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Organic & Biomolecular Chemistry Mar 2013A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of...
Hydrothiolation of benzyl mercaptan to arylacetylene: application to the synthesis of (E) and (Z)-isomers of ON 01910·Na (Rigosertib®), a phase III clinical stage anti-cancer agent.
A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of (Z) and (E)-styryl benzyl sulfides where base catalyzed hydrothiolations have failed. The scope of this reaction was successfully extended for the synthesis of (E)-ON 01910·Na, a phase III clinical stage anti-cancer agent and its inactive geometrical isomer (Z)-ON 01910·Na. It is interesting to note that all the E-isomers synthesized have shown better cytotoxicity profile on cancer cells compared to the Z-isomers.
Topics: Alkynes; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Glycine; Humans; K562 Cells; Molecular Structure; Stereoisomerism; Structure-Activity Relationship; Sulfhydryl Compounds; Sulfones
PubMed: 23386308
DOI: 10.1039/c3ob27220f -
International Journal of Molecular... Mar 2023Cardiovascular complications combined with COVID-19 (SARS-CoV-2) lead to a poor prognosis in patients. The common pathogenesis of ischemic cardiomyopathy (ICM) and...
Cardiovascular complications combined with COVID-19 (SARS-CoV-2) lead to a poor prognosis in patients. The common pathogenesis of ischemic cardiomyopathy (ICM) and COVID-19 is still unclear. Here, we explored potential molecular mechanisms and biomarkers for ICM and COVID-19. Common differentially expressed genes (DEGs) of ICM (GSE5406) and COVID-19 (GSE164805) were identified using GEO2R. We performed enrichment and protein-protein interaction analyses and screened key genes. To confirm the diagnostic performance for these hub genes, we used external datasets (GSE116250 and GSE211979) and plotted ROC curves. Transcription factor and microRNA regulatory networks were constructed for the validated hub genes. Finally, drug prediction and molecular docking validation were performed using cMAP. We identified 81 common DEGs, many of which were enriched in terms of their relation to angiogenesis. Three DEGs were identified as key hub genes (, , and ) in the protein-protein interaction analysis. These hub genes had high diagnostic performance in the four datasets (AUC > 0.7). Mir-16-5p and KLF9 transcription factor co-regulated these hub genes. The drugs vindesine and ON-01910 showed good binding performance to the hub genes. We identified , , and as markers for the co-pathogenesis of ICM and COVID-19, and showed that co-pathogenesis of ICM and COVID-19 may be related to angiogenesis. Vindesine and ON-01910 were predicted as potential therapeutic agents. Our findings will contribute to a deeper understanding of the comorbidity of ICM with COVID-19.
Topics: Humans; Systems Biology; Molecular Docking Simulation; Vindesine; COVID-19; SARS-CoV-2; Computational Biology; Myocardial Ischemia; Comorbidity; MicroRNAs; Biomarkers; Transcription Factors; Cardiomyopathies; Gene Expression Profiling
PubMed: 37047484
DOI: 10.3390/ijms24076511 -
Journal of Medicinal Chemistry Jan 2020Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine...
Platinum-Based Modification of Styrylbenzylsulfones as Multifunctional Antitumor Agents: Targeting the RAS/RAF Pathway, Enhancing Antitumor Activity, and Overcoming Multidrug Resistance.
Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rigosertib were designed. Among them, compound showed the most potent antitumor activity in vitro with IC values at the nanomolar level against the tested tumor cell lines and 1000-fold higher than cisplatin against the multidrug resistant cells (A549/CDDP, A549/DOX, and SKOV-3/CDDP cells), while it showed only moderate cytotoxicity against normal cells (HEUVC cells). Compound could clearly disturb signaling transduction between RAS and CRAF by directly bonding to CRAF and inhibit CRAF activation. Besides, the enhanced intracellular platinum level made more potent than cisplatin in DNA damage, reactive oxygen species accumulation, and mitochondrial membrane potential decrease. Moreover, induced apoptosis by the endogenous pathway and efficiently inhibited tumor growth in the A549 xenograft model without side effects.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Coordination Complexes; DNA Damage; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; G2 Phase Cell Cycle Checkpoints; Glycine; Human Umbilical Vein Endothelial Cells; Humans; Mice, Inbred BALB C; Neoplasms; Platinum; Proto-Oncogene Proteins c-raf; Reactive Oxygen Species; Signal Transduction; Sulfones; Xenograft Model Antitumor Assays; ras Proteins
PubMed: 31820986
DOI: 10.1021/acs.jmedchem.9b01223 -
Journal of Medicinal Chemistry Mar 2014ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along...
Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2-((styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities.
ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along with an impressive safety profile. While ON01910 is highly active against cancer cells, it has a low oral availability and requires continuous intravenous infusion or multiple gram doses to ensure sufficient drug exposure for biological activity in patients. We have identified two novel series of styrylsulfonyl-methylpyridines. Lead compounds 8, 9a, 18 and 19a are highly potent mitotic inhibitors and selectively cytotoxic to cancer cells. Impressively, these compounds possess excellent pharmaceutical properties and two lead drug candidates 9a and 18 demonstrated antitumor activities in animal models.
Topics: Aminopyridines; Animals; Annexin A5; Antineoplastic Agents; Apoptosis; Area Under Curve; Biological Availability; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Design; Drug Discovery; Glycine; Half-Life; Indicators and Reagents; Kaplan-Meier Estimate; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Microsomes, Liver; Models, Molecular; Rats; Structure-Activity Relationship; Styrenes; Sulfonamides; Sulfones; Xenograft Model Antitumor Assays
PubMed: 24471873
DOI: 10.1021/jm4019614 -
Stem Cells and Development Apr 2019Spinal muscular atrophy (SMA) is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Only ∼10% of the products of SMN2, a paralogue of SMN1,...
Spinal muscular atrophy (SMA) is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Only ∼10% of the products of SMN2, a paralogue of SMN1, are functional full-length SMN (SMN-FL) proteins, whereas SMN2 primarily produces alternatively spliced transcripts lacking exon 7. Reduced SMN protein levels in SMA patients lead to progressive degeneration of spinal motor neurons (MNs). In this study, we report an advanced platform based on an SMN2 splicing-targeting approach for SMA drug screening and validation using an SMN2 splicing reporter cell line and an in vitro human SMA model through induced pluripotent stem cell (iPSC) technology. Through drug screening using a robust cell-based luciferase assay to quantitatively measure SMN2 splicing, the small-molecule candidate compound rigosertib was identified as an SMN2 splicing modulator that led to enhanced SMN protein expression. The therapeutic potential of the candidate compound was validated in MN progenitors differentiated from SMA patient-derived iPSCs (SMA iPSC-pMNs) as an in vitro human SMA model, which recapitulated the biochemical and molecular phenotypes of SMA, including lower levels of SMN-FL transcripts and protein, enhanced cell death, and reduced neurite length. The candidate compound exerted strong splicing correction activity for SMN2 and potently alleviated the disease-related phenotypes of SMA iPSC-pMNs by modulating various cellular and molecular abnormalities. Our combined screening platform representing a pMN model of human SMA provides an efficient and reliable drug screening system and is a promising resource for drug evaluation and the exploration of drug modes of action.
Topics: Alternative Splicing; Animals; Cell Line; Glycine; Humans; Mice; Mice, Transgenic; Models, Neurological; Muscular Atrophy, Spinal; Sulfones; Survival of Motor Neuron 2 Protein
PubMed: 30667343
DOI: 10.1089/scd.2018.0181 -
Oncogene Mar 2009Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL...
Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin D1 mRNA translation, decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR) and eIF4E-binding protein (eIF4E-BP), lowered the cap site binding activity of eIF4E and directly inhibited activity of phosphatidylinositol-3 kinase (PI-3K). Analysis of apoptotic signaling pathways revealed that ON 01910.Na induced the release of cytochrome c from mitochondria, altered expression of Bcl-2 family of proteins and stimulated activation of caspases. Taken together, styryl sulfonyls can cause a rapid decrease of cyclin D1 by blocking cyclin D1 mRNA translation through inhibition of the PI-3K/Akt/mTOR/eIF4E-BP signaling pathway and triggering a cytochrome c-dependent apoptotic pathway in MCL cells.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cyclin D1; Eukaryotic Initiation Factor-4E; Extracellular Signal-Regulated MAP Kinases; Forkhead Box Protein O1; Forkhead Transcription Factors; Glycine; Humans; Lymphoma, Mantle-Cell; Mitogen-Activated Protein Kinase Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Biosynthesis; Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Signal Transduction; Sulfones; TOR Serine-Threonine Kinases; p38 Mitogen-Activated Protein Kinases; raf Kinases
PubMed: 19198627
DOI: 10.1038/onc.2008.502 -
PloS One 2013Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of...
Lymphoma-specific biomarkers contribute to therapeutic strategies and the study of tumorigenesis. Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. However, only 50% of patients experience long-term survival after current treatment; therefore, developing novel therapeutic strategies is warranted. Comparative proteomic analysis of two DLBCL lines with a B-lymphoblastoid cell line (LCL) showed differential expression of Ran GTPase-activating protein 1 (RanGAP1) between them, which was confirmed using immunoblotting. Immunostaining showed that the majority of DLBCLs (92%, 46/50) were RanGAP1(+), while reactive lymphoid hyperplasia (n = 12) was RanGAP1(+) predominantly in germinal centers. RanGAP1 was also highly expressed in other B-cell lymphomas (BCL, n = 180) with brisk mitotic activity (B-lymphoblastic lymphoma/leukemia: 93%, and Burkitt lymphoma: 95%) or cell-cycle dysregulation (mantle cell lymphoma: 83%, and Hodgkin's lymphoma 91%). Interestingly, serum RanGAP1 level was higher in patients with high-grade BCL (1.71 ± 2.28 ng/mL, n = 62) than in low-grade BCL (0.75 ± 2.12 ng/mL, n = 52) and healthy controls (0.55 ± 1.58 ng/mL, n = 75) (high-grade BCL vs. low-grade BCL, p = 0.002; high-grade BCL vs. control, p < 0.001, Mann-Whitney U test). In vitro, RNA interference of RanGAP1 showed no effect on LCL but enhanced DLBCL cell death (41% vs. 60%; p = 0.035) and cell-cycle arrest (G0/G1: 39% vs. 49%, G2/M: 19.0% vs. 7.5%; p = 0.030) along with decreased expression of TPX2 and Aurora kinases, the central regulators of mitotic cell division. Furthermore, ON 01910.Na (Estybon), a multikinase inhibitor induced cell death, mitotic cell arrest, and hyperphosphorylation of RanGAP1 in DLBCL cell lines but no effects in normal B and T cells. Therefore, RanGAP1 is a promising marker and therapeutic target for aggressive B-cell lymphoma, especially DLBCL.
Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Enzyme Inhibitors; GTPase-Activating Proteins; Humans; Lymphoma, B-Cell; Phosphorylation; RNA Interference
PubMed: 24223200
DOI: 10.1371/journal.pone.0079863 -
PloS One 2013Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly...
Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.
Topics: Acetanilides; Animals; Antineoplastic Agents; Biological Assay; Cell Cycle Proteins; Dose-Response Relationship, Drug; Embryo, Nonmammalian; Glycine; High-Throughput Screening Assays; Humans; Male; Mice; Mice, Nude; Mitosis; Molecular Docking Simulation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Proto-Oncogene Proteins; Quinolines; Small Molecule Libraries; Sulfones; Xenograft Model Antitumor Assays; Zebrafish; Polo-Like Kinase 1
PubMed: 23658603
DOI: 10.1371/journal.pone.0053317 -
Cancer Chemotherapy and Pharmacology Dec 2009ON 01910.Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and II trials. The purpose of this research was to evaluate the pharmacokinetic...
