Zhou Xiang, Born Ella J, Allen Cheryl, Holstein Sarah A, Wiemer David F
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242-1294, USA.
Bioorg Med Chem Lett. 2015 Jun 1;25(11):2331-4. doi: 10.1016/j.bmcl.2015.04.021. Epub 2015 Apr 17.
The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.
已制备了[2-(3-吡啶基)-1-羟基亚乙基-1,1-膦酰基羧酸（或PEHPC）和[2-(3-吡啶基)-1-亚乙基-1,1-膦酰基羧酸（或PEPC）的N-氧化物衍生物，并对它们针对几种利用类异戊二烯的酶的活性进行了评估。母体吡啶是已知的γ-谷氨酰转移酶II抑制剂，但在与分离酶的测定中，N-氧化物衍生物的生物活性没有改善。然而，PEHPC N-氧化物确实在骨髓瘤细胞中诱导了细胞内轻链的显著积累，这与Rab香叶基香叶基化的抑制一致。
