Synthesis and evaluation of new pyridyl/pyrazinyl thiourea derivatives: Neuroprotection against amyloid-β-induced toxicity

Park, Jung-eun,Elkamhawy, Ahmed,Hassan, Ahmed H.E.,Pae, Ae Nim,Lee, Jiyoun,Paik, Sora,Park, Beoung-Geon,Roh, Eun Joo Elsevier 2017 European journal of medicinal chemistry Vol.141 No.-

<P><B>Abstract</B></P> <P>Herein, we report synthesis and evaluation of new twenty six small molecules against β amyloid (Aβ)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The neuroprotective effect of seventeen compounds against Aβ-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Fifteen derivatives eliciting increased green to red fluorescence percentage less than 40.0% were evaluated for their impact on ATP production, cell viability and neuroprotection against Aβ-induced neuronal cell death. Among evaluated compounds, derivatives <B>9w</B>, <B>9r</B> and <B>9k</B> had safe profile regarding ATP production and cell viability. In addition, they exhibited significant neuroprotection (69.3, 51.8 and 48.2% respectively). Molecular modeling study using CDocker algorithm predicted plausible binding modes explaining the elicited mPTP blocking activity. Hence, this study suggests compounds <B>9w</B>, <B>9r</B> and <B>9k</B> as leads for further development of novel therapy to Alzheimer's disease.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Biological activity of seventeen compounds against Aβ-induced mPTP opening was superior to that of Cyclosporin A. </LI> <LI> Derivatives <B>9w</B>, <B>9r</B>, and <B>9k</B> had safe profile regarding ATP production and cell viability. </LI> <LI> Molecular modeling study predicted plausible binding modes explaining the elicited mPTP blocking activity. </LI> <LI> This study suggests compounds <B>9w</B>, <B>9r</B>, and <B>9k</B> as leads for further development of novel therapy to Alzheimer's disease. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Extractive Nitrogenous Constituents and Their Monthly Variation of Fresh Laver Porphyra yezoensis

Choon-Kyu Park,Cheul-Hoon Park,Jung-Nim Park 한국식품과학회 2001 Food Science and Biotechnology Vol.10 No.4

잇바디돌김의 함질소 엑스성분조성 및 월별변동

박춘규(Choon-Kyu Park),박철훈(Cheul-Hoon Park),박정임(Jung-Nim Park) 한국식품영양과학회 2001 한국식품영양과학회지 Vol.30 No.4

