Identification of cytokine-regulated tissue specific STAT5 target genes

Chaeun Oh,Eunchae Park,Sungju Jung,Su Min Yoon,Su-hyang Han,Sunyoung Jang,Sumin Oh,Kyung Hyun Yoo 한국실험동물학회 2018 한국실험동물학회 학술발표대회 논문집 Vol.2018 No.7

Design, synthesis and anti-melanogenic effect of cinnamamide derivatives

Ullah, Sultan,Park, Yujin,Ikram, Muhammad,Lee, Sanggwon,Park, Chaeun,Kang, Dongwan,Yang, Jungho,Akter, Jinia,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.21

<P><B>Abstract</B></P> <P>Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (<I>E</I>)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides <B>4</B> (93.72% inhibition), <B>9</B> (78.97% inhibition), and <B>10</B> (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides <B>4</B> and <B>9</B> having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, <B>4</B>, <B>9</B>, and <B>10</B>, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (<I>E</I>)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues

Ullah, Sultan,Park, Chaeun,Ikram, Muhammad,Kang, Dongwan,Lee, Sanggwon,Yang, Jungho,Park, Yujin,Yoon, Sik,Chun, Pusoon,Moon, Hyung Ryong Academic Press 2019 Bioorganic chemistry Vol.87 No.-

<P><B>Abstract</B></P> <P>Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (<I>E</I>)-β-phenyl-α,β-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids’ structure intrinsically features this (<I>E</I>)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (<B>4</B>, <B>9</B>, <B>14</B>, and <B>19</B>) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 µM compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the β-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 – 79.67% inhibition) at 25 μM than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (<B>9</B>) = cyclopentylamino (<B>14</B>) < cyclohexylamino (<B>19</B>) < <I>N</I>-methylpiperazino (<B>4</B>) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 μM was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Twenty cinnamamide derivatives were synthesized as potential tyrosinase inhibitors. </LI> <LI> Four cinnmamides exhibited over 90% mushroom tyrosinase inhibitions than kojic acid. </LI> <LI> In B16F10 cells, four compounds strongly decreased tyrosinase activity and melanin. </LI> <LI> In docking study, four cinnamamides bind to tyrosinase strongerly than kojic acid. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

A New Histone Deacetylase Inhibitor, MHY4381, Induces Apoptosis via Generation of Reactive Oxygen Species in Human Prostate Cancer Cells

( Sachan Richa ),( Prasanta Dey ),( Chaeun Park ),( Jungho Yang ),( Ji Yeon Son ),( Jae Hyeon Park ),( Su Hyun Lee ),( Mee-young Ahn ),( In Su Kim ),( Hyung Ryong Moon ),( Hyung Sik Kim ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.2

Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC₅₀ value of MHY4381 was lower in DU145 cells (IC₅₀=0.31 µM) than in LNCaP (IC₅₀=0.85 µM) and PC-3 cells (IC₅₀=5.23 µM). In addition, the IC₅₀ values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

Electron transfer and electron carrier of enzymes significantly improved the reduction of indigo to leuco indigo

이종일,( Hong Dinh Duong ),( Chanhee Jung ),( Yeajin Park ),( Chaeun Kim ) 한국공업화학회 2019 한국공업화학회 연구논문 초록집 Vol.2019 No.1

In this study, the reduction of indigo to leuco indigo by glucose was enhanced by using enzyme glucose oxidase (GOD) and laccase (LA). Generally, indigo accepted electrons from the glucose oxidation reaction or from intermediates of glucose degradation and after that converted to leuco-form. In case of GOD or LA involved the indigo reduction, the redox centers of GOD and LA acted as an electron carrier from the reducing glucose or direct electron transfer to indigo molecules. Therefore, the turnover rate of electron flow between glucose and indigo through enzymes was increased and led to increase of leuco-indigo production. That was about 5 times higher in cases of using enzymes as compared without using enzymes

The tyrosinase inhibitory effects of isoxazolone derivatives with a (<i>Z</i>)-β-phenyl-α, β-unsaturated carbonyl scaffold

Kim, Su Jeong,Yang, Jungho,Lee, Sanggwon,Park, Chaeun,Kang, Dongwan,Akter, Jinia,Ullah, Sultan,Kim, Yeon-Jeong,Chun, Pusoon,Moon, Hyung Ryong Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.14

