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>

Making rational choice in utilizing maternal service: a qualitative study in Lao PDR

( Ngan Kim Do ),( Minah Kang ),( Chaeun Lee ),( Sychareun Vanphanom ) 한국정책학회 2013 한국정책학회 학술대회 Vol.2013 No.2

Lack of knowledge and understanding of women and their family members on the benefit of maternal care services is presumed to be a major determinant of mothers` decision to utilize health facilities and skilled birth attendants. This study investigated the perspective of women and their family on maternal health services in Lao PDR to determine their rationality in service utilization ignorance. A qualitative study (n=99) was conducted in Xiengkhouang province, located in the North-East of Lao PDR. Data was collected through 36 semi-structured individual interviews and 24 focus group interviews with mothers, spouses and elderly women from both rural and non-rural areas. Not only women and their spouses but also the elderly recognize the benefit of modern maternal services compared to traditional practices. However, the maternal health services are not well utilized in Lao PDR. The main deterrent factor is not poor recognition but low quality and availability of services at the community level, and low level of satisfaction when utilizing services.

Development of ratiometric fluorescent oxygen-sensing membranes for oxygen sensors

이종일,( Hong Dinh Duong ),( Chaeun Kim ),( Chanhee Jung ),( Chang Hwan Jung ),( Ok-jae Sohn ) 한국공업화학회 2019 한국공업화학회 연구논문 초록집 Vol.2019 No.1

Oxygen concentration is an important parameter in various applications. Principle of oxygen sensors are based on the dynamic luminescence quenching by molecular oxygen that is described by Stern-Volmer equation. In this study, the fluorescence quenching of Pt(II) meso-tetra(pentafluorophenyl)porphine (PtP) by oxygen molecules is exploited for fabrication of the oxygen-sensing membrane. The quantum dots (QDs) or green dye (GN) is used as a reference dye to perform ratiometric fluorescence measurements. Before the fabrication of the sensing membrane, PtP is captured in polystyrene particles (PS). GN is captured in silica particles or melamine formaldehyde resin particles. All dye particles are supported by polymer poly(styrene-coacrylonitrile) to produce a thin oxygen-sensing membrane. The sensing membrane is sensitive with oxygen in the concentration range of 0% - 100% and fast reversibility.

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.

Toxicological evaluation of organic contaminants in aquatic system using zebrafish embryo

Hwang-Ju Jeon(전황주),Hyeseung Choe,Chaeun Kim,Sung-Eun Lee 한국농약과학회 2021 한국농약과학회 학술발표대회 논문집 Vol.2021 No.11

A threat to living organisms resulting from climate change on this planet leads to growing concern about the environment. One of these parts was Agriculture originated organic pollutants, known as a group of environmental contaminants. These contaminants cause many negative effects and even death on living organisms including aquatic vertebrates. But, many toxicological studies were still focused on their viewpoint only on the death problem. In this phenomenon, we tried to explore the possible toxicological effects of EPN on the early developmental stage of aquatic vertebrates using zebrafish embryos. In the acute toxicity test of AB strain zebrafish embryo, both pericardial and yolk sac edemas were observed at 500 ppb EPN treated group. Moreover, the presence of 250 ppb EPA makes zebrafish embryo obtain hematoma near the heart. To confirm phenotype of zebrafish more clearly, three different transgenic line were used including Tg[fli1a:EGFP], Tg[cmlc2:EGFP], and Tg[gata1:GFP]. In transgenic zebrafish, the malformation of the embryos was still observed. Especially, in the fluorescent image of Tg[cmlc2:EGFP], the formation of the heart seemed to be disturbed seriously. In the real-time qPCR data, the level of the transcripts related to early-stage heart formation, nppa, and myl7, were up and down-regulated to 2.0 and 0.26-fold respectively. In addition, the heart rate of the embryo was decreased at 250 and 500 ppb. Taking all these results together, EPN has the possibility of negative effects on the early-stage development of aquatic vertebrates including hematoma, malformation of the heart, and abnormal development of the internal circulatory system. Therefore, continuous monitoring and proper management are required.

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

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.