We have designed dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin isolated from Amycolatopsis. In the course of our further screening of NF-kappa B inhibitors, we isolated 9-methystreptimidone from Streptomyces. We then prepared the derivatives having rather simple structures. We looded for the compounds that inhibit LPS-induced NO production in a mouse macrophage cell line RAW264.7. As a result, we found that DTCM0glutarimide, a novel derivative of 9-methylstreptimidone, inhibited the LPS-induced NO production. Then, we looked into the mechanism of inhibition. It inhibited LPS-induced expression of iNOS and COX-2. However, it did not inhibit NF-kappa B activation. Instead, we found that DTCM-glutarimide inhibited nuclear translocations of AP-1 consisting of c-Jun and c-Fos. In the present research, we further looked into the mechanism of AP-1 inhibition. It also inhibited the phosphorylation of c-Jun and c-Fos in cultured macrophage cells. Using recombinant JNK and c-Jun, DTCM-glutarimide inhibited the in vitro phosphorylation of c-Jun by JNK. In one hand, DTCM-glutarimide inhibited RANCL-induced osteoclast differentiation in mouse bone marrow-deried primary culture macrophages. It alst inhibited the invasion of mouse melanoma B16 cells in Mtrigel chamber assay. Thus, a novel piperidine compound, DTCM-glutarimide, was found to be a new AP-1 inhibitor that can be used for the cellular experiments. As a mechanism of inhibition, it is likely to inhibit phosphorylation of AP-1 components.
