Novel scaffold evolution through combinatorial 3D-QSAR model studies of two types of JNK3 inhibitors

Jung, Hoyong,Aman, Waqar,Hah, Jung-Mi Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.10

<P><B>Abstract</B></P> <P>JNK3 is an emerging target for neurodegenerative diseases including AD and PD, with histological selectivity. Specifically, in AD, JNK3 is the main protein kinase for APP phosphorylation, which is an important mechanism for Aβ processing, and a biomarker of Alzheimer’s disease. Therefore, targeting JNK3 is a reasonable strategy for drug discovery in neurodegenerative diseases. In order to find a novel scaffold for JNK3 inhibitors, we performed 3D-QSAR modeling studies with two different JNK3 inhibitor series. The CoMFA model was obtained with a q<SUP>2</SUP> value of 0.806 and an r<SUP>2</SUP> value of 0.850. Based on CoMFA and CoMSIA models, rational design was conducted and led to a novel scaffold, <I>N</I>-(thiophen-2-yl)-8<I>H</I>-pyrazolo[1,5-<I>a</I>]pyrido[1,2-<I>c</I>]pyrimidine-10-carboxamide.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

De Novo Design and Synthesis of a γ-Turn Peptidomimetic Scaffold and Its Application as JNK3 Allosteric Ligand.

Kim, Mi-Hyun,Lee, Junghun,Hah, Jung-Mi Wiley-VCH 2015 Chemistry - An Asian Journal Vol.10 No.6

<P>As a way to develop a neuroprotective agent for the JNK3-JIP1-binding site, peptidomimetics of JIP-1 as JNK3 allosteric regulators have been examined. The study consisted of in silico scaffold hopping, molecular docking, solution and solid-phase peptide syntheses, and Kd measurements using surface plasmon resonance. As a peptidomimetic of JIP1, heptamer mimetic 16 (Kd =2.72?μm) displayed a higher affinity than decamer JIP1 (Kd =23.6?μm). The high affinity of 16 implies that the characteristic γ-turn mimetic structure, 'φ-X-φ' hydrophobic motif in 16, increased its affinity toward the JIP-site of JNK3.</P>

Larvicidal activity of Myrtaceae essential oils and their components against Aedes aegypti, acute toxicity on the water flea, Daphnia magna, and aqueous residue

HYE-MI PARK,JUNHEON KIM,KYU-SIK CHANG,BYUNG-SEOK KIM,YU-JUNG YANG,GIL-HAH KIM,SANG-CHUL SHIN,IL-KWON PARK 한국응용곤충학회 2010 한국응용곤충학회 학술대회논문집 Vol.2010 No.05

The larvicidal activities of 11 Myrtaceae essential oils and their components against Aedes aegypti were tested by the immersion method. We also tested the acute toxicity of 4 active oils and their components against the water flea, Daphnia magna. Further, the aqueous residues of these oils and their components were determined at 2 and 7 days after suspending in water. Among the 11 oils tested, 0.1 mg/mL of Melaleucalinariifolia, M. dissitiflora, M. quinquenervia, and Eucalyptus globulus oils showed strong larvicidal activity against A. aegypti. Among the test compounds, allyl isothiocyanate, γ-terpinene, p-cymene, (+)-limonene, (-)-limonene, γ-terpinene, and (E)-nerolidol showed strong larvicidal activity against A. aegypti. The acute toxicity test revealed M. linariifolia was the most toxic to D. magna. Among test compounds, allyl isothiocyanate was the most toxic to D. magna. Two days after treatment, the residues of M. dissitiflora, M. linariifolia, M. quinquenervia, and E. globulus oils in water were 55.4, 46.6, 32.4, and 14.8%, respectively. Low concentrations of allyl isothiocyanate, γ -terpinene, p-cymene, (-)-limonene, (+)-limonene, and γ-terpinene were detected in the water at 2 days after treatment. Therefore, Myrtaceae essential oils and their components could be developed as control agents against mosquito larvae.