PURPOSE
ON 01910.Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and II trials. The purpose of this research was to evaluate the pharmacokinetic profile of ON 01910.Na across several species, and to evaluate the effects of protein binding and duration of exposure on its in vitro cytotoxic activity.
METHODS
Data were collated from several preclinical investigations, where the plasma disposition and tissue distribution of ON 01910.Na were assessed after administration (10-150 mg/kg, IP or IV) to several species (mouse, rat, and dog). Plasma protein binding was assessed using ultrafiltration. Cytotoxic activity of ON 01910.Na was determined in DU145 cells, and activity was correlated to unbound drug concentration and the duration of exposure.
RESULTS
ON 01910.Na exhibits extensive plasma protein binding and the compound displays rapid elimination from the circulation in all three animal species (t(1/2) range 0.404-0.870 h). Tissue distribution studies in mice revealed highest drug accumulation in the liver, followed by the kidneys. ON 01910.Na is not extensively metabolized in vivo and urinary excretion is predominant at higher doses. ON 01910.Na cytotoxicity in DU145 cells was adversely affected by protein binding in the incubation medium. Drug cytotoxicity was greatly enhanced upon extending the duration of exposure at reduced drug concentrations.
CONCLUSIONS
Due to the short half-life and rapid clearance of the drug, administration of ON 01910.Na by continuous IV infusion is a likely treatment option for cancer patients.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Female; Glycine; Half-Life; Humans; Infusions, Intravenous; Kidney; Liver; Male; Mice; Prostatic Neoplasms; Protein Binding; Rats; Species Specificity; Sulfones; Tissue Distribution
PubMed: 19466411
DOI: 10.1007/s00280-009-1022-9 -
Laboratory Investigation; a Journal of... Oct 2012Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase and its kinase activity is closely interrelated to cell cycle progression, various types of cancer...
Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase and its kinase activity is closely interrelated to cell cycle progression, various types of cancer development and often correlates with poor prognosis. Thus, it is of prime importance to characterize the phenotypes of Plk1 inhibition in cells for drug development and clinical application. Here, we report a novel kinase inhibitory chemical, CBB2001, which specifically inhibited Plk1 kinase activity in vitro with an IC(50) of 0.39 μM. In cervical carcinoma HeLa cells, we found that treatment of CBB2001 caused mitotic cell cycle arrest (EC(50)=0.72 μM) and induction of 'polo' cells (EC(50)=0.32 μM). Interestingly, the cell cycle arrest induced by CBB2001 was associated with accumulation of Plk1 (EC(50)=0.61 μM) and Geminin (EC(50)=0.43 μM) proteins, but distinct from the phenotypes induced by Aurora kinase inhibitors. The inhibitory effects of CBB2001 were phenocopied by RNA interferences of Plk1. We also confirmed the cell cycle inhibitory effects of CBB2001 in other cancer cells. Moreover, CBB2001 inhibited the growth of HeLa cells with an IC(50) of 0.85 μM in MTT assays, which is better than that of reported Plk1 inhibitory chemicals ON01910 (IC(50)=6.46 μM) and LFM-A13 (IC(50)=37.36 μM). CBB2001 also inhibited mouse xenograft tumor growth. Furthermore, CBB2001 inhibited mitotic exit and delayed degradation of APC/C substrates, Geminin, Cyclin B1 and Aurora A. These specific phenotypes may serve as specific features for Plk1 inhibition and for Plk1-based clinic trials.
Topics: Amides; Animals; Aurora Kinase A; Aurora Kinases; Benzimidazoles; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Cell Proliferation; Cyclin B1; Female; Geminin; Glycine; Humans; Inhibitory Concentration 50; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Nitriles; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Sulfones; Thiazoles; Polo-Like Kinase 1
PubMed: 22890557
DOI: 10.1038/labinvest.2012.114