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Cytotoxicity and DNA Topoisomerase Inhibitory Activity of Benz[f]indole-4,9-dione Analogs
PARK, Hyen Joo,LEE, Hyun-Jung,LEE, Eun-Jin,HWANG, Hye Jin,SHIN, Sang-Hee,SUH, Myung-Eun,KIM, Choonmi,KIM, Hwa Jung,SEO, Eun-Kyung,LEE, Sang Kook 梨花女子大學校 藥學硏究所 2003 藥學硏究論文集 Vol.- No.12
A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoqninone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Co12 (colon cancer), and SNU-638 (stomach cancer), and also for the inhibition of human DNA topoisomerases Ⅰ and Ⅱ activity in vitro. Several compounds including 2-amino-3-ethoxycarbonyl-N-mcthyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC_(50)< 20.0 ㎍/㎖ in the panel of cancer cell lines. Especially, 2-hydroxy-3-ethoxycarbonyl-N-(3,4-dimethyl-phenyl)-benz[f]indole-4,9-dione had potential selective cytotoxicity against lung cancer cells (IC_(50)=0.4㎍/㎖)) compared to colon (IC_(50)>20.0㎍/㎖) and stomach (IC_(50)>20.0㎍/㎖) cancer cells. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase Ⅰ and Ⅱ activities were used. In a topoisomerase Ⅰ-mediated relaxation assay using human placenta DNA topoisomerase Ⅰ and supercoiled pHOTI plasmid DNA, 2-amino-3-ethoxycarboHyl-N-(4-fluorophenyl)-benz[f]indole-4,9-dione had the most potent inhibitory activity among the compounds tested. However, most of the compounds showed only weak inhibition of the DNA topoisomerase Ⅱ-mediated KDNA (Kinetoplast DNA) decatenation assay, except for 2-amino-3-cthoxycarbonyl-N-(4-mcthylphcnyl)-benz[f]indole-4,9-dione and 2-amino-3-ethoxycarbonyl-N-(2-bromoehtyl)-benz[f]indole-4,9-dione with a moderate inhibitory activity. These results suggest that several active compounds had relatively selective inhibitory activity against toposiomearse I compared to toposiomerase Ⅱ. No obvious correlation was observed between the cytotoxicity of the individual compound and the inhibitory activity of DNA relaxation and decatenation by topoisomerase Ⅰ and Ⅱ, respectively, in vitro. 1,4-Naphthoquinone derivatives with an amino group at the 2-position have been reported to have good antineoplasmic, carcinostatic actions' and bacterial growth inhibition. Based on the cytotoxic potential of 1,4-naphthoquinone derivatives, in our continuing efforts to develop novel antitumor agents, we have been synthesized benz[f]indole-4,9-dione analogs, heterocyclic pyrrole ring derivatives attached to 1,4-naphthoquinone. In this study we evaluated the cytotoxic potential of additional benz[f]indole-4,9-dione analogs in cultured human solid tumor cell lines including human lung (A549), colon (Col2), and stomach (SNU-638) cancer cells. Further, a variety of antitumor agents currently used in chemotherapy or evaluated in clinical trials are known to inhibit DNA topoisomerase Ⅰ (topo Ⅰ) or Ⅱ (topo Ⅱ). DNA topoisomerases are enzymes that catalyze the passage of individual DNA strands (type 1) or double helices (type Ⅱ) through one another, which is manifested in the interconversion between topological isomers of DNA. These enzymes have important roles in replication, recombination, transcription, chromosome condensation, and the maintenance of genome stability, and hence are good targets for antineoplastic drugs. The antitumor drugs camptothecin, doxorubicin, and etoposide are representative topo Ⅰ or topo Ⅱ inhibitors. Therefore, in this study, to investigate one possible mechanism of action of the cytotoxic activity of benz[f]indole-4,9-dione analogs, we evaluated their ability to inhibit topo Ⅰ or topo Ⅱ activities with DNA relaxation and a DNA decatenation assay, respectively. We report here that benz[f]-indole-4,9-dione analogs show potential cytotoxicity against cancer cell lines with topo Ⅰ or Ⅱ inhibitory activity.
