Synthesis of New 1-(2-, 3-, Or 4-Methanesulfonylphenyl)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene Regioisomers: A Search for Novel Cyclooxygenase and Lipoxygenase Inhibitors
Synthesis of New 1-(2-, 3-, Or 4-Methanesulfonylphenyl)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene Regioisomers: A Search for Novel Cyclooxygenase and Lipoxygenase Inhibitors
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DOI：
10.1002/jhet.23
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发表时间：
2009-01-01
影响因子：
2.4
通讯作者：
Knaus, Edward E.
中科院分区：
文献类型：
--
作者：
Chowdhury, Morshed A.;Chen, Hua;Knaus, Edward E.
设计了一组乙炔区域异构体，使得环加氧酶-2（考克斯-2）SO2 Me药效团位于乙炔C-1苯基环的邻位、Meta位或对位，并且铁螯合5-脂氧合酶（5-LOX）N-羟基吡啶-2（1H）-酮部分通过其C-5位连接到乙炔模板（支架）上的C-2位。通过钯催化的Sonogashira交叉偶联反应合成了这些目标线性乙炔区域异构体。使用体外基于细胞的抑制试验获得的结构-活性数据表明，这类新的1-（2-、3或4-甲磺酰基苯基）-2-[5-（N-羟基吡啶-2（1H）-酮）]乙炔区域异构体不抑制考克斯-2或（5-LOX）酶，并且它们缺乏体内抗炎活性。
A group of acetylene regioisomers were designed such that a cyclooxygenase-2 (COX-2) SO2Me pharmacophore was located at the ortho-, meta-, or para-position of the acetylene C-1 pheryl ring, and an iron-chelating 5-lipoxygenase (5-LOX) N-hydroxypyridin-2(1H)-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). These target linear acetylene regioisomers were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. Structure-activity data acquired using in vitro cell-based inhibition assays indicated that this novel class of 1-(2-, 3, or 4-methanesulfonylphenyl)-2-[5-(N-hydroxypyridin-2(1H)-one)]acetylene regioisomers did not inhibit the COX-2 or (5-LOX) enzymes, and that they are devoid of in vivo anti-inflammatory activities.