Search

[Display omitted] • 29 HDAC6 inhibitors featuring Schisandrin C-analogous Cap were designed and synthesized. • SAR study identified compound 24h as the most attractive one throughout this series. • 24h exhibited single-digit nanomolar IC 50 against HDAC6, along with favorable selectivity over HDAC1, 8 and 11. • In A549 cells, 24h was capable of reversing IL-6-mediated PD-L1 upregulation. • 24h displayed acceptable oral bioavailability, high oral exposure, and long elimination half-life in SD rats. HDAC6 inhibitors (HDAC6is) represent an emerging therapeutic option for triggering anti-cancer immune response. In this work, a novel series of HDAC6is, derived from an in-house analog of the traditional Chinese medicine monomer Schisandrin C, were designed and synthesized for SAR study. Throughout the 29 target compounds, 24a , 24b and 24h exerted single-digit nanomolar enzymatic activity and remarkably elevated subtype selectivity compared to the clinically investigated HDAC6i Ricolinostat (Selectivity index = 3.3). In A549 tumor cells, 24h , as the representative in this series (IC 50 = 7.7 nM; selectivity index = 31.4), was capable of reversing IL-6-mediated PD-L1 upregulation, highlighting its immunomodulatory capability. Importantly, unlike numerous other hydroxamate-based HDACis, 24h displayed an acceptable oral bioavailability in Sprague-Dawley rats, along with high plasma exposure, long elimination half-life and slow clearance. With the aforementioned attractive performance, 24h deserves further in vivo investigation as an immunomodulatory therapeutic agent for batting human malignance. [ABSTRACT FROM AUTHOR]