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Stereoselective Synthesis of L-Deoxyaltronojirimycin from L-Serine
Rengasamy, Rajesh,Curtis-Long, Marcus J.,Ryu, Hyung-Won,Oh, Kyeong-Yeol,Park, Ki-Hun Korean Chemical Society 2009 Bulletin of the Korean Chemical Society Vol.30 No.7
(2S,3R)-3-Hydroxy-2-(hydroxymethyl)-3,6-dihydro-2H-pyridine 8, an important precursor for the synthesis of polyhydroxylated piperidine azasugars, has been prepared from L-serine. Highly stereoselective nucleophilic addition to amino aldehyde 5 gave the corresponding allylic alcohol 6 which proceeded to give dihydro-2H-piridine 7a via a Grubbs II catalyzed RCM. Stereoselective H-bond directed epoxidation of allylic alcohol led to the oxiranyl alcohol 9 which was easily converted to L-deoxyaltronojirimycin by regioselective ring opening.
Yuk, Heung Joo,Curtis-Long, Marcus J.,Ryu, Hyung Won,Jang, Ki Chang,Seo, Woo Duck,Kim, Jun Young,Kang, Kyu Young,Park, Ki Hun American Chemical Society 2011 Journal of agricultural and food chemistry Vol.59 No.23
<P>Soybean leaves are eaten as seasonal edible greens in Korea. Analysis of the ethyl acetate extract of these leaves showed that it exhibited potent and selective neuraminidase inhibition, which began at the R3 stage and peaked at R7. Ten pterocarpans, including the new 6a-hydroxypterocarpan <B>10</B>, were isolated from soybean leaves and their inhibition activities tested against a range of glycosidases. The relationship between structure and enzyme inhibition was investigated: 6a-hydroxypterocarpans exhibited much higher inhibition against neuraminidase (IC<SUB>50</SUB> = 2.4–89.4 μM) than α-glucosidase (IC<SUB>50</SUB> = 90.4– >100 μM). Glyceollin VII (<B>7</B>) displayed 40-fold greater activity (IC<SUB>50</SUB> = 2.4 μM) against neuraminidase than α-glucosidase (IC<SUB>50</SUB> = 90.4 μM). On the other hand, coumestanes (<B>1</B>–<B>3</B>) were good α-glucosidase inhibitors (IC<SUB>50</SUB> = 6.0–42.6 μM). In kinetic analysis, the most potent neuraminidase inhibitors (<B>5</B>–<B>10</B>) were noncompetitive. HPLC analysis indicated that most pterocarpan synthesis began from the R3 stage, and a rapid change of pterocarpan concentrations was observed between the R4 and R7 stages.</P>
Kim, Dae Wook,Seo, Kyung Hye,Curtis-Long, Marcus J.,Oh, Kyeong Yeol,Oh, Jong-Won,Cho, Jung Keun,Lee, Kon Ho,Park, Ki Hun Informa UK Ltd. 2014 Journal of enzyme inhibition and medicinal chemist Vol.29 No.1
<P>Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro) is a key enzyme that plays an important role in SARS virus replication. The ethanol extract of the seeds of <I>Psoralea corylifolia</I> showed high activity against the SARS-CoV PLpro with an IC<SUB>50</SUB> of value of 15 µg/ml. Due to its potency, subsequent bioactivity-guided fractionation of the ethanol extract led to six aromatic compounds (<B>1-6</B>), which were identified as bavachinin (<B>1</B>), neobavaisoflavone (<B>2</B>), isobavachalcone (<B>3</B>), 4′-O-methylbavachalcone (<B>4</B>), psoralidin (<B>5</B>) and corylifol A (<B>6</B>). All isolated flavonoids (<B>1-6</B>) inhibited PLpro in a dose-dependent manner with IC<SUB>50</SUB> ranging between 4.2 and 38.4 µM. Lineweaver-Burk and Dixon plots and their secondary replots indicated that inhibitors (<B>1-6</B>) were mixed inhibitors of PLpro. The analysis of <I>K</I><SUB>I</SUB> and <I>K</I><SUB>IS</SUB> values proved that the two most promising compounds (<B>3</B> and <B>5</B>) had reversible mixed type I mechanisms.</P>
Seo, Woo Duck,Yuk, Heung Joo,Curtis-Long, Marcus J.,Jang, Ki Chang,Lee, Jin Hwan,Han, Sang-Ik,Kang, Hang Won,Nam, Min Hee,Lee, Sung-Joon,Lee, Ji Hae,Park, Ki Hun American Chemical Society 2013 Journal of agricultural and food chemistry Vol.61 No.5
