Conoformation and atropisomeric properties of indometacin derivatives

Conoformation and atropisomeric properties of indometacin derivatives
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吲哚美辛衍生物的构象和阻转异构性质

DOI：
10.1002/chem.201300064
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发表时间：
2013
期刊：
Chemistry A European Journal
影响因子：
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通讯作者：
Hideyo Takahashi
Hideyo Takahashi
中科院分区：
--
文献类型：
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作者：
Shintaro Wakamatsu;Yuka Takahashi;Hidetsugu Tabata;Tetsuta Oshitari;Norihiko Tani;Isao Azumaya;Yukiteru Katsumoto;Takeyuki Tanaka;Shinzo Hosoi;Hideaki Natsugari;Hideyo Takahashi

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通过限制吲哚美辛的N-苯甲酰基吲哚基团绕N <$C7 ′和/或C7′ <$C1 ′键的旋转，研究了吲哚美辛的N-苯甲酰基吲哚基团的立体化学。在2′，6 ′-二取代的化合物中，发现了阻转异构体的性质，并将阻转异构体以稳定的形式分离出来。检测其抑制环氧化酶-1（考克斯-1）和环氧化酶-2（考克斯-2）的生物学能力。只有aR-异构体显示出对考克斯-1的特异性抑制，而考克斯-2不受任一阻转异构体的抑制。利用NMR研究和X射线晶体学中的构象分析以及CD光谱结合计算来阐明生物活性构象。
The stereochemistry around theN‐benzoylated indole moiety of indometacin was studied by restricting the rotation about the NC7′ and/or C7′C1′ bond. In the 2′,6′‐disubstituted ones, an atropisomeric property was found and the atropoisomers were separated and isolated as stable forms. Their biological abilities to inhibit cyclooxygenase‐1 (COX‐1) and cyclooxygenase‐2 (COX‐2) were examined. Only the aR‐isomer showed specific inhibition of COX‐1, and COX‐2 was not inhibited by either atropisomer. Conformational analysis in NMR studies and X‐ray crystallography, and CD spectra in combination with calculations were utilized to elucidate the bioactive conformations.