한국 남해안에서 양식생산되고 있는 김류의 함질소엑스성분 조성 및 월별 변동을 구명하기 위하여 1998년 1월부터 4월까지 월별로 전남 장흥군에서 양식된 잇바디돌김, Porphyradentata 생엽을 매월 1회씩 채취하여 맛과 밀접한 관계가 있는 함질소엑스성분 즉, 엑스분질소, 유리아미노산, 결합아미노산, ATP관련화합물, 4급암모늄염기 등을 분석하여 방사무늬김, P. yezoensis와 비교하였다. 엑스분질소함량은 760~872 ㎎/100 g(건물)이었다. 유리아미노산은 27~31종이 분석되었으며, 그 총량은 2,404~3,966 ㎎/100 g(건물)이었다. 함량이 많은 유리아미노산으로서는 alanine, taurine, glutamine, glutamic acid, aspartic acid 등이었다. 결합아미노산은 가수분해 후 16~23종에서 증가하였으며, 유리아미노산 총량의 36.0~112.0% 수준이었다. ATP관련화합물 총량은 73.3~94.4 ㎎/100 g(2.04~4.43 μ㏖/g, 건물)이었다. Betaine류로서는 homarine과 trigonelline이 모든 시료에서 검출되었고, β-alaninebetaine과 γ-butyrobetaine은 일부시료에서 검출되었다. TMA는 모든 시료에서 확인되었으며, TMAO는 일부시료에서 분리되었다. 잇바디돌김 생엽의 함질소엑스성분 특징은 방사무늬김에서처럼 유리아미노산과 결합아미노산 함량이 풍부하여 질소분포의 약 90%에 달하는 중요한 맛성분이었으나 그 성분조성의 월별 변동에는 다소 차이를 보여 대부분의 성분들이 1, 3월에 높고 2, 4월에 낮았다. 잇바디돌김은 방사무늬김에 비해 전반적으로 함질소엑스성분 함량이 약간 낮은 수준이었다. In order to investigate the composition and monthly variation of extractive nitrogenous components in the laver Porphyra dentata cultured at the south coast of Korea, the fresh laver was analyzed separately for the amounts of free amino acids, combined amino acids, ATP and its related compounds, and quaternary ammonium basis in fresh laver were measured. The extractive nitrogen contents of fresh laver extracts were 760~870 ㎎/100 g (dry basis). Twenty-seven to thirty-one kinds of free amino acids were detected in the laver extracts and their total amounts were 2,404~3,966 ㎎/100g (on dry basis). The laver extracts showed rich in free amino acids such as alanine, taurine, glutamic acid, glutamine and aspartic acid. Sixteen to twenty-three kinds of combined amino acids were detected in the extracts and their total amounts were 1,429~2,692 ㎎/100 g (on dry basis). Proline, glutamic acid, glycine, phosphoserine, serine were the main combined amino acids in the extracts. The amounts of ATP and related compounds were 73.3~94.4 ㎎/100 g (2.04~4.43 μ㏖/g, on dry basis). Homarine and trigonelline were detected in all specimens but β-alaninebetaine, γ-butyrobetaine were found in some. Small amounts of trimethylamine were detected in all samples. Free and combined amino acids were occupying almost 90% of extractive nitrogen. Most of free and combined amino acids showed a marked monthly variation with a maximum in January and March, and a minimum in February and April. The fresh laver P. dentata did not differ much from the fresh laver P. yezoensis in qualitative com-position of extractive components, but their contents were generally low level.

방사무늬김 건제품의 함질소 엑스성분 조성

박춘규(Choon Kyu Park),박철훈(Cheul Hoon Park),박정임(Jung Nim Park) 한국수산과학회 2001 한국수산과학회지 Vol.34 No.4

한국 근해에서 양식되고 있는 김류의 함질소엑스성분조성 및 월별변동현상을 구명하기 위하여 1998년 1월부터 4월까지 전남 장흥군에서 양식된 방사무늬김 Porophyra yezoensis을 매월 1회씩 채취하여 건제품으로 가공한 다음 맛과 밀접한 관계가 있는 함질소엑스성분 즉, 엑스분질소, 유리아미노산, 결합아미노산, ATP관련화합물, 4급암모늄염기 등을 분석하였다. 엑스분질소함량은 976∼1,196㎎/100g (건물)이었다. 유리아미노산은 28∼31종이 검출되었으며, 그 총량은 5,648∼6,845㎎/100g(건물)이었다. 함량이 많은 유리아미노산으로서는 alanine, glutamic acid, taurine, phosphoserine, aspartic acid 등이었다. 결합아미노산은 가수분해 후 18∼22종에서 증가되었으며, 그 총량은 1,194-1,4066㎎/100g (건물)이었으며, 유리아미노산총량의 19.6-22.9% 수준으로서 중요한 함질소 엑스성분이었다. ATP관련화합물총량은 111.6∼195.5㎎/100g (3.30∼6.00μ㏖/g, 건물)수준이었다. Betaine류는 마른 김에서 homarine이 모든 시료에서 검출되었고, trigonelline은 1월 시료에서만 확인되었다. Glycinebetaine, β-alaninebetaine 및 γ-butyrobetaine은 가공과정 중 소실되었다. TMA는 모든 시료에서 검출되었고, TMA는 일부시료에서만 확인되었다. 방사무늬김은 生藥을 건제품으로 가공함으로서 유리아미노산은 증가하고 결합 아미노산 함량은 감소되었다. 또한 ATP 관련화합물은 증가한 반면 TMAO와 TMA, betaine류는 전반적으로 감소되었다. In order to investigate the composition of dried laver, Porphyra yezoensis cultured at the south coast of Korea, the dried laver was analyzed separately for extractive nitrogen, free and combined amino acids, ATP and related compounds and quaternary ammonium basis using specimens collected monthly from January to April 1998. The extractive nitrogen contents of dried laver extracts were 976∼1,196㎎/100g (on dry basis). Twenty-eight to thirty-one kinds of free amino acids were found in the dried laver extracts and their total amounts were 5,648∼6,845㎎/100g (on dry basis). The extracts were rich in free amino acids such as alanine, glutamic acid, taurine, phosphoserine and aspartic acid. Eighteen to twenty-two kinds of combined amino acids from oligopeptides were found in the extracts and their total amounts were 1,194∼1,406㎎/100g (on dry basis). The amounts of ATP and related compounds were 111.6∼195.5㎎/100g (3.30∼6.00 μ㏖/g on dry basis). Homarine was detected in all samples but glycinebetaine, β-alaninebetaine and γ-butyrobetaine disappeared during processing. TMAO was detected in all samples but low TMA was found in some. During processing of dried laver, P. yezoensis, free amino acids, ATP and its related compounds were increased but the other constituents such as combined amino acids, TMAO and TMA and betaines were decreased in all specimens.

