Publications by authors named "Kwang-Su Park"

32 Publications

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.

J Am Chem Soc 2021 Sep 14. Epub 2021 Sep 14.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.1c04841DOI Listing
September 2021

A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells.

Cell Chem Biol 2021 Aug 30. Epub 2021 Aug 30.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address:

Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agents that effectively suppress NSD3-mediated oncogenic actions are currently lacking. We report the NSD3-targeting proteolysis targeting chimera (PROTAC), MS9715, which achieves effective and specific targeting of NSD3 and associated cMyc node in tumor cells. MS9715 is designed by linking BI-9321, a NSD3 antagonist, which binds NSD3's PWWP1 domain, with an E3 ligase VHL ligand. Importantly, MS9715, but not BI-9321, effectively suppresses growth of NSD3-dependent hematological cancer cells. Transcriptomic profiling demonstrates that MS9715, but not BI-9321, effectively suppresses NSD3-and cMyc-associated gene expression programs, resembling effects of the CRISPR-Cas9-mediated knockout of NSD3. Collectively, these results suggest that pharmacological degradation of NSD3 as an attractive therapeutic strategy, which co-suppresses NSD3- and cMyc-related oncogenic nodes, is superior to blocking the PWWP1 domain of NSD3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chembiol.2021.08.004DOI Listing
August 2021

Comparative Cytotoxicity Study of PM2.5 and TSP Collected from Urban Areas.

Toxics 2021 Jul 14;9(7). Epub 2021 Jul 14.

Environmental Health Research Department, National Institute of Environmental Research, Incheon 404-708, Korea.

Ambient particulate matter 2.5 (PM2.5) and total suspended particles (TSPs) are common airborne pollutants that cause respiratory and cardiovascular diseases. We investigated the differences of cytotoxicity and mechanism between PM2.5 and TSP activity in human alveolar epithelial A549 cells. Atmospheric samples from the central district of Seoul were collected and their chemical compositions were analyzed by inductively-coupled plasma mass spectrometry and ion chromatography. PM2.5 and TSP contained high concentrations of heavy metals (Cu, Fe, Zn, and Pb). The most abundant ions in PM2.5 were SO, NH, and NO. A549 cells were exposed to PM2.5 and TSP (25-200 µg/mL) for 24 h. TSP was more cytotoxic than PM2.5 per unit mass. PM2.5 induced oxidative stress, as evidenced by increased levels of a glutamate-cysteine ligase modifier, whereas low-concentration TSP increased hemeoxygenase-1 levels. PM2.5 and TSP did not affect c-Jun N-terminal kinase expression. The levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in PM2.5- and TSP-treated cells decreased significantly in the cytosol and increased in the nucleus. Thus, Nrf2 may be a key transcription factor for detoxifying environmental airborne particles in A549 cells. TSP and PM2.5 could activate the protective Kelch-like ECH-associated protein 1/Nrf2 pathway in A549 cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/toxics9070167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309706PMC
July 2021

Advancing targeted protein degradation for cancer therapy.

Nat Rev Cancer 2021 Jun 15. Epub 2021 Jun 15.

Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41568-021-00365-xDOI Listing
June 2021

Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Kurt-Mothes-Str.3, 06120 Halle/Saale, Germany.

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor . In an effort to improve the activity and explore the structure-activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the analogs. This resulted in the discovery of diverse selective compounds, among which and showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22115910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199216PMC
May 2021

A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6.

J Med Chem 2021 04 16;64(7):3697-3706. Epub 2021 Feb 16.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (SGC6870). is a potent PRMT6 inhibitor (IC = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6- complex and kinetic studies revealed binds a unique, induced allosteric pocket. Additionally, engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, 's enantiomer, (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, - is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c02160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035306PMC
April 2021

Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor.

