3,4-Dihydro-3-oxo-2H-1,2,4-benzothiadiazine 1,1-dioxide 유도체 합성 및 aldose reductase 저해 연구

Abstract

당뇨성 백내장은 당뇨병의 합병증의 하나로, 고혈당 상태에서 증가된 glucose가 세포내로 들어 와, polyol pathway에 의해 생성된 sorbitol이 frutose로 전환되지 못하고 수정체 내에 적체되어 투명도가 흐려짐으로써 궁극적으로는 시각상실을 일으키는 질병이다. 1980년대 후반에 polyol pathway에서 속도 결정 단계 효소인 aldose reductase를 저해함으로써 백내장을 막을 수 있는 것으로 밝혀져 aldose reductase 저해제가 당뇨성 백내장 치료제로서 활발히 연구되고 있다. 본 연구에서는 aldose reductase저해제로 알려진 α- [3-3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]-acetic acid를 lead compound로 하여, diimide의 carbonyl기를 bioisostere인 sulfonyl기로 바꾼 계열로서, carboxyl기를 가지지 않고 N위치에 저급 alkyl기가 치환되어 있는 6-alkyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine 1,1-dioxide계열의 물질들과 2번 위치의 N 또는 4번 위치의 N에 acetic acid가 치환되어 있는 α-(N-alkyl-3,4-dihydro-3-oxo-2H-1,2,4-benzothiadia zin-N-yl)-acetic acid 1,1-dioxide계열의 물질들을 합성하고, 이들의 invitro aldose reductase 저해 효과를 측정하였다. 합성한 화합물들의 aldose reductase 저해 효과를 측정하였을 때 benzothiadiazine ring에 carboxyl기와 aromatic ring이 모두 치환된 화합물들의 Ic_(50) 값은 3.98×10^(-6)M -1.87×10^(-5)M로 나타났다.;Diabetic cataract, one of the complications of diabetes, is a disease in which an increased amount of glucose occurs in the state of hyperglycemia. In the lens, this excess glucose enters the sorbitol(polyol) pathway. The first enzyme in this pathway, aldose reductase, reduces glucose to sorbitol. But if sorbitol is unable to convert to fructose via this pathway, sorbitol is accumulated in the lens which causes decreased transparency, and ultimately, the disease will cause blindness. In the late 80's, it was known that by inhibiting the rate limiting enzyme, aldose reductase, in the polyol pathway prevents diabetic cataract. Therefore, aldose reductase inhibitor has been used as a treatment agent for the diabetic cataract. In this study, a known aldose reductase inhibitor, α-[3-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-l-yl]-acetic acid was modified by substituting the carbonyl group of lead compound with the bioisosteric sulfonyl group. Therefore the derivitves of 3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine 1,1-dioxide with various substituents at C-6, N-2, and N-4 position were synthesized. The in vitro aldose reductase inhibitory effect was tested using the enzyme isolated from rabbit lens. The IC_(50) values of the 3,4-dihydro-3-oxo-2H-1,2,4-benzothiadiazine 1,1-dioxide derivitives that have an acetic acid substituted at the N-4 position and an aryl group substituted at the N-2 position were 3.98×10^(-6)M-1.87×10^(-5)M range.