10 NF-κB阻害剤(-)-DHMEQ標的分子のSPRおよびMALDI TOF-MSによる解析(口頭発表の部)
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We have designed and synthesized a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). DHMEQ is synthesized from dihydroxyaniline through several steps. Optically active DHMEQ can be prepared by a chiral colomun (1). DHMEQ inhibited animal models of rheumatoid arthritis, cancer cachexia, and renal inflammation, and it also suppressed the growth of prostate carcinoma, thyroid carcinoma, breast carcinoma, pancreatic carcinoma, multiple myeloma, and adult T-cell leukemia in nude or SCID mice without any toxicity (2). However, its molecular target has not been elucidated. (-)-DHMEQ strongly inhibited the activation of NF-κB in EMSA. Although DHMEQ was shown to strongly inhibit nuclear translocation of NF-κB in Jurkat and COS-1 cells (3) and in ATL cells (4), we found that (-)-DHMEQ rather weakly inhibited the nuclear translocation in NSCLC A549 cells. Then, we looked into the mechanism of inhibition in A549 cells, and found that (-)-DHMEQ inhibited the binding of NF-κB to κB DNA. It did not inhibit the binding of Oct-1. Next we prepared recombinant p65 including the DNA binding region and NLS. In the reconstitution system with recombinant p65 and κB DNA, the mobility shift was clearly observed, that was inhibited by (-)-DHMEQ. Physical binding of (-)-DHMEQ to p65 was analyzed by surface plasmon resonance. (-)-DHMEQ was added to the fixed p65 plate, and we could observe the interaction between them. In MALDI-TOF MS analysis, addition of (-)-DHMEQ shifted the MW peak of recombinant p65. On the other hand, an inactive analogue of DHMEQ did not shift the peak. Thus it is likely that (-)-DHMEQ directly binds to p65.
- 天然有機化合物討論会の論文
- 2007-08-24
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