J Med Chem 2020 05 14;63(10):5477-5487. Epub 2020 May 14.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Protein arginine methyltransferase 6 (PRMT6) plays important roles in several biological processes associated with multiple cancers. Well-characterized potent, selective, and cell-active PRMT6 inhibitors are invaluable tools for testing biological and therapeutic hypotheses. Although there are several known reversible PRMT6 inhibitors, covalent PRMT6 inhibitors have not been reported. Based on a cocrystal structure of PRMT6-MS023 (a type I PRMT inhibitor), we discovered the first potent and cell-active irreversible PRMT6 inhibitor, (MS117). The covalent binding mode of compound to PRMT6 was confirmed by mass spectrometry and kinetic studies and by a cocrystal structure. Compound did not covalently modify other closely related PRMTs, potently inhibited PRMT6 in cells, and was selective for PRMT6 over other methyltransferases. We also developed two structurally similar control compounds, (MS167) and (MS168). We provide these valuable chemical tools to the scientific community for further studying PRMT6 physiological and pathophysiological functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286362PMC
May 2020

Discovery of a first-in-class EZH2 selective degrader.

Nat Chem Biol 2020 02 9;16(2):214-222. Epub 2019 Dec 9.

Mount Sinai Center for Therapeutics Discovery, Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41589-019-0421-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982609PMC
February 2020

Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).

J Med Chem 2019 10 24;62(20):8996-9007. Epub 2019 Jul 24.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.

By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound (MS31). Compound potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1-compound complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b00522DOI Listing
October 2019

Structural Modification of (-)-Epigallocatechin Gallate (EGCG) Shows Significant Enhancement in Mitochondrial Biogenesis.

J Agric Food Chem 2018 Apr 10;66(15):3850-3859. Epub 2018 Apr 10.

Department of Integrative Bioscience and Biotechnology, Bio/Molecular Informatics Center , Konkuk University , Hwayang-dong, Gwangjin-gu , Seoul 143-701 , Korea.

(-)-Epigallocatechin-3-gallate (EGCG) is known as a mitochondria-targeted molecule that can prevent mitochondrial deterioration and induce mitochondrial biogenesis by modulating key regulators of mitochondrial metabolism. In this study, we tackled whether derivatization of EGCG could result in enhancement of its effects on mitochondrial biogenesis. EGCG, EGCG peracetate (AcEGCG), and its 4″- O-alkyl substituted congeners prepared by previously reported procedures were biologically evaluated. Interestingly, EGCG and AcEGCG were only marginally effective in inducing mitochondrial biogenesis, while AcEGCG congeners with an alkyl group at the 4″- O position showed significantly increased biological activity compared to their parent compound. Among these series, 3f with a methyl-branched carbonate chain at the 4″- O position of the AcEGCG scaffold showed the most enhancement in inducing mitochondrial biogenesis. Hepa1-6 cells treated with 3f exhibited increases in both mitochondrial mass (1.5 times) and relative mtDNA content to nDNA (1.5 times). As a mitochondrial biogenesis enhancer, 3f also increased expression levels of regulators for mitochondrial function, including PGC-1α (4.0 fold), p-AMPK (2.5 fold), SIRT1 (4.2 fold), ERRα (1.8 fold), NRF-1 (1.6 fold), NRF-2 (1.7 fold), and mtTFA (1.6 folds). Investigation of oxidative phosphorylation by mitochondria in the presence of 3f revealed that 3f increased the NAD/NADH ratio, the amount of cytochrome c, ATP synthesis, and oxygen consumption in Hepa1-6 cells by 2.2, 1.4, 1.5, and 2.1 fold, respectively. Taken together, these results warrant an extensive structure-activity relationship study for EGCG derivatives to develop novel mitochondrial biogenesis enhancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jafc.8b00364DOI Listing
April 2018

A Novel Probe with a Chlorinated α-Cyanoacetophenone Acceptor Moiety Shows Near-Infrared Fluorescence Specific for Tau Fibrils.

Chem Pharm Bull (Tokyo) 2017 ;65(12):1113-1116

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University.

