinolide-type sesquiterpenoid with 1,4-ether ring ruptured and containing a chlorine atom, and compounds 13–16 were reported from this plant for the first time. All compounds were tested for their inhibiting effects on prostate cancer cells. As a result, compounds 1, 3, and 8–14 exhibited significant anti-prostate cancer activity against PC-3 and LNCaP cells with IC50 values ranging from 2.2 ± 0.4 to 8.5 ± 0.7 μM and 3.0 ± 0.7 to 10.5 ± 1.1 μM, respectively. The preliminary structure-activity relationship was discussed. Further investigation showed that compound 1 induced apoptosis in PC-3 cells.

Study of the Anticancer and Antimicrobial Biological Activity of a New Series of Thiohydantoin Derivatives

Recently, some prostate cancer patients have acquired resistance to the second -generation drugs (anzalutamide and apalutamide) prescribed for the treatment of this disease due to the emergence of the F876L mutation, which represents a challenge to modern medicine. In this study, a new series of 2-thiohydantoin derivatives were prepared through the reaction of different derivatives of maleimide (1c-4c) with isothiocyanate derivatives. The prepared compounds were diagnosed using FT-IR,1H-NMR ,13C-NMR, Mass spectra. The prepared series compounds has been studied against prostate cancer cells. The MTT assay was used to determine the activity of the prepared compounds against prostate cancer cells. The data indicated, depending on the IC50 values, that some of the prepared compounds have anti-prostate cancer activity. The results indicate that compounds 1d and 2d have good anti-prostate cancer activity compared to the rest of the compounds. The prepared series of compounds were also studied against selected types of bacteria and fungi, as the results showed that some of the compounds in the series had anti-bacterial and anti-fungal activity.

Investigation on the mechanisms by which the herbal remedies induce anti-prostate cancer activity: uncovering the most practical natural compound

Prostate cancer (PCa) is one of the most reported cancers among men worldwide. Targeting the essential proteins associated with PCa could be a promising method for cancer treatment. Traditional and herbal remedies (HRs) are the most practical approaches for PCa treatment. Here, the proteins and enzymes associated with PCa were determined based on the information obtained from the DisGeNET database. The proteins with a gene-disease association (GDA) score greater than 0.7 and the genes that have a disease specificity index (DSI) = 1 were selected as the target proteins. 28 HRs with anti-PCa activity as a traditional treatment for PCa were chosen as potential bioactive compounds. More than 500 compound-protein complexes were screened to find the top-ranked bioactives. The results were further evaluated using the molecular dynamics (MD) simulation and binding free energy calculations. The outcomes revealed that procyanidin B2 3,3′‐di‐O‐gallate (B2G2), the most active ingredient of grape seed extract (GSE), can act as an agonist for PTEN. PTEN has a key role in suppressing PCa cells by applying phosphatase activity and inhibiting cell proliferation. B2G2 exhibited a considerable binding affinity to PTEN (11.643 kcal/mol). The MD results indicated that B2G2 could stabilize the key residues of the phosphatase domain of PTEN and increase its activity. Based on the obtained results, the active ingredient of GSE, B2G2, could play an agonist role and effectively increase the phosphatase activity of PTEN. The grape seed extract is a useful nutrition that can be used in men’s diets to inhibit PCa in their bodies. Communicated by Ramaswamy H. Sarma

Discovery of a novel 1H-pyrazole- [3,4-b] pyridine-based lysine demethylase 5B inhibitor with potential anti-prostate cancer activity that perturbs the phosphoinositide 3-kinase/AKT pathway.

Lysine demethylase 5B (KDM5B) is a member of the Jumonji AT-rich interactive domain 1 family. Its main function is to demethylate di/trimethyl histone H3 lysine 4 and it plays a crucial role in the occurrence and development of cancer. In this study, we performed structure-based optimization of KDM5B inhibitors based on our previous work and the most active compound we synthesized was 11ad. Molecular modeling studies and thermal shift assays revealed that 11ad specifically targets KDM5B at the molecular and cellular levels. Crucially, 11ad demonstrated good pharmacokinetic properties and anti-prostate cancer activity in a xenograft model. Furthermore, unexpectedly, the specificity of 11ad for prostate cancer was found to be related to its inhibition of the phosphoinositide 3-kinase/AKT pathway. This is the first report of a KDM5B inhibitor affecting this pathway. Taken together, our findings indicate that 11ad is a novel KDM5B inhibitor that may serve as a lead compound for the development of treatments for prostate cancer.

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Anticancer Activity of Methyl Protodioscin against Prostate Cancer by Modulation of Cholesterol-Associated MAPK Signaling Pathway via FOXO1 Induction.