소신호 모델을 이용한 대용량 벅 컨버터에서의 제어기 특성 비교
박주용(Joo-Yong Park),윤철(Yun Chul),윤병근(Byung-keun Yun),김우현(Woo-Hyun Kim),권우현(Woo-Hyen Kwon) 대한전자공학회 2016 대한전자공학회 학술대회 Vol.2016 No.6
본 논문에서는 대용량 벅 컨버터 보상기 중 산업계에서 많이 사용하는 3 Pole 2 Zero 보상기와 PI 제어기에 대해서 대용량 전력변환 시스템의 동특성을 MATLAB Simulink를 이용한 모의실험을 통해 분석하였다. 대용량 벅 컨버터를 small-signal model을 이용해 대표적인 제어기법들로 모의 실험한 결과, PI 제어기가 3 Pole 2 Zero 제어기보다 더 좋은 특성을 가지는 것을 확인하였다.
Lee, Hee Joo,Park, Sung Jun,Sin, Hyen Je,Na, Yu Jeong,Kim, Cheal The Royal Society of Chemistry 2015 NEW JOURNAL OF CHEMISTRY Vol.39 No.5
<P>A new colorimetric chemosensor with an electron-withdrawing group (-NO2) 1 for the detection of CN- and F- has been simply developed. Receptor 1 showed selectively colorimetric responses to CN- in aqueous solution and F- in acetonitrile, respectively. An obvious color change of 1 from yellow to colorless was observed for CN- through a nucleophilic addition mechanism, while F- was detected through a deprotonating mechanism with a distinct color change from pale yellow to orange. The binding modes of receptor 1 with two analytes (CN- and F-) were proposed to be 1 : 1, based on the Job plot, H-1 NMR titration, and ESI-mass spectrometry analysis.</P>
Um, Soohyun,Park, So Hyun,Kim, Jihye,Park, Hyen Joo,Ko, Keebeom,Bang, Hea-Son,Lee, Sang Kook,Shin, Jongheon,Oh, Dong-Chan American Chemical Society 2015 ORGANIC LETTERS Vol.17 No.5
<P>Coprisamides A and B (<B>1</B> and <B>2</B>) were isolated from a bacterium in the gut of the dung beetle <I>Copris tripartitus</I>. Spectroscopic analysis revealed that the planar structures of <B>1</B> and <B>2</B> are novel cyclic heptapeptides bearing unusual units, such as β-methylaspartic acid and 2,3-diaminopropanoic acid branched to valine and 2-heptatrienyl cinnamic acid. Absolute configurations were established by chemical derivatization and chiroptical spectroscopy. The coprisamides displayed significant activity for induction of quinone reductase.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/orlef7/2015/orlef7.2015.17.issue-5/acs.orglett.5b00249/production/images/medium/ol-2015-00249s_0002.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ol5b00249'>ACS Electronic Supporting Info</A></P>
간경변증과 동반된 간세포암종에서 Microsatellite Instability와 DNA 복제오류 교정유전자들의 메틸화
박정호 ( Jung Ho Park ),조성범 ( Sung Bum Cho ),이완식 ( Wan Sik Lee ),박창환 ( Chang Hwan Park ),주영은 ( Young Eun Joo ),김현수 ( Hyen Soo Kim ),최성규 ( Sung Kyu Choi ),유종선 ( Jong Sun Rew ),이재혁 ( Jae Hyek Lee ),김세종 ( S 대한소화기학회 2006 대한소화기학회지 Vol.48 No.5
목적: 최근 간세포암종 발생과정에서 DNA 복제오류 교정유전자의 관련성을 시사해 주고 있으며 그 중에서도 DNA 복구과정에서 복제오류 교정계(mismatch repair system)와 O6-methylguanine-DNA methyltransferase (MGMT)의 중요한 연관성이 있음이 제시되었다. 대상 및 방법: 2000년부터 2003년까지 간세포암종으로 수술을 시행 받아 병리조직학적으로 진단된 환자들 중에서 간경변증이 동반된 40예를 대상으로 하여 hMLH1, MGMT, hMSH3과 같은 DNA 복제오류 교정유전자의 프로모터 부위 메틸화유무와 그 빈도를 조사하고 microsatellite instability (MSI)와 면역조직화학염색을 통한 이들 유전자 산물의 발현 여부와의 상관성 및 임상 특징과 연관성을 조사하였다. 결과: 수술 후 절제된 간세포암종의 평균 크기는 4.2±2.6㎝였다. 