The inhibitory activities against HDAC and HDAC of title

The inhibitory activities against HDAC1 and HDAC6 of title compounds were evaluated in a fluorescent assay using SAHA and ACY-1215 as positive control. The results were displayed in A. Compounds – with linker containing 5–7 carbons showed good inhibitory activities against HDAC6. They also displayed obvious selectivity to HDAC6 over HDAC1 (selectivity index >10), which was comparable with that of ACY-1215, the selective HDAC6 inhibitor under clinical trials. Additionally, these results were consistent with the biological effect in cells based on the western blot analysis (). After incubation in human MM cell line RPMI-8226 at 10 μM for 24 h, compound – increased the level of Ac-tubulin significantly, and only compound increased the level of Ac-H3 obviously. Then, binding affinities to Bcl-2 protein of compounds were further evaluated by a fluorescence polarization (FP)-based method using ABT-199 as positive control (). All of the compounds showed high binding affinities, which was comparable with that of ABT-199. It indicated that the replacement of the tetrahydropyranyl methyl group of ABT-199 by hydroxamic EGTA group with different aliphatic chains had little effect on the binding to Bcl-2 protein. Based on the above results, compounds were potent Bcl-2/HDAC dual-target inhibitors. They were evaluated the growth inhibitory activities against human MM cell lines RPMI-8226 and U266 (), and ABT-199, ACY-1215 and SAHA were used as positive controls. RPMI-8226 cell line seems to be sensitive to these compounds than U266 cell line. On RPMI-8226 cell line, these compounds displayed obviously better growth inhibitory activities than positive controls. It indicated that the Bcl-2/HDAC dual-target inhibitors show potential value for the treatment of MM. In summary, encouraged by the synergistic interactions between Bcl-2 inhibitors and HDAC inhibitors, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized in this study. Among them, compounds – showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They displayed good growth inhibitory activities against human MM cell line RPMI-8226, obviously better than Bcl-2 inhibitor ABT-199 and HDAC inhibitors ACY-1215 and SAHA. The studies presented here prove the potential value of Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma, and provide a new structural type for the development of novel antitumor agents. Acknowledgments We thank the Shanghai Rising-Star Program of China (16QA1404800), the State Key laboratory of Drug Research of China (SIMM1601KF-01), and the National Natural Science Foundation of China (Grant Nos. 21572266 and 81673472) for financial support.
Introduction We have recently demonstrated in rats that daily supplementation with the Bimuno™ galacto-oligosaccharide (B-GOS®) prebiotic prevented olanzapine-mediated weight gain (Kao et al., 2018) and improved cognitive flexibility (Gronier et al., 2018). Prebiotics are substrates that are selectively utilized by host microorganisms and confers health benefits (Gibson et al., 2017). The fermentation of B-GOS® yields significant amounts of the short chain fatty acids (SCFAs) acetate, propionate and butyrate (Grimaldi et al., 2017), and we have demonstrated that B-GOS®-derived acetate enters the circulation and influences central gene expression (Gronier et al., 2018). Increasing acetate availability to the brain has been shown to impart epigenetic changes which involve the addition or removal of acetyl groups on histone molecules bound to genomic DNA (Gao et al., 2016). Histone modifications are modulated by the activities of histone deacetylase (HDAC) and histone aceyltransferase (HAT). Increased HDAC activity removes acetyl groups on histones, which decreases DNA unwinding thereby limiting gene expression. Conversely, HAT adds acetyl groups on to histones, which promotes DNA uncoiling and elevates gene transcription (Gorisch et al., 2005). The changes in central gene expression that we have previously reported in response to prebiotic feeding (Gronier et al., 2018, Savignac et al., 2013, Williams et al., 2016), may have been the downstream result of bacteria-derived acetate on epigenetic mechanisms.