Podichetty Anil Kumar, Faust Andreas, Kopka Klaus, Wagner Stefan, Schober Otmar, Schäfers Michael, Haufe Günter
Organisch-Chemisches Institut and International NRW Graduate School of Chemistry, Westfälische Wilhelms-Universität, Corrensstrasse 40, D-48149 Münster, Germany.
Bioorg Med Chem. 2009 Apr 1;17(7):2680-8. doi: 10.1016/j.bmc.2009.02.048. Epub 2009 Mar 1.
A series of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives has been synthesized and tested as inhibitors of caspases-3 and -7, which are known to be downstream enzymes critical in the execution of apoptosis. N-Propyl- and N-butyl isatins, as well as the corresponding terminal alcohols and regioisomeric fluorobutyl derivatives were shown to be excellent inhibitors having different binding potencies for caspases-3 and -7. In contrast, the corresponding fluoroethyl and fluoropropyl compounds were about 100-1000 times less active. Fluorinated N-benzyl isatins as well as trifluoroalkyl and difluoroalkyl derivatives were moderate inhibitors. However, isatins bearing different alkylether groups at N-1 are very weak or not active as inhibitors of caspases-3 and -7.
一系列新的N-取代（S）-5-[1-（2-甲氧基甲基吡咯烷基）磺酰基]异吲哚酮衍生物已被合成，并作为半胱天冬酶-3和-7的抑制剂进行了测试，已知这两种酶是细胞凋亡执行过程中的关键下游酶。N-丙基和N-丁基异吲哚酮，以及相应的末端醇和区域异构体氟丁基衍生物被证明是对半胱天冬酶-3和-7具有不同结合能力的优秀抑制剂。相比之下，相应的氟乙基和氟丙基化合物的活性约低100-1000倍。氟化N-苄基异吲哚酮以及三氟烷基和二氟烷基衍生物是中等抑制剂。然而，在N-1位带有不同烷基醚基团的异吲哚酮作为半胱天冬酶-3和-7的抑制剂非常弱或无活性。