잇바디돌김 건제품의 함질소 엑스성분 조성

박춘규(Choon Kyu Park),박철훈(Cheul Hoon Park),박정임(Jung Nim Park) 한국수산과학회 2001 한국수산과학회지 Vol.34 No.4

우리 나라 남해안에서 양식 생산되고 있는 김류의 함질소엑스 성분조성 및 월별 변동현상을 구명하기 위하여 1988년 1월부터 4월까지 월별로 전남 장흥군 지선에서 양식된 잇바디돌김, Porphyra dentata를 매월 1회씩 채취하여 건제품으로 가공한 다음 맛과 밀접한 관계가 있는 함질소엑스성분, 즉 엑스분질소, 유리아미노산, ATP관련화합물, 4급암모늄염기 등을 분석하여 전보에서 분석한 잇바디돌김 生藥과 비교하였다. 엑스분질소량은 670∼1,304㎎/100g (건물)이었다. 유리아미노산은 28∼29종이 검출되었으며, 그 총량은 2,796∼6,277㎎/100g (건물)이었다. 함량이 많고 중요한 유리아미노산으로는 alanine, taurine, glutamic acid, glutamine, phosphoserine 등이었다. 결합아미노산은 가수분해 후 18∼21종에서 증가되었으며, 그 총량은 1,406∼2,142㎎/100g (건물)이었으며, 유리아미노산총량의 26.4∼55.7% 수준으로서 중요한 함질소 엑스성분으로 밝혀졌다. ATP관련화합물총량은 65.7∼124.7㎎/100g (2.13∼3.68μ㏖/g, 건물) 수준이었다. Betaine류로서는 homarine이 모든 시료에서 검출되었고, β-alanine, γ-butyrobetaine, tritonelline은 가공 중 소실되었다. TMAO와 TMA는 모든 시료에서 검출되었다. 잇바디돌김 生葉을 건제품으로 가공과정 중 유리아미노산, TMAO와 TMA가 증가하였고, 결합아미노산, ATP관련화합물, betaine류가 감소되었다. In order to investigate the composition of dried laver, Porphyra dentata cultured at the south coast of Korea, the dried laver was analyzed for extractive nitrogen, free amino acids, combined amino acids, ATP and its related compounds and quaternary ammonium basis. The extractive nitrogen contents of dried laver extracts were 670∼1,304㎎/100g (on dry basis). From twenty-eight to twenty-nine kinds of free amino acids were found in the dried laver extracts and their total amounts were 2,796∼6,277㎎/100g (on dry basis). The extracts were rich in free amino acids such as alanine, taurine, glutamic acid, glutamine and phosphoserine. From eighteen to twenty-one kinds of combined amano acids were found in the extracts and their total amounts were 1,406∼2,142㎎/100g (on dry basis). The amounts of ATP and its related compounds were 65.7∼124.7㎎/100g (2.13∼3.68 μ㏖/g on dry basis). Homarine was detected in all samples but β-alaninebetaine, γ-butyrobetaine and trigonelline disappeared during processing. TMAO and TMA were detected in all samples. During processing of dried laver, free amino acids, TMAO and TMA were increased but the other constituents such as combined amino acids, ATP and its related compounds and betaines were decreased in all specimens.

