3,4-Dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide 유도체 합성 및 세포 독성 연구

1982년부터 Howbert 등이 고형암 치료를 위해 diarylsulfonylurea를 합성하여 murine solid tumors와 human tumor xenografts에 대해 실험한 결과 항암효과가 우수한 sulofenur (LY186641) 를 개발하게 되었다. 본 연구에서는 sulofenur를 lead화합물로 하여 diarylsulfonylurea가 환을 이룬 4-aryl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide 계열의 물질들과 2번 위치의 질소와 3번 위치의 탄소에 치환기를 도입한 물질들을 합성하였다. 합성 방법은 다음과 같다. Aromatic amines을 sodium amide 하에서 bromobenzene과 반응시켜 diphenylamine 유도체를 얻었다. 이 화합물을 chlorosulfonylisocyanate와 반응시키고 aluminium chloride를 가한 후 Friedel-Crafts 조건으로 끓여 주어 4-aryl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide계열의 화합물들을 합성하였다. 계속하여 이 화합물에 3,4-dichlorobenzychloride를 potassium carbonate하에서 반응시켜 4-aryl-2-(3,4-dichlorobenzyl)-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide 계열의 화합물을 11-53% 의 수득률로 합성하였다. (화합물 1-14) Aromatic acid와 2-aminobenzene sulfonamide를 diphosphorus pentaoxide와 1,2-ethylene dichloride하에서 반응시켜 3-alkyl-2H-1,2,4-benzothiadiazine-1,1-dioxide 유도체를 합성하였다 (화합물 15-19) 이와 같이 합성된 화합물들의 세포독성효과를 SRB assay를 통해 조사하였다. 그러나 lead화합물인 sulofenur와 ED_(50) 값을 비교해 보았을 때 합성한 화합물들이 sulofenur보다 높은 ED_(50) 값을 나타내었다. 결과적으로 diarylsulfonylurea의 세포독성효과에 있어서는 benzothiadiazine의 A ring구조가 indan이 되는 것과 비고리화 화합물이 되는 것이 중요했다.;From 1982 Howbert and coworkers synthesized the diarylsulfonylureas for curing agent effective against solid tumors and discovered that sulofenur (LY186641) had good therapeutic efficacy against murine solid tumors and human tumor xenografts. In this study, we determined sulofenur as lead compound and synthesized the derivatives of 4-aryl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide, which is cyclized form of diarylsulfonylurea, and ones with various substituents at N-2 and or C-3 position to decrease renal toxicity of sulofenur. The synthetic methods are as follows: Aromatic amines were reacted with bromobenzene in the presence of sodium amide to yield the derivatives of diphenylamine. These compounds were reacted with chlorosulfonylisocyanate, followed with addition of aluminium chlroride to obtain 4-aryl-3, 4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1, 1-dioxides. When these compound were heated with 3,4-dichlrobenzylchloride in the presence of potassium carbonate, 4-aryl-2-(3,4-dichlorobenzyl)-3, 4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxides(compound 1-14) were obtained in 11-53% yields. Aromatic acids were reacted with 2-aminobenzene sulfonamide in the presence of diphosphorus pentaoxide and 1,2-ethylene dichloride to yield 3-alkyl-2H-1,2,4-benzothiadiazine-1,1-dioxide.(compound 15-19) Their in vitro cytotoxic effects against A549(human lung), SK-OV-3(human ovarian), SK-MEL-2(human melanoma), XF498(human CNS), HCT15(human colon) cells were tested by SRB assay. However, the ED _(50) values of the synthesized compounds were higher than that of sulofenur. In conclusion, indan structure in A ring and nincyclic sulfonylurea structure were important for cytotoxic activities of diarylsulfonylureas.목차 = ⅲ 논문개요 = ⅷ Ⅰ. 서론 = 1 Ⅱ. 실험 재료 및 방법 = 13 1. 실험재료 = 13 1) 시약 = 13 2) 기기 = 13 2. 합성 방법 = 15 1) 4-phenyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(1)의 합성 = 15 2) 7-Ethoxy4-phenyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(2)의 합성 = 16 3) 4-phenyl-6,7-propano-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(3)의 합성 = 17 4) 6-Methyl-4-phenyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(4)의 합성 = 18 5) 6-Methoxy-4-phenyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(5)의 합성 = 19 6) 4-Benzyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(6)의 합성 = 21 7) 4-Chlorobenzyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(7)의 합성 = 22 8) 4-Chlorobenzyl-7-ethoxy-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(8)의 합성 = 23 9) 4-Chlorobenzyl-6,7-propano-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(9)의 합성 = 24 10) 4-Chlorobenzyl-6-methyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(10)의 합성 = 25 11) 4-Chlorobenzyl-6-methoxy-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(11)의 합성 = 27 12) 4-Chlorobenzyl-6-chloro-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(12)의 합성 = 28 13) 4-Chlorobenzyl-6-methyl-2-(3,4-dichlorobenzyl)-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(13)의 합성 = 29 14) 4-Chlorobenzyl-6-chloro-2-(3,4-dichlorobenzyl)-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine-1,1-dioxide(14)의 합성 = 30 15) 3-(4-Chlorophenylethenyl)-2H-1,2,4-benzothiadiazine-1,1-dioxide(15)의 합성 = 31 16) 3-(3,4-Dichlorophenylethenyl)-2H-1,2,4-benzothiadiazine-1,1-dioxide(16)의 합성 = 31 17) 3-{Phenyl-(2-methylethenyl)}-2H-1,2,4-benzothiadiazine-1,1-dioxide(17)의 합성 = 32 18) 3-Phenyl-2H-1,2,4-benzothiadiazine-1,1-dioxide(18)의 합성 = 33 19) 3-Benzyll-2H-1,2,4-benzothiadiazine-1,1-dioxide(19)의 합성 = 33 3. 약효 검색 = 34 1) 시약 및 기구 = 34 2) 세포 배양 = 35 3) 항암활성 측정 = 35 Ⅲ. 결과 및 고찰 = 38 1. 합성에 대한 고찰 = 38 3. 약효 검색에 대한 고찰 = 42 Ⅳ. 결론 = 51 참고문헌 = 53 ABSTRACT = 5