<P><B>Abstract</B></P> <P>Thirteen (<I>Z</I>)-4-(substituted benzylidene)-3-phenylisoxazol-5(4<I>H</I>)-ones were designed to confirm the geometric effect of the double bond of the β-phenyl-α, β-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds <B>1a</B>–<B>1m</B>, which all possessed the (<I>Z</I>)-β-phenyl-α, β-unsaturated carbonyl scaffold, were synthesized using a tandem reaction consisting of an isoxazolone ring formation and a Knoevenagel condensation, and three starting materials, ethyl benzoylacetate, hydroxylamine and benzaldehydes. Some of the compounds showed inhibitory activity against mushroom tyrosinase as potent as compounds containing the “(<I>E</I>)”-β-phenyl-α, β-unsaturated carbonyl scaffold. Compounds <B>1c</B> and <B>1m</B> showed greater inhibitory activity than kojic acid: IC<SUB>50</SUB> = 32.08 ± 2.25 μM for <B>1c</B>; IC<SUB>50</SUB> = 14.62 ± 1.38 μM for <B>1m</B>; and IC<SUB>50</SUB> = 37.86 ± 2.21 μM for kojic acid. A kinetic study indicated that <B>1m</B> inhibited tyrosinase in a competitive manner and that it probably binds to the enzyme’s active site. In silico docking simulation supported binding of <B>1m</B> (−7.6 kcal/mol) to the active site of tyrosinase with stronger affinity than kojic acid (−5.7 kcal/mol). Similar results were obtained using cell-based assays, and in B16F10 cells, compound <B>1m</B> dose-dependently inhibited tyrosinase activity and melanogenesis. These results indicate the anti-melanogenic effect of compound <B>1m</B> is due to the inhibition of tyrosinase and (<I>Z</I>)-isomer of the β-phenyl-α, β-unsaturated carbonyl scaffold can, like its congener the (<I>E</I>)-isomer, act as an excellent scaffold for tyrosinase inhibition.</P> <P><B>Highlights</B></P> <P> <UL> <LI> (<I>Z</I>)-β-phenyl-α, β-unsaturated carbonyl compounds are prepared by a tandem reaction. </LI> <LI> (<I>Z</I>)-geometry is proved to be a core part of potent tyrosinase inhibitors. </LI> <LI> Compounds with the (<I>Z</I>)-geometry show anti-melanogenic activity in cell-based assays. </LI> <LI> Docking results support the compounds may bind to the active site of tyrosinase. </LI> <LI> Kinetic study implies the competitive inhibition between compounds and the substrate. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Evaluation of a novel tyrosinase inhibitor, (Z)-3-(3-bromo-4-hydroxybenzylidene) thiochroman-4-one (MHY1498) in vitro and in silico

( Eun Jin Bang ),( Sang Gyun Noh ),( Su Gyeong Ha ),( Hee Jin Jung ),( Dae Hyun Kim ),( Dongwan Kang ),( Sanggwon Lee ),( Chaeun Park ),( Hyung Ryong Moon ),( Hae Young Chung ) 한국장기요양학회 2018 한국장기요양학회 추계학술대회자료집 Vol.2018 No.-

Tyrosinase is a key enzyme that catalyzes the initial rate-limiting steps of melanin synthesis. Excessive melanogenesis and hyperpigmentation is the major cause of serious skin disorders that include melasma, senile lentigines, age spots, freckles and more. In order to find effective and safe tyrosinase inhibitors, we rationally designed and synthesized a novel compound (Z)-3-(3-bromo - 4 - h y d r o x y b e n z y l i d e n e) t h i o c h r o m a n - 4 - one (MHY1498) and investigated its tyrosinase inhibitory activity by in silico molecular docking simulation and in vitro experiments. The novel chemical structure of MHY1498 was synthesized as a hybrid structure of previously reported potent tyrosinase inhibitors, (Z)-5-(substituted benzylidene) thiazolidine-2,4-diones and 2-(substituted phenyl) benzo[d]thiazoles as was confirmed in vitro and in vivo. MHY1498 showed potent inhibitory effects on mushroom tyrosinase with significantly less IC50 value of 4.1±0.6 μM, whereas positive control compound Kojic acid was of 22.0±4.7 μM. In silico multi-docking simulation indicated that MHY1498 had greater affinity (-6.6 kcal/mol) to the active enzymatic site of mushroom tyrosinase and mechanistic kinetic study showed that it inhibited competitively. Furthermore, in B16F10 melanoma cells stimulated with α-melanocyte stimulating hormone, MHY1498 inhibited melanin contents and tyrosinase activity. In conclusion, our data demonstrate that MHY1498, a synthesized novel compound, effectively inhibits tyrosinase activity and may be used as a modulating compound for anti-melanogenic agent.