Development of a novel, tau-selective near-infrared fluorescence (NIRF) probe was attempted by combining the 3,5-dimethoxy-N,N-dimethylaniline-4-yl moiety with an α-cyanoacetophenone via hexatrienyl π-linker. In particular, for structure-activity relationship study of the α-cyanoacetophenones, a chlorine substituent was introduced to the aromatic ring to give a series of compounds (2a-2d). Among those, compound 2c with meta-chloro aryl substituent was identified as a tau-selective NIRF probe: selectivity for tau over amyloid β (Aβ) and bovine serum albumin (BSA) was estimated to be 10.3 and 19.5 fold, respectively. The mechanism for tau-selectivity of 2c was found to be based on the specific recognition of the microenviroment of tau fibrils, which was endowed by its molecular rotor-like properties. The tau-selective NIRF probe 2c was also able to stain tau fibrils in tau-green fluorescent protein (GFP)-transgenic human neuroblastoma cells (SH-SY5Y cells).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/cpb.c17-00559DOI Listing
January 2018

Characterizing isotopic compositions of TC-C, NO3-N, and NH-N in PM in South Korea: Impact of China's winter heating.

Environ Pollut 2018 Feb 7;233:735-744. Epub 2017 Nov 7.

Chemicals Research Division, National Institute of Environmental Research (NIER), Incheon 22689, Republic of Korea. Electronic address:

The origin of PM has long been the subject of debate and stable isotopic tools have been applied to decipher. In this study, weekly PM samples were simultaneously collected at an urban (Seoul) and rural (Baengnyeong Island) site in Korea from January 2014 through February 2016. The seasonal variation of isotopic species showed significant seasonal differences with sinusoidal variation. The isotopic results implied that isotope species from Baengnyeong were mostly originated from coal combustion during China's winter heating seasons, whereas in summer, the isotopic patterns observed that were more likely to be from marine. In Seoul, coal combustion related isotopic patterns increased during China's winter heating period while vehicle related isotopic patterns were dominated whole seasons by default. Therefore, aerosol formation was originated from long-range transported coal combustion-related NO by vehicle-related NH in Seoul. δN-NH in Seoul showed highly enriched N compositions in all seasons, indicating that NH from vehicle emission is the important source of NH in PM in Seoul. In addition, Baengnyeong should be consistently considered as a key region for observing the changes of isotopic features depend on the contribution of individual emissions to the atmospheric as a result of the reduction of coal consumption in China.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2017.10.072DOI Listing
February 2018

A Difluoroboron β-Diketonate Probe Shows "Turn-on" Near-Infrared Fluorescence Specific for Tau Fibrils.

ACS Chem Neurosci 2017 10 26;8(10):2124-2131. Epub 2017 Jul 26.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea.

Tau aggregation in neuronal cells has recently received significant attention as a robust predictor of the progression of Alzheimer's disease (AD) because of its proven correlation with the degree of cognitive impairment in AD patients. Accordingly, noninvasive imaging of tau aggregates has been highlighted as a promising diagnostic tool for AD. We have previously identified a tau-specific "turn-on" near-infrared fluorescent (NIRF) probe (1), and, in this study, structural modification was performed to optimize its physicochemical as well as fluorescence properties. Thus, a series of fluorescent dyes (2a-2j) composed of a variously substituted difluoroboron β-diketonate and an N,N-dimethylaniline moiety linked by a length-extendable π-bridge were prepared. Among those, isobutyl-substituted difluoroboron β-ketonate with a π-conjugated 1,4-butadienyl linker (2e) showed the most promising properties as a tau-specific NIRF probe. Compared with 1, the "turn-on" fluorescence of 2e was more specific to tau fibrils, and it showed 8.8- and 6.2-times higher tau-over-Aβ and tau-over-BSA specificity, respectively. Also, the fluorescence intensity of 2e upon binding to tau fibrils was substantially higher (∼2.9 times) than that observed from 1. The mechanism for tau-specificity of 2e was investigated, which suggested that the molecular rotor-like property of 2e enables specific recognition of the microenvironment of tau aggregates to emit strong fluorescence. In transgenic cell lines stably expressing GFP-tagged tau proteins, 2e showed good colocalization with tau-GFP. Moreover, the fluorescence from 2e exhibited almost complete overlap with p-Tau antibody staining in the human AD brain tissue section. Collectively, these observations demonstrate the potential of 2e as a tau-specific fluorescent dye in both in vitro and ex vivo settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.7b00224DOI Listing
October 2017

Bioinorganic Nanohybrid Catalyst for Multistep Synthesis of Acetaminophen, an Analgesic.