The 3-D-QSAR Study of Antitumor Arylsulfonylimidazolidinone Derivatives by CoMFA and CoMSIA

Park Choo, Hea-Young,Choi, Suyoung,Jung, Sang-Hun,Koh, Hun Yeong,Pae, Ae Nim 梨花女子大學校 藥學硏究所 2003 藥學硏究論文集 Vol.- No.12

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies for a series of arylsulfonylimidazolidinone derivatives having antitumor activity were conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices anaysis (CoMSIA). The in vitro cytotoxicity against human lung carcinoma (A549) exhibited a strong correlation with steric and electrostatic factors of the molecules. Four different types of models have been built using CoMFA and CoMSIA method with AMI charge or Gasteiger-Huckel charge. By comparison of the statistical results of these models, model I obtained by CoMFA study with AMI showed the best predictability of the antitumor activities based on the cross- validated value (0.642), conventional r² (0.981), standard error of estimate (0.106) and PRESS value (0.170).

QSAR Study of Quinolinediones with Inhibitory Activity of Endothelium-Dependent Vasorelaxation by CoMSIA

Park Choo, Hea-Young,Choi, Suyoung,Ryu, Chung-Kyu,Kim, Hwa-Jung,Lee, In Youn,Pae, Ae Nim,Koh, Hun Yeong 梨花女子大學校 藥學硏究所 2003 藥學硏究論文集 Vol.- No.12

The 3D-QSAR study of quinolinediones which showed potent inhibitory effect on the acetylcholine induced vaso-relaxation of rat aorta with the endothelium was conducted by CoMSIA. The statistical result, cross-validated q² (0.741) and r² (0.960) values, gave reliability to the prediction of inhibitory activity of this series.

Compositions of Extractive Nitrogenous Constituents and Their Monthly Variation for Fresh Capsosiphon fulvescens

Jung, Kyoo-Jin,Park, Jung-Nim The Korean Society of Food Science and Nutrition 2010 Preventive Nutrition and Food Science Vol.15 No.2

To elucidate the composition of extractive nitrogenous components in the fresh Capsosiphons fulvescens cultured off the southern coast of Korea, and to determine the monthly variation of these nitrogenous components, extract samples collected monthly from December to March at Jangheung-gun, Jeonnam Province were analyzed for total nitrogen, free and combined amino acids, ATP and related compounds, betaines, trimethylamine oxide (TMAO) and trimethylamine (TMA). The content of extractive nitrogen was 1,090~1,233 mg/100 g on dry basis. The number of 21~25 ninhydrin-positive substances was detected in the analysis of free amino acids, and their total amount was 3,710~4,788 mg/100 g on dry basis. Among them, free proline, asparagine, glutamic acid, alanine, taurine and glutamine were found to be abundant. The combined amino acids amounted to 1,573~2,121 mg/100 g in total and the total amount of ATP and related compound was 33.8~84.0 mg/100 g ($1.06{\sim}2.46\;{\mu}mol/g$) on dry basis. Betaine, glycinebetaine, $\beta$-alaninebetaine, $\gamma$-butyrobetaine, homarine and trigonelline were detected in most of samples. Levels of free and combined amino acids, ATP and related compounds fluctuated from sample to sample, with their contents higher in December and January and lower in March.

Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Aβ-induced mitochondrial dysfunction

Park, Insun,Londhe, Ashwini M.,Lim, Ji Woong,Park, Beoung-Geon,Jung, Seo Yun,Lee, Jae Yeol,Lim, Sang Min,No, Kyoung Tai,Lee, Jiyoun,Pae, Ae Nim Springer-Verlag 2017 Journal of computer-aided molecular design Vol.31 No.10

Synthesis of Piperazinylalkylisoxazoline Analogues and Their Binding Affinities for Dopamine Receptor Subtypes

Jung, Ji-Young,Jung, Sun-Ho,Koh, Hun-Yeong,Pae, Ae-Nim,Park, Woo-Kyu,Kong, Jae-Yang Korean Chemical Society 2006 Bulletin of the Korean Chemical Society Vol.27 No.11