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscoreaceae, has lipid-lowering and broad anticancer properties. However, the efficacy of MPD in treating prostate cancer remains unexplored. Therefore, the present study aimed to evaluate the anticancer activity and action mechanism of MPD in prostate cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, and flow cytometer assays revealed that MPD suppressed proliferation, migration, cell cycle, and invasion and induced apoptosis of DU145 cells. Mechanistically, MPD decreased cholesterol concentration in the cholesterol oxidase, peroxidase and 4-aminoantipyrine phenol (COD-PAP) assay, disrupting the lipid rafts as detected using immunofluorescence and immunoblot analyses after sucrose density gradient centrifugation. Further, it reduced the associated mitogen-activated protein kinase (MAPK) signaling pathway protein P-extracellular regulated protein kinase (ERK), detected using immunoblot analysis. Forkhead box O (FOXO)1, a tumor suppressor and critical factor controlling cholesterol metabolism, was predicted to be a direct target of MPD and induced by MPD. Notably, in vivo studies demonstrated that MPD significantly reduced tumor size, suppressed cholesterol concentration and the MAPK signaling pathway, and induced FOXO1 expression and apoptosis in tumor tissue in a subcutaneous mouse model. These results suggest that MPD displays anti-prostate cancer activity by inducing FOXO1 protein, reducing cholesterol concentration, and disrupting lipid rafts. Consequently, the reduced MAPK signaling pathway suppresses proliferation, migration, invasion, and cell cycle and induces apoptosis of prostate cancer cells.

Antiproliferative and Antiprostate Cancer Activities of Heterocyclic Compounds Derived from Cyclohexane-1,4-dione.

2-Amino-6-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (3) was prepared from the reaction of cyclohexane-1,4-dione with elemental sulfur and malononitrile in 1,4-dioxane and triethylamine as catalyst. The latter compound reacted with triethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce 4H-thieno[2,3-f]chromene derivatives 10a,b. In addition, fused pyran and pyridine derivatives were synthesized starting from compound 3. The cytotoxicity of the synthesized compounds was studied on six cancer cell lines together with c-Met kinase and PC-3 cell line. The most active compounds were tested against five tyrosine kinases and Pim-1 kinase, most of which showed strong inhibition, encouraging further work.

A Novel L-Phenylalanine Dipeptide Inhibits the Growth and Metastasis of Prostate Cancer Cells via Targeting DUSP1 and TNFSF9.

Prostate cancer (PCa) is a common malignant cancer of the urinary system. Drug therapy, chemotherapy, and radical prostatectomy are the primary treatment methods, but drug resistance and postoperative recurrence often occur. Therefore, seeking novel anti-tumor compounds with high efficiency and low toxicity from natural products can produce a new tumor treatment method. Matijin-Su [N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol, MTS] is a phenylalanine dipeptide monomer compound that is isolated from the Chinese ethnic medicine Matijin (Dichondra repens Forst.). Its derivatives exhibit various pharmacological activities, especially anti-tumor. Among them, the novel MTS derivative HXL131 has a significant inhibitory effect against prostate tumor growth and metastasis. This study is designed to investigate the effects of HXL131 on the growth and metastasis of human PCa cell lines PC3 and its molecular mechanism through in vitro experiments combined with proteomics, molecular docking, and gene silencing. The in vitro results showed that HXL131 concentration dependently inhibited PC3 cell proliferation, induced apoptosis, arrested cell cycle at the G2/M phase, and inhibited cell migration capacity. A proteomic analysis and a Western blot showed that HXL131 up-regulated the expression of proliferation, apoptosis, cell cycle, and migration-related proteins CYR61, TIMP1, SOD2, IL6, SERPINE2, DUSP1, TNFSF9, OSMR, TNFRSF10D, and TNFRSF12A. Molecular docking, a cellular thermal shift assay (CETSA), and gene silencing showed that HXL131 had a strong binding affinity with DUSP1 and TNFSF9, which are important target genes for inhibiting the growth and metastasis of PC3 cells. This study demonstrates that HXL131 exhibited excellent anti-prostate cancer activity and inhibited the growth and metastasis of prostate cancer cells by regulating the expression of DUSP1 and TNFSF9.

Development of novel cyanopyridines as PIM-1 kinase inhibitors with potent anti-prostate cancer activity: Synthesis, biological evaluation, nanoparticles formulation and molecular dynamics simulation

Recently, inhibition of PIM-1 enzyme is found as an effective route in the fight against proliferation of cancer. Herein, new cyano pyridines that target PIM-1 kinase were designed, synthesized, and biologically evaluated. Two prostate cell lines were used to examine each of the new compounds in vitro for anticancer activity, namely, PC-3 and DU-145. The cyanopyridine derivatives 2b, 3b, 4b, and 5b with an N,N-dimethyl phenyl group at the pyridine ring's 4-position showed considerable antitumor effect on the tested cell lines. Additionally, the high selectivity index revealed that these compounds were less cytotoxic to normal WI-38 cells. Furthermore, they exhibited strong inhibitory effect on PIM-1 having IC50 = 0.248, 0.13, 0.326 and 0.245 μM, respectively. The most powerful derivatives2b, 3b, 4b, and 5b, were chosen for further examination of their inhibitory potential on both kinases (PIM-2 and PIM-3). Interestingly, upon loading compound 3b in a cubosomes formulation with nanometric size, improvements in cytotoxicity and inhibitory effect on PIM-1 kinase were observed. In silico ADME parameters study revealed that compound 3b is orally bioavailable without penetration to the blood-brain barrier. Further, the docking simulations revealed the ability of our potent compounds to well accommodate the PIM-1 kinase active site forming stable complexes. In a 150 ns MD simulation, the most powerful PIM-1 inhibitor 3b produced stable complex with the PIM-1 enzyme (RMSD = 1.76). Furthermore, the 3b–PIM-1 complex has the low binding free energy (−242.2 kJ/mol) according to the MM-PBSA calculations.