ACS Appl Mater Interfaces 2016 Nov 31;8(44):30058-30065. Epub 2016 Oct 31.

Sungkyunkwan Advanced Institute of Nanotechnology, Sungkyunkwan University , Suwon 440-746, Korea.

A bioinorganic nanohybrid catalyst was synthesized by combining esterase with a platinum nanoparticle (PtNP). The combination of two catalysts resulted in enhanced catalytic activities, esterase hydrolysis, and hydrogenation in PtNPs, as compared to each catalyst alone. This hybrid catalyst can be successfully used in the multistep synthesis of acetaminophen (paracetamol), an analgesic and antipyretic drug, in a one-pot reaction with high yield and efficacy within a short time, demonstrating that the nanobiohybrid catalyst offers advantages in the synthesis of fine chemicals in industrial applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.6b12875DOI Listing
November 2016

A Smart Near-Infrared Fluorescence Probe for Selective Detection of Tau Fibrils in Alzheimer's Disease.

ACS Chem Neurosci 2016 11 1;7(11):1474-1481. Epub 2016 Sep 1.

Department of Integrative Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea.

Development of a novel, tau-selective smart near-infrared fluorescence (NIRF) probe was attempted by combining the previously identified core scaffold 3,5-dimethoxy-N,N-dimethylaniline-4-yl moiety, with the characteristic donor-π-acceptor architecture of the smart NIRF Aβ probes DANIR-2c and MCAAD-3. A series of compounds (2 and 3) were prepared, which were identified as "turn-on" NIRF probes for the visual detection of tau aggregates and Aβ fibrils (λ = 650 nm, Stokes shifts = 70-110 nm). In particular, combination of the 3,5-dimethoxy-N,N-dimethylanilin-4-yl moiety and the donor part of MCAAD-3 endowed the resulting probes, 3g and 3h, with significant selectivity toward tau aggregates (selectivity for tau over Aβ = 5.7 and 3.8); they showed much higher fluorescence intensities upon binding to tau aggregates (FI = 49 and 108) than when bound to Aβ fibrils (FI = 9 and 28). Quantitative analysis of binding affinities and fluorescence properties of 3g and 3h revealed that microenvironment-sensitive molecular rotor-like behavior, rather than binding affinity to the target, is responsible for their selective turn-on fluorescence detection of tau fibrils. Selective fluorescent labeling of tau fibrils by 3g and 3h was further demonstrated by immunofluorescence staining of human Alzheimer's disease brain sections, which showed colocalization of the probes (3g and 3h) and phosphorylated tau antibody.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.6b00174DOI Listing
November 2016

Photocurrent enhancement of SiNW-FETs by integrating protein-shelled CdSe quantum dots.

Nanoscale 2016 Jan;8(4):1921-5

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea. and Sungkyunkwan Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon 440-746, South Korea.

We proposed a new strategy to increase the photoresponsivity of silicon NW field-effect transistors (FETs) by integrating CdSe quantum dots (QDs) using protein shells (PSs). CdSe QDs were synthesized using ClpP, a bacterial protease, as protein shells to control the size and stability of QD and to facilitate the mounting of QDs on SiNWs. The photocurrent of SiNW-FETs in response to light at a wavelength of 480 nm was enhanced by a factor of 6.5 after integrating CdSe QDs because of the coupling of the optical properties of SiNWs and QDs. As a result, the photoresponsivity to 480 nm light reached up to 3.1 × 10(6), the highest value compared to other SiNW-based devices in the visible light range.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5nr07901bDOI Listing
January 2016

A curcumin-based molecular probe for near-infrared fluorescence imaging of tau fibrils in Alzheimer's disease.

Org Biomol Chem 2015 Dec;13(46):11194-9

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea.