<P>Adenosine 5′-monophosphate-activated protein kinase (AMPK) is an intracellular sensor that can regulate glucose levels within the cell. For this reason, it is well-known to be a target for drugs against diabetes and obesity. AMPK was activated significantly by the hexane extract of barley sprouts. This AMPK activation emerges across the growth stages of the sprout, becoming most significant (3 times above the initial stages) 10 days after sprouting. After this time, the activation decreased between 13 and 20 days post-sprouting. Analysis of the hexane extracts by gas chromatography–mass spectrometry showed that the amounts of policosanols (PCs, which are linear, primary aliphatic alcohols with 20–30 carbons) in the plant dramatically increased between 5 days (109.7 mg/100 g) and 10 days (343.7 mg/100 g) post-sprouting and then levels fell back down, reaching 76.4 mg/100 g at 20 days post-sprouting. This trend is consistent with PCs being the active ingredient in the barley plants. We validate this by showing that hexacosanol is an activator of AMPK. The richest cultivar for PCs was found to be the Daejin cultivar. Cultivars had a significant effect on the total PC content (113.2–183.5 mg/100 g) within the plant up to 5 days post-sprouting. However this dependence upon the cultivar was not so apparent at peak stages of PC production (10 days post-sprouting). The most abundant PC in barley sprout, hexacosanol, contributed 62–80% of the total PC content at every stage. These results are valuable to determine the optimal times of harvest to obtain the highest yield of PCs.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2013/jafcau.2013.61.issue-5/jf3041879/production/images/medium/jf-2012-041879_0004.gif'></P>
Ryu, Hyung Won,Oh, Sei-Ryang,Curtis-Long, Marcus J.,Lee, Ji Hye,Song, Hyuk-Hwan,Park, Ki Hun American Chemical Society 2014 Journal of agricultural and food chemistry Vol.62 No.6
<P>Enzyme binding affinity has been recently introduced as a selective screening method to identify bioactive substances within complex mixtures. We used an assay which identified small molecule binders of acetylcholinesterase (AChE) using the following series of steps: incubation of enzyme with extract; centrifugation and filtration; identification of small molecule content in the flow through. The crude extract contained 10 peaks in the UPLC chromatogram. However, after incubation the enzyme, six peaks were reduced, indicating these compounds bound AChE. All these isolated compounds (<B>2</B>, <B>3</B>, and <B>5</B>–<B>8</B>) significantly inhibited human AChE with IC<SUB>50</SUB>s = 5.4–15.0 μM and butyrylcholinsterase (IC<SUB>50</SUB>s = 0.7–11.0 μM). All compounds exhibited reversible mixed kinetics. Consistent with the binding screen and fluorescence quenching, γ-mangostin <B>6</B> had a much higher affinity for AChE than 9-hydroxycalabaxanthone <B>9</B>. This validates this screening protocol as a rapid method to identify inhibitors of AChE.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2014/jafcau.2014.62.issue-6/jf405072e/production/images/medium/jf-2013-05072e_0005.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf405072e'>ACS Electronic Supporting Info</A></P>
Cho, Jung-Keun,Rengasamy, Rajesh,Curtis-Long, Marcus John,Kim, Jin-Hyo,Lee, Ji-Won,Park, Ki-Hun The Korean Society for Applied Biological Chemistr 2011 Applied Biological Chemistry (Appl Biol Chem) Vol.54 No.6
Azasugars derived from L-alanine and L-serine were screened for inhibitory activity against ${\alpha}$-rhamnosidase. The enantiomers of 1,6-dideoxynojirimycin ($ent$-1,6-dDNJ) (1) and ($2S$,$3R$)-2-(hydroxymethyl)piperidin-3-ol (5) showed highly specific and potent inhibition against ${\alpha}$-rhamnosidase with $K_i$ values of 4.2 and $16.6{\mu}M$, respectively. Structure of the best inhibitor features the same stereochemical configuration as L-rhamnose at C2, C3, and C4 centers. In kinetic studies, both compounds exhibited competitive inhibition behavior. Compound 1 manifested simple reversible slow-binding inhibition with the following kinetic parameters: ${\kappa}_3=1.17nM^{-1}\;min^{-1}$, ${\kappa}_4=5.96{\times}10^{-3}min^{-1}$, and $K_i^{app}$=5.1 mM.
Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits.