수돗물불소농도조정사업이 지역주민의 골밀도에 미치는 영향

학위논문(석사) --서울대학교 대학원 :환경보건학과,2008. 2.Maste

DNA Methylation Is Regulated by Sumoylation through Action of E3 SUMO ligase AtSIZ1 in Arabidopsis

학위논문 (석사)-- 서울대학교 대학원 : 식물생산과학부(작물생명과학전공), 2012. 2. 서학수.In eukaryotes, gene expression is controlled at multiple levels, and DNA methylation, one of several epigenetic mechanisms, also has large influence on transcription. Sumoylation is an important posttranslational modification regulating various biological processes. We therefore investigated the effect of sumoylation on epigenetic gene expression. To do this, we used siz1-2 mutant, one of T-DNA insertional mutated alleles of AtSIZ1 encoding an Arabidopsis E3 SUMO ligase. DNA methylation was examined by McrBC-PCR using genomic DNAs that were isolated from one-week old or four-week old wild-type and siz1-2 mutant plants. Results showed that the methylation levels of retrotransposon ATGP1, ATCOPIA4, ATLINE1-4, ATSN1 and DNA transposon ATMU1 were much lower in siz1-2 mutant than in wild-type at mature stage while there is no significant difference in their methylation levels between wild-type and siz1-2 mutant plants at seedling stage. Evaluation of the methylcytosine proportion in CG, CHG and CHH sites of ATMU1 by bisulfite sequencing revealed that methylation levels in both CHG and CHH sites were decreased in siz1-2 mutants in comparison with that in wild-type plants, in particular in CHH site. However, methylation in CG site was only slightly low in siz1-2 mutant plants. Interestingly, this phenomenon also only occurs at maturation stage. All of these data demonstrate that AtSIZ1 can regulate DNA or histone methyltransferse activities through its E3 SUMO ligase activity, resulting in modulation of gene expression, which strongly implies that sumoylation is tightly linked with DNA methylation.Maste

기본 도형을 이용한 인터렉티브 비쥬얼 사운드 표현 연구 : 인터렉티브 사운드 인스톨레이션 `Harmonia`를 중심으로

학위논문(석사) --서울대학교 대학원 :디자인학부 시각디자인전공,2008.8.Maste

Aaron Copland Piano Sonata(1939-1941)에 대한 연구 분석

학위논문(석사)--서울대학교 대학원 :음악학과 피아노전공,1999.Maste

The Effect of Adjusted Water Fluoridation on Bone Mineral Density

Adjusted water fluoridation has been disputed because of its various effects on human health. Previous studies have been concerned with the difference in bone mineral density (BMD) between water fluoridated (WF) and none water fluoridated (NWF) districts. The aim of this study is to examine whether water fluoridation affects BMD. BMD was measured by dual energy X-ray absorptiometry (DXA). 386 adults(174 males and 212 females) in Ansan (WF) district and 399 adults (176 males and 223 females) in Sihwa (NWF) district, participated in this study. The Ansan and Sihwa districts are similar in residential environment and living class. The relationship between serum fluoride concentration and BMD was also examined by analysis of the serum fluoride concentrations from 402 inhabitants of the Ansan district. In females, the BMD of subjects living in Ansan () was a little higher than that of Sihwa subjects (), although it is not significant, after adjusting for BMI, physical activity level, educational achievement, smoking volume, menopause status, and number of births. However, the BMD of Ansan subjects () in their forties was statistically higher than that of Sihwa (0.498{\pm}0.019). No relationship was found in males. In residential periods, there was significant difference (Ansan , Sihwa , p=0.0125) in the BMD between females of two districts, particularly in the group of over 6 year long-term inhabitants. On the contrary, there was no remarkable difference in males from the two districts. Serum fluoride concentrations in females were associated with BMD, especially in the age group of forties (p=0.0457). No relationship was observed in the male group. Analysis of adult BMD over the age of 20 in a water fluoridated and a none water fluoridated district, confirms more or less a higher BMD in the water fluoridated (WF) district, especially for females. It is assumed that the difference between two districts came somewhat from the effect of water fluoridation