In recent years, there has been growing interest in the near-infrared (NIR) fluorescence imaging of tau fibrils for the early diagnosis of Alzheimer's disease (AD). In order to develop a curcumin-based NIR fluorescent probe for tau fibrils, structural modification of the curcumin scaffold was attempted by combining the following rationales: the curcumin derivative should preserve its binding affinity to tau fibrils, and, upon binding to tau fibrils, the probe should show favorable fluorescence properties. To meet these requirements, we designed a novel curcumin scaffold with various aromatic substituents. Among the series, the curcumin derivative with a (4-dimethylamino-2,6-dimethoxy)phenyl moiety showed a significant change in its fluorescence properties (22.9-fold increase in quantum yield; Kd, 0.77 μM; λem, 620 nm; Φ, 0.32) after binding to tau fibrils. In addition, fluorescence imaging of tau-green fluorescent protein-transfected SHSY-5Y cells with confirmed that detected tau fibrils in live cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5ob01847aDOI Listing
December 2015

Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors.

J Med Chem 2015 Sep;58(18):7596-602

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , 1 Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea.

The Janus kinase (JAK) family comprises four members (JAK1, JAK2, JAK3, and Tyk2) that play a key role in mediating cytokine receptor signaling. JAK inhibition thus modulates cytokine-mediated effects. In particular, selective inhibition of JAK1 or JAK3 may provide an efficient therapeutic agent for the treatment of inflammatory diseases, with minimized side effects. In this study, as part of our continued efforts to develop a selective JAK1 inhibitor, a series of 1,2-disubstituted benzimidazole-5-carboxamide derivatives was prepared and their inhibitory activities against all four JAK isozymes were evaluated. A clear structure-activity relationship was observed with respect to JAK1 selectivity; this highlighted the importance of hydrogen bond donors at both N(1) and R2 positions located within a specific distance from the benzimidazole core. One of the synthesized compounds, 1-(2-aminoethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide (5c), showed remarkable JAK1 selectivity (63-fold vs JAK2, 25-fold vs JAK3, and 74-fold vs Tyk2). Molecular docking revealed that the 2-aminoethyl and piperidin-4-yl substituents of 5c function as probes to differentiate the ATP-binding site of JAK1 from that of JAK2, resulting in preferential JAK1 binding. A kinase panel assay confirmed the JAK1 selectivity of 5c, which showed no appreciable inhibitory activity against 26 other protein kinases at 10 μM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.5b01263DOI Listing
September 2015

Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity.

Org Biomol Chem 2015 Oct;13(37):9564-9

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea.

A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ42 oligomerization (IC50 = 17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled the preformed Aβ42 fibrils with an EC50 of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ42-oligomers as well as Aβ42-fibrils.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5ob01463hDOI Listing
October 2015

Quercetin-POM (pivaloxymethyl) conjugates: Modulatory activity for P-glycoprotein-based multidrug resistance.

Phytomedicine 2015 Jul 5;22(7-8):778-85. Epub 2015 Jun 5.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea. Electronic address:

Background: We previously demonstrated that the bioactivity of quercetin could be improved through conjugation with a hydrolysable pivaloxymethyl (POM) group.

Purpose: Present study aimed to evaluate MDR (multidrug resistance)-modulatory activity of the quercetin-POM conjugates.

Study Design/methods: MDR-modulatory activity was determined by measuring cytotoxicity of various anticancer agents to MDR MES-SA/Dx5 cell lines upon combination with the quercetin-POM conjugates.

Results: The quercetin-7-O-POM conjugate (7-O-POM-Q) was significantly more potent than quercetin in reversing MDR, which recovered the cytotoxicity of various anticancer agents with EC50 values of 1.1-1.3 µM. A series of mechanistic studies revealed that 7-O-POM-Q competes with verapamil in binding to the same drug-binding site of the major MDR target, Pgp (P-glycoprotein), and inhibits Pgp-mediated drug efflux with a similar potency as verapamil. The physicochemical properties of 7-O-POM-Q were then evaluated, which confirmed that 7-O-POM-Q has remarkably enhanced cellular uptake and intracellular localization compared with quercetin. Additionally, it is noteworthy that 7-O-POM-Q undergoes slow hydrolysis to quercetin over a prolonged period of time.

Conclusion: The quercetin-POM conjugate showed significantly improved MDR-reversing activity compared with quercetin, which could be attributed to its capacity to maintain high intracellular concentrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2015.05.055DOI Listing
July 2015

Metabolic engineering of Escherichia coli for the biosynthesis of flavonoid-O-glucuronides and flavonoid-O-galactoside.

