Design, synthesis and bioactivity evaluations of 8-substituted-quinoline-2-carboxamide derivatives as novel histone deacetylase (HDAC) inhibitors.

The inhibition of histone deacetylases (HDACs) has been considered a promising therapeutic strategy for treatment of many diseases, especially cancer. In the current study, a series of 8-substituted quinoline-2-carboxamide derivatives were designed and synthesized as potent HDAC inhibitors. The most potent compound 21 g (IC50 = 0.050 µM) exhibited 3-fold greater HDAC inhibitory activity compared to the known HDAC inhibitor Vorinostat (IC50 = 0.137 µM). Additionally, compound 21g exhibited low toxicity against normal cells(IC50 in HUVEC cell > 50 µM) and showed good liver microsomal stability, therefore, may serve as a new lead compound for further development.

Design, synthesis and biological evaluation of hydantoin derivatives as Mcl-1 selective inhibitors.

As a member of Bcl-2 protein family, myeloid cell leukemia-1 (Mcl-1) plays a critical role in cell apoptosis and has become a promising anti-cancer drug target. Herein, we designed and synthesized a series of hydantoin derivatives as novel Mcl-1 inhibitors based on our previously developed lead compound. Among them, compound M23 and M24 exhibited good binding affinities against Mcl-1 with Ki values of 0.49 µM and 0.33 µM respectively. Especially, compound M23 exhibited good selectivity over Bcl-xL, whereas compound M24 possessed good selectivity over both Bcl-2 and Bcl-xL. Furthermore, we also investigated the effects of these new Mcl-1 inhibitors on cell proliferation, apoptosis and mitochondrial membrane potential, as well as the stability in plasma.

Design, synthesis and biological evaluation of 3, 4-disubstituted-imidazolidine-2, 5-dione derivatives as HDAC6 selective inhibitors.

HDAC6 isoform selective inhibitors can be pursued as an alternative to pan-HDACs inhibitors due to their therapeutic effect and low toxicity. Efforts of the structure optimization of our previous compound 10c (IC50 = 4.4 nM) resulted in a new series of 3, 4-disubstituted-imidazolidine-2, 5-dione based HDAC6 inhibitors with better HDAC6 inhibitory activities and improved selectivities. The most potent compound 71 exhibited a low nanomolar HDAC6 inhibitory activity (IC50 = 2.1 nM) and showed 5545-fold, 5864-fold as well as 1638-fold selectivity relative to HDAC1, HDAC2 and HDAC8, respectively. Western blot analysis further confirmed that compound 71 selectively increased the acetylation level of α-tubulin without affecting histone H3. Moreover, compound 71 also possesses good properties in term of caspase-3 activation, apoptosis induction, anti-proliferative activity, cytotoxicity and plasma stability. Therefore, compound 71 can be applied in cancer therapy or used as a lead compound to develop more potent HDAC6 selective inhibitor.