간호사의 에니어그램 성격 유형에 따른 직무 스트레스와 스트레스 대처방식

강미정(Mi Jung Kang),하양숙(Yang Sook Hah) 대한스트레스학회 2010 스트레스硏究 Vol.18 No.1

본 연구는 에니어그램 성격유형 검사를 통하여 간호사의 성격 유형과 직무 스트레스, 스트레스 대처방식간의 관계를 알아보기 위해 수행되었다. 연구 도구는 한국형 에니어그램 성격 유형 검사도구와 직무 스트레스 측정도구, 스트레스 대처방식 측정도구를 이용하였으며 총 368부의 자료 분석은 SPSS win 12.0 program을 이용하였다. 연구의 결과는 다음과 같다. 먼저 간호사의 에니어그램 성격유형을 살펴보면, 조정자형인 9형이(n=172, 46.7%)이 가장 많았으며, 다음으로 개혁가인 1형(n=61, 16.6%), 조력가인 2형(n=39, 10.6%)순으로 나왔으며 도전자인 8형이(n=9, 2.4%) 가장 적게 나타났다. 대형 종합병원에서 근무하는 간호사들이 단순히 환자만을 돌보는 것이 아니라 보호자 및 의사와의 관계, 간호부 내의 상하관계, 타 부서와의 유기적인 협력이 필요하므로 원만한 인간관계가 요구될 뿐 아니라 중증도가 높은 환자들을 간호하기 때문에 응급 대처 능력이 뛰어나야 하며 고도의 스트레스에 잘 견딜 수 있어야 한다. 따라서 자신을 내세우기 보다는 타인의 의견을 경청하고 가급적 갈등이나 긴장을 피하고자 노력하는 평화주의자이며 마음이 넓고 인내심이 강한 편인 9형 유형이 많은 것으로 사료된다. 에니어그램 성격유형별 직무스트레스는 4형이 2.79점으로 가장 높았으며 7형이 가장 낮은 점수를 보였으나(2.51) 에니어그램 성격유형과 전체 직무 스트레스와의 관계는 통계적으로 유의하지는 않았다. 하부영역별로 보면, ‘전문직으로서의 갈등’ 영역과 ‘대인관계갈등’영역에서 유의미한 차이가 있었다. 마지막으로 에니어그램 성격유형별 스트레스 대처방식은 충성가인 6형을 제외한 모든 유형에서 사회적 지지 추구 대처를 가장 많이 사용하였으며, 그 다음 순서대로 문제중심적 대처, 소망적 사고, 정서적 완화 추구의 순서로 대처하였다. 6형의 경우는 사회적 지지 추구 다음으로 소망적 사고, 문제 중심적 대처, 정서적 완화추구를 사용하였다. 하부영역을 살펴보면 ‘정서 완화적 대처’ 영역에서 통계적으로 유의한 결과가 나타났다(F=2.81, p=0.00). 본 연구는 간호업무 현장에서 많은 스트레스를 받는 간호사들의 자기 이해를 통한 원만한 인간관계 개선을 위한 에니어그램 워크샵 프로그램 개발 및 연구의 기초 자료로 활용될 수 있다는 데 그 의의가 있다고 하겠다. The purpose of this study was to justify the relationship among personality structure and job stress and stress coping skill of nurses at a hospital. Testing tools were Enneagram Korean version, tool of measuring job stress and tool of measuring stress coping skill. This research was carried on the 403 nurses in Seoul National University of Hospital located in Seoul, Korea. 368 survey sheets were obtained and analyzed by using SPSS Win 12.0. The results of this research are following. First, in the result of the inventory of the Enneagram personality of nurses, 9th type, The Meditator (n=172, 46.7%) was the largest, and 1st type, The Reformer (n=61, 16.6%) and 2nd type, The Helper (n=9, 2.4%) were next, and the 8th, The Challenger (n=9, 2.4%) was the least. According to enneagram personality, 4th type, The Individualist reported the highest job stress (2.79 point) and 7th type, The Enthusiast reported the lowest job stress (2.51 point). But we found no significant correlations between Enneagram personality and job stress. In job stress"s subtype, results showed that there are the significant correlations between the "conflict in roles as specialists" and the "conflict in interpersonal relationship". Finally, the results showed that the most participant using the "seek social support" as a stress coping skill, the "problem-focused coping" style was the second to come, the "wishful though"t was third, and the "emotion-focused coping" style was the last. 6th type, The Loyalist, was exceptionally using the "seek social support" as a coping skill mostly, but the "wishful thought" was second, and the "problem-focused" and "emotion-focused" was the next. (Korean J Str Res 2010;18:1∼10)

Quantum Dot-Based Aptasensor for Sensitive Protein Detection

Shin, Seon-Mi,Kim, Yea-Seul,Kang, Ho-Jung,Hah, Sang-Soo Korean Chemical Society 2010 Bulletin of the Korean Chemical Society Vol.31 No.7

Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting multiple protein kinases as anticancer agents

Lee, Junghun,Jung, Hoyong,Kim, Minjung,Lee, Eunkyu,Im, Daseul,Aman, Waqar,Hah, Jung-Mi Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.8

<P><B>Abstract</B></P> <P>A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (<B>8a</B>–<B>8i</B>, <B>9a</B>–<B>9m</B>) and urea (<B>10a</B>–<B>10d</B>, <B>11a</B>–<B>11d</B>) with diverse hydrophobic moieties. One of the most potent inhibitor <B>10d</B>, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-<I>1H</I>-thieno [3,4-<I>b</I>][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC<SUB>50</SUB> = 3.73 nM) and is a promising candidate for further development in therapeutics for cancer.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Larvicidal activity of Myrtaceae essential oils and their components against Aedes aegypti, acute toxicity on Daphnia magna, and aqueous residue.