Appl Microbiol Biotechnol 2015 Mar 17;99(5):2233-42. Epub 2014 Dec 17.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, 143-701, Republic of Korea.

Most flavonoids are glycosylated and the nature of the attached sugar can strongly affect their physiological properties. Although many flavonoid glycosides have been synthesized in Escherichia coli, most of them are glucosylated. In order to synthesize flavonoids attached to alternate sugars such as glucuronic acid and galactoside, E. coli was genetically modified to express a uridine diphosphate (UDP)-dependent glycosyltransferase (UGT) specific for UDP-glucuronic acid (AmUGT10 from Antirrhinum majus or VvUGT from Vitis vinifera) and UDP-galactoside (PhUGT from Petunia hybrid) along with the appropriate nucleotide biosynthetic genes to enable simultaneous production of their substrates, UDP-glucuronic acid and UDP-galactose. To engineer UDP-glucuronic acid biosynthesis, the araA gene encoding UDP-4-deoxy-4-formamido-L-arabinose formyltransferase/UDP-glucuronic acid C-4″ decarboxylase, which also used UDP-glucuronic acid as a substrate, was deleted in E. coli, and UDP-glucose dehydrogenase (ugd) gene was overexpressed to increase biosynthesis of UDP-glucuronic acid. Using these strategies, luteolin-7-O-glucuronide and quercetin-3-O-glucuronide were biosynthesized to levels of 300 and 687 mg/L, respectively. For the synthesis of quercetin 3-O-galactoside, UGE (encoding UDP-glucose epimerase from Oryza sativa) was overexpressed along with a glycosyltransferase specific for quercetin and UDP-galactose. Using this approach, quercetin 3-O-galactoside was successfully synthesized to a level of 280 mg/L.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00253-014-6282-6DOI Listing
March 2015

Quercetin-POC conjugates: Differential stability and bioactivity profiles between breast cancer (MCF-7) and colorectal carcinoma (HCT116) cell lines.

Bioorg Med Chem 2013 Apr 4;21(7):1671-9. Epub 2013 Feb 4.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.

In the course of our ongoing efforts to develop novel quercetin conjugates with enhanced stability profiles, we introduced an isopropyloxycarbonylmethoxy (POC) group to 7-OH and/or 3-OH of quercetin and prepared three novel quercetin conjugates. The quercetin-POC conjugates were stable up to 96 h in PBS but slowly hydrolyzed with half-lives of 1-54 h in cell-free culture medium, which is reminiscent of the stability profiles of the previously reported quercetin-POM (pivaloxymethyl) conjugates. However, the quercetin-POC conjugates were more susceptible to passive transport, intracellular hydrolysis, and metabolism in breast cancer (MCF-7) cell line compared with their POM congeners to result in low concentration of quercetin in this cell line and thereby low antiproliferative effect. In contrast, upon incubation with colorectal carcinoma HCT116 cells, the quercetin-POC conjugates were shown to undergo slow hydrolysis and metabolism to maintain concentrations of the active quercetin species high enough to exert enhanced cytotoxicity. Taken together, the quercetin-POC conjugates synthesized in this study exhibited cell type-specific stability as well as bioactivity profiles, which warrants further investigation into the underlying mechanisms and therapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2013.01.057DOI Listing
April 2013

Depression, anxiety, stress perception, and coping strategies in korean military patients with chronic prostatitis/chronic pelvic pain syndrome.

Korean J Urol 2012 Sep 19;53(9):643-8. Epub 2012 Sep 19.

Department of Urology, St. Paul's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

Purpose: The objective of this study was to examine the psychological features and coping strategies of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Materials And Methods: The participants consisted of 55 military personnel suffering from CP/CPPS and 58 military personnel without CP/CPPS symptoms working at the Military Capital Hospital. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) was used to assess CP/CPPS symptoms. The Responses to Hospital Anxiety and Depression (HAD) scale, Social Readjustment Rating Scale, and Global Assessment of Recent Stress (GARS) scale were compared between the two groups. The Weisman Coping Strategy Scale was used to assess coping ability with CP/CPPS.

