Design, synthesis, and biological evaluation of quinazoline derivatives as dual HDAC1 and HDAC6 inhibitors for the treatment of cancer

Abstract Fifty‐eight quinazoline‐based compounds were designed and synthesized based on the structural optimizations from the lead compound 23bb in an attempt to search for more potent dual HDAC 1 and HDAC 6 inhibitors. Among them, 32c ( HDAC 1, IC 50 = 31.10 ± 0.37 nM; HDAC 6, IC 50 = 16.15 ± 0.62 nM) and 32d ( HDAC 1, IC 50 