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

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