간세포암종 병기분류에서 BCLC stage A1은 12예(30%), A2는 3예(8%), A3는 8예(20%), A4는 3예(8%), B는 8예(20%), C는 6예(15%)였고, TNM stage I은 4예, II는 24예(60%), III는 7예(18%), IVa는 5예(13%)였다. 간세포암종의 조직 분화도 등급에 따라 고분화도 8예(20%), 중분화도 19예(48%), 저분화도 13예(32%) 보였다. 수술 후 간세포암종 재발은 총 25예(63%)에서 발생하였으며, 수술 후 간세포암종 재발 또는 간기능 저하로 사망한 경우는 15예(38%)였다. hMLH1, MGMT, hMSH3 유전자의 메틸화를 보이는 경우가 동반된 간경변증에서 각각 3예(8%), 27예(68%), 28예(70%)였고, 간세포암종에서 각각 2예(5%), 29예(73%), 30예(75%)로 간경변증과 간세포암종에서 높은 빈도를 보이는 DNA 복제오류 교정유전자는 hMSH3, MGMT였고 낮은 빈도를 보이는 것은 hMLH1이었다. MSI 상태는 대부분의 증례들이 안정 MSI였으며 단지 3예(8%)에서만 MSI가 관찰되었다. MGMT, hMLH1, hMSH3 단백에 대한 면역조직화학염색결과 양성반응을 보인 경우가 6예(15%), 16예(40%), 11예(28%)였다. MGMT의 경우 유전자 메틸화에 따라 MGMT 단백 소실이 있는 경향을 보였으나 의미있는 상관관계는 보이지 않았다(p=0.10). 간세포암종의 조직 분화도, 수술 후 재발 및 예후 등 임상 특징과 유전자 메틸화와는 의미있는 상관관계를 보이지 않았다(p>0.05). 결론: 간경변증과 동반된 간세포암종 환자에서 DNA 복제오류 교정유전자 중 MGMT와 hMSH3 유전자 메틸화 빈도가 높게 나타났다. 또한 간세포암종에서 낮은 빈도의 MSI를 보였으며 DNA 복제오류 교정유전자와 MSI는 서로 상관관계가 없었다. 수술 후 재발이나 예후와 같은 임상적인 특징과 DNA 복제오류 교정유전자들의 메틸화는 의미있는 상관관계는 보이지 않았다. Backgrounds/Aim: Epigenetic silencing of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT), hMLH1 and hMSH3, by promoter hypermethylation have been observed in various cancers. However, the relationship between hypermethylation of DNA mismatch repair genes and microsatellite instability (MSI) has not been studied in hepatocellular carcinoma (HCC) associated with cirrhosis. Methods: We investigated the methylation pattern of CpG islands of 3 genes using methylation-specific PCR (MSP) and MSI in 40 patients with paired hepatocellular carcinoma and associated cirrhosis. Results: hMSH3 and MGMT were the most methylated genes in both cirrhosis (70% and 68%, respectively) and HCC (75% and 73%, respectively). The methylation of hMLH1 was rarely found in both cirrhosis (8%) and HCC (5%). Gene promoters methylated in cirrhosis were also methylated in HCC with the exception of 9 cases found to be methylated either in cirrhosis or HCC. Of 40 cases of HCC associated with cirrhosis, three had MSI-positive phenotype in which two were MSI-low and one was MSI-high. One MSI-positive phenotype was present both in cirrhosis and in HCC, while two were only in HCC. There was no significant correlation between aberrant DNA methylation of mismatch repair genes and MSI status in HCC associated with cirrhosis. Immunohistochemical expressions of hMLH1, MGMT, and hMSH3 proteins were present in 16 (40%), 6 (15%), and 11 (28%) of 40 cases of HCC respectively. There was no significant correlaton between the aberrant DNA methylation of mismatch repair genes and clinical characteristics such as histological differentiation, postoperative recurrence and mortality. Conclusions: The methylation of MGMT and hMSH3 among DNA repair genes are frequent, but those of hMLH1 and MSI is very rare in both cirrhosis and HCC. There is no significant correlation between the methylation of DNA repair genes and clinical characteristics of HCC. (Korean J Gastroenterol 2006;48:327-336)