Song, Yeong Hun,Kim, Dae Wook,Curtis-Long, Marcus John,Yuk, Heung Joo,Wang, Yan,Zhuang, Ningning,Lee, Kon Ho,Jeon, Kwon Seok,Park, Ki Hun Pharmaceutical Society of Japan 2014 Biological & pharmaceutical bulletin Vol.37 No.6
<P>Tribulus terrestris fruits are well known for their usage in pharmaceutical preparations and food supplements. The methanol extract of T. terrestris fruits showed potent inhibition against the papain-like protease (PLpro), an essential proteolylic enzyme for protection to pathogenic virus and bacteria. Subsequent bioactivity-guided fractionation of this extract led to six cinnamic amides (1-6) and ferulic acid (7). Compound 6 emerged as new compound possessing the very rare carbinolamide motif. These compounds (1-7) were evaluated for severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro inhibitory activity to identify their potencies and kinetic behavior. Compounds (1-6) displayed significant inhibitory activity with IC50 values in the range 15.8-70.1??M. The new cinnamic amide 6 was found to be most potent inhibitor with an IC50 of 15.8??M. In kinetic studies, all inhibitors exhibited mixed type inhibition. Furthermore, the most active PLpro inhibitors (1-6) were proven to be present in the native fruits in high quantities by HPLC chromatogram and liquid chromatography with diode array detection and electrospray ionization mass spectrometry (LC-DAD-ESI/MS).</P>
α-Rhamnosidase inhibitory activities of polyhydroxylated pyrrolidine
Kim, Jin-Hyo,Marcus J. Curtis-Long,Seo, Woo-Duck,Lee, Jin-Hwan,Lee, Byong-Won,Yoon, Yong-Jin,Kang, Kyu-Young,Park, Ki-Hun Plant molecular biology and biotechnology research 2005 Plant molecular biology and biotechnology research Vol.2005 No.
We designed and synthesized polyhydroxylated pyrrolidines 1-12 from L-tyrosine, L-phenylalanine, and D-tyrosine through iodine-mediated intramolecular cyclization followed by Woodward-Prevost reaction. The synthetic polyhydroxylated pyrrolidines were identified with structure-based inhibitory activity and selective inhibitory activity against α-rhamnosidase. (2S,3S,4R)-deacetyl anisomycin 7 was the best inhibitor among the 12 polyhydroxylated pyrrolidines because it possesses the same stereoconfiguration a1 C1, C2, C3 as α-L-rhamnopyranoside. An investigation into the nature of the inhibition showed that the synthetic pyrrolidines are competitive inhibitors. They also did not have remarkable inhibitory activity against seven glycosidases (χ-glucosidase, α-mannosidase, χ-amylase, β-glucosidase, β-galactosidase, β-amylase, and invertase).
Inhibition Effects of Mangosenone F from Garcinia mangostana on Melanin Formation in B16F10 Cells
Ryu, Hyung Won,Jeong, Seong Hun,Curtis-Long, Marcus J.,Jung, Sunin,Lee, Ji Won,Woo, Hyun Sim,Cho, Jung Keun,Park, Ki Hun American Chemical Society 2012 Journal of agricultural and food chemistry Vol.60 No.34
<P>Melanogenesis can be controlled by tyrosinase inhibition or by blocking the maturation processes of tyrosinase and its related proteins. Mangostenone F was isolated from the seedcases of Garcinia mangostana. Mangostenone F was shown to be inactive against tyrosinase (IC<SUB>50</SUB> > 200 μM) but was a potent α-glucosidase inhibitor in vitro (IC<SUB>50</SUB> = 21.0 μM). Mangostenone F was found to inhibit production of melanin in the mouse melanoma cell line B16F10. Importantly, unlike most glycosidase inhibitors, mangostenone F displayed very low cytotoxicity (EC<SUB>50</SUB> > 200 μM). The Western blot for expression levels of proteins involved in melanogenesis showed that mangostenone F down-regulated tyrosinase and TRP-2 expression. Treating B16F10 cells with mangostenone F significantly increased the susceptibility of tyrosinase to endoglycosidase H digestion, indicating that tyrosinase was unable to mature fully and pass to the <I>trans</I>-golgi apparatus. Consistent with these data, in lysate assays, mangostenone F was shown to be a better inhibitor of α-glucosidases than deoxynojirimycin, a representative glycosidase inhibitor.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jafcau/2012/jafcau.2012.60.issue-34/jf3015987/production/images/medium/jf-2012-015987_0004.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jf3015987'>ACS Electronic Supporting Info</A></P>
Piperidine Azasugars Displaying Competitive α-Rhamnosidase Inhibition and their Kinetic Mechanism
Jung Keun Cho,Rajesh Rengasamy,Marcus John Curtis-Long,김진효,Ji Won Lee,박기훈 한국응용생명화학회 2011 Applied Biological Chemistry (Appl Biol Chem) Vol.54 No.6
Azasugars derived from L-alanine and L-serine were screened for inhibitory activity against α-rhamnosidase. The enantiomers of 1,6-dideoxynojirimycin (ent-1,6-dDNJ) (1) and (2S,3R)-2-(hydroxymethyl)piperidin-3-ol (5) showed highly specific and potent inhibition against α-rhamnosidase with Ki values of 4.2 and 16.6 μM, respectively. Structure of the best inhibitor features the same stereochemical configuration as L-rhamnose at C2, C3, and C4 centers. In kinetic studies, both compounds exhibited competitive inhibition behavior. Compound 1 manifested simple reversible slow-binding inhibition with the following kinetic parameters: k3=1.17 nM−1 min−1, k4 = 5.96 ×10−3 min−1, and Ki app=5.1 mM.