Park, Hye-Mi,Kim, Junheon,Chang, Kyu-Sik,Kim, Byung-Seok,Yang, Yu-Jung,Kim, Gil-Hah,Shin, Sang-Chul,Park, Il-Kwon Entomology Dept., B.P. Bishop Museum 2011 Journal of medical entomology Vol.48 No.2

<P>The larvicidal activity of 11 Myrtaceae essential oils and their constituents was evaluated against Aedes aegypti L. Of the 11, Melaleuca linariifolia Sm., Melaleuca dissitiflora F. Muell., Melaleuca quinquenervia (Cav.) S. T. Blake, and Eucalyptus globulus Labill oils at 0.1 mg/ml exhibited > or = 80% larval mortality. At this same concentration, the individual constituents tested, allyl isothiocyanate, alpha-terpinene, p-cymene, (+)-limonene, (-)-limonene, gamma-terpinene, and (E)-nerolidol, resulted in > or = 95% mortality. We also tested the acute toxicity of these four active oils earlier mentioned and their constituents against Daphnia magna Straus. M. linariifolia and allyl isothiocyanate was the most toxic to D. magna. Twodays after treatment, residues of M. dissitiflora, M. linariifolia, M. quinquenervia, and E. globulus oils in water were 55.4, 46.6, 32.4, and 14.8%, respectively. Less than 10% of allyl isothiocyanate, alpha-terpinene, p-cymene, (-)-limonene, (+)-limonene, and gamma-terpinene was detected in the water at 2 d after treatment. Our results indicated that oils and their constituents could easily volatilize in water within a few days after application, thus minimizing their effect on the aqueous ecosystem. Therefore, Myrtaceae essential oils and their constituents could be developed as control agents against mosquito larvae.</P>

Synthesis and Antiproliferative Activity of Pyridinylcarbonylpyrimidines Against Melanoma Cell Line

Ahn, Hye-Mi,Lee, Jun-A,Kim, Hwan,Oh, Chang-Hyun,Lee, So-Ha,Sim, Tae-Bo,Hah, Jung-Mi,Kim, Dong-Jin,Yoo, Kyung-Ho Korean Chemical Society 2011 Bulletin of the Korean Chemical Society Vol.32 No.4

The synthesis of the series of pyrimidinylamines 1a-d and pyrimidinylureas 1e-u bearing a novel pyridinylcarbonylpyrimidine scaffold and their antiproliferative activities against A375 human melanoma cell line were described. Among them, three compounds 1e, 1h, and 1o showed superior antiproliferative activities to Sorafenib ($IC_{50}=5.5{\mu}M$) as a reference compound. In our series, urea compound 1o having 4-chloro-3-trifluoromethyl moiety on the benzene nucleus exhibited very good antiproliferative activity with $IC_{50}$ value of $1.4{\mu}M$.

Hologram and Receptor-Guided 3D QSAR Analysis of Anilinobipyridine JNK3 Inhibitors

Jae Yoon Chung,Art E Cho,Jung-Mi Hah 대한화학회 2009 Bulletin of the Korean Chemical Society Vol.30 No.11

Hologram and three dimensional quantitative structure activity relationship (3D QSAR) studies for a series of anilinobipyridine JNK3 inhibitors were performed using various alignment-based comparative molecular field analysis (COMFA) and comparative molecular similarity indices analysis (CoMSIA). The in vitro JNK3 inhibitory activity exhibited a strong correlation with steric and electrostatic factors of the molecules. Using four different types of alignments, the best model was selected based on the statistical significance of CoMFA (q2 = 0.728, r2 = 0.865), CoMSIA (q2 = 0.706, r2 = 0.960) and Hologram QSAR (HQSAR: q2 = 0.838, r2 = 0.935). The graphical analysis of produced CoMFA and CoMSIA contour maps in the active site indicated that steric and electrostatic interactions with key residues are crucial for potency and selectivity of JNK3 inhibitors. The HQSAR analysis showed a similar qualitative conclusion. We believe these findings could be utilized for further development of more potent and selective JNK3 inhibitors.

Hologram and Receptor-Guided 3D QSAR Analysis of Anilinobipyridine JNK3 Inhibitors

Chung, Jae-Yoon,Cho, Art-E,Hah, Jung-Mi Korean Chemical Society 2009 Bulletin of the Korean Chemical Society Vol.30 No.11

Hologram and three dimensional quantitative structure activity relationship (3D QSAR) studies for a series of anilinobipyridine JNK3 inhibitors were performed using various alignment-based comparative molecular field analysis (COMFA) and comparative molecular similarity indices analysis (CoMSIA). The in vitro JNK3 inhibitory activity exhibited a strong correlation with steric and electrostatic factors of the molecules. Using four different types of alignments, the best model was selected based on the statistical significance of CoMFA ($q_2\;=\;0.728,\;r_2\;=\;0.865$), CoMSIA ($q_2\;=\;0.706,\;r_2\;=\;0.960$) and Hologram QSAR (HQSAR: $q_2\;=\;0.838,\;r_2\;=\;0.935$). The graphical analysis of produced CoMFA and CoMSIA contour maps in the active site indicated that steric and electrostatic interactions with key residues are crucial for potency and selectivity of JNK3 inhibitors. The HQSAR analysis showed a similar qualitative conclusion. We believe these findings could be utilized for further development of more potent and selective JNK3 inhibitors.