Results: The NIH-CPSI score of the CP/CPPS group was significantly higher than that of the control group for all domains including pain, urinary symptoms, quality of life, and summed score. The Anxiety and Depression domain of the HAD showed significant differences between the two groups. There were no significant differences in the Social Readjustment Rating Scale between the two groups, but the sum of the GARS score was higher in the CP/CPPS group than in the control group. These were correlated with the pain, quality of life, and sum domains of the NIH-CPSI. The Weisman Coping Strategy Scale showed that intellectualization, redefinition, and flexibility were higher in frequency in descending order, and that fatalism, externalization, and self-pity were lower in frequency.

Conclusions: The CP/CPPS patients had depression, anxiety, and higher perception of stress. In particular, these were closely related to the pain and quality of life of the patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4111/kju.2012.53.9.643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460008PMC
September 2012

Remarkable stability and cytostatic effect of a quercetin conjugate, 3,7-bis-O-pivaloxymethyl (POM) quercetin.

ChemMedChem 2012 Feb 18;7(2):229-32. Epub 2011 Nov 18.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201100478DOI Listing
February 2012

2-Arylmethylaminomethyl-5,6-dihydroxychromone derivatives with selective anti-HCV activity.

Bioorg Med Chem Lett 2011 Jun 20;21(11):3202-5. Epub 2011 Apr 20.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.

Anti-HCV activity of aryl diketoacid (ADK) has been characterized by its two pharmacophoric elements, α,β-diketo acid moiety and substituted aryl ring. In this study, as a part of our ongoing efforts to discover a novel anti-HCV compound mimicking the ADK scaffold, we designed 2-arylmethylaminomethyl-5,6-dihydroxychromone derivatives of which the dihydroxychromone moiety as well as the arylmethylaminomethyl substituent (R-PhCH(2)NHCH(2)-) were anticipated in exact match with the pharmacophore model of the ADK. The dihydroxychromone derivatives (3a-3u), thus prepared, showed biological activity in a substituent-dependent fashion, thereby leading to selective anti-HCV effect (EC(50)=2.0-14.0 μM, CC(50) >100 μM) with the substituent groups such as Cl, Br, I, and Me specifically at the 3-position of the aromatic ring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2011.04.055DOI Listing
June 2011

Enhanced stability and intracellular accumulation of quercetin by protection of the chemically or metabolically susceptible hydroxyl groups with a pivaloxymethyl (POM) promoiety.

J Med Chem 2010 Dec 19;53(24):8597-607. Epub 2010 Nov 19.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea.

In order to increase stability of quercetin, its metabolically and chemically susceptible hydroxyl groups 7-OH and 3-OH respectively were transiently blocked with a pivaloxymethyl (POM) promoiety to provide two novel quercetin conjugates [7-O-POM-Q, 3-O-POM-Q]. In the absence of stabilizer (ascorbic acid), the synthesized conjugates showed significantly increased stability in cell culture media [t(½) = 4 h, 52 h] compared with quercetin (t(½) < 30 min) and quercetin prodrug 1 (t(½) = 0.8 h). In addition, the quercetin conjugate 2 underwent efficient cellular uptake and intracellular levels of its hydrolysis product, quercetin, were maintained up to 12 h. Stability and intracellular accumulation of were demonstrated by its stabilizer-independent cytostatic effect and induction of apoptotic cell death. Even though was more stable than, it failed to penetrate cell membranes. However, the remarkable stability of warrants further investigation of quercetin conjugates with various promoieties at the 3-OH position.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm101252mDOI Listing
December 2010

3-O-arylmethylgalangin, a novel isostere for anti-HCV 1,3-diketoacids (DKAs).

Bioorg Med Chem 2010 Nov 16;18(21):7331-7. Epub 2010 Sep 16.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.

Through chelation of the metal ions at the enzyme active site, 1,3-diketoacids (DKAs) show potent inhibition of viral enzymes such as HIV integrase and HCV NS5B. In order to optimize the antiviral activity of the DKAs, structural modification of their metal-binding units, keto-enol acids or monoketo acids, have been actively performed. In this study, we proposed 3-O-arylmethylgalangin 3 as an alternative to ortho-substituted aromatic DKA, a potent inhibitor of HCV NS5B. As a proof-of-concept study, a series of 3-O-arylmethylgalangin derivatives (3a-3r) were prepared and their inhibitory activity against HCV NS5B was estimated. Structure-activity relationship of the 3-O-arylmethylgalangin derivatives was in good accordance with that of the ortho-substituted aromatic DKA series. In particular, two galangin ethers (3g and 3i) completely superimposable with the most potent ortho-substituted aromatic DKA analogue (2) in atom-by-atom fashion showed equipotent inhibitory activity to that of 2. Taken together, this result provides convincing evidence that the 3-O-arylmethylgalangin can successfully mimic the chelating function of the DKA pharmacophore to show potent inhibitory activity against the target enzyme, HCV NS5B.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2010.09.021DOI Listing
November 2010

7-O-Arylmethylgalangin as a novel scaffold for anti-HCV agents.

Bioorg Med Chem Lett 2010 Oct 6;20(19):5709-12. Epub 2010 Aug 6.

Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.

In spite of potent antiviral activity, suboptimal physicochemical properties of aryl diketo acids (ADKs) necessitates modification of the core 1,3-diketo acid functionality into a novel scaffold. As the metal-binding affinity of the diketo acid is the key to the antiviral activity of ADKs, we anticipated 3,5-dihydroxy-4-oxo arrangement of galangin scaffold would serve as an excellent mimic for the diketo acid functionality. In this study, through synthesis and biological evaluation of various galangin derivatives, we have shown that the diketo acid functionality can be successfully replaced with the galangin scaffold by specific combination of the substituents to result in identification of a novel galangin derivative (3s) with anti-HCV activity (EC(50)=0.9 μM) comparable to the ADK counterpart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2010.08.012DOI Listing
October 2010

Synthesis and anti-hepatitis C virus (HCV) activity of 3'-C-substituted-methyl pyrimidine and purine nucleosides.

Bioorg Med Chem 2010 Jul 31;18(13):4812-20. Epub 2010 May 31.

Department of Bioinspired Science, Ewha Womans University, 11-1 Seodaemun-gu, Daehyun-dong, Seoul 120-750, Republic of Korea.

On the basis of potent anti-hepatitis C virus (HCV) activity of 2'-C-hydroxymethyladenosine, 3'-C-substituted-methyl-ribofuranosyl pyrimidine and purine nucleosides were designed and synthesized from D-xylose. Among compounds tested, all adenine analogues, 4a, 4d, and 4g showed significant anti-HCV activity in a replicon-based cell assay irrespective of the substituent (Y=OH, N₃, or F) at the 3'-C-substituted methyl position, among which 4g (Y=N₃) was the most potent, but it is also cytotoxic. This study guarantees the 3'-C-substituted-methyl nucleoside serves as a new template for the development of new anti-HCV agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2010.05.002DOI Listing
July 2010

Facilitation of polymerase chain reaction with thermostable inorganic pyrophosphatase from hyperthermophilic archaeon Pyrococcus horikoshii.

Appl Microbiol Biotechnol 2010 Jan;85(3):807-12

Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, Republic of Korea.

An inorganic pyrophosphatase (PPases) was cloned from the hyperthermophilic archaeon Pyrococcus horikoshii and was expressed in and purified from Escherichia coli. The recombinant inorganic pyrophosphatase (PhPPase) exhibited robust catalytic activity of the hydrolysis of pyrophosphate into two orthophosphates at high temperatures (70 degrees C to 95 degrees C). Thermostable pyrophosphatase activity was applied into polymerase chain reaction (PCR) due to its ability to push chemical equilibrium toward the synthesis of DNA by removing pyrophosphate from the reaction. A colorimetric method using molybdate and reducing agents was used to measure PCR progress by detecting and quantifying inorganic phosphate in the PhPPase-coupled PCR mixture. Compared to PCR mixtures without PhPPase, the thermostable PhPPase enhanced the amount of PCR product in the same number of cycles. Thus, thermostable PPase may overcome the limitations of thermodynamically unfavorable DNA polymerization in PCR by yielding more products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00253-009-2314-zDOI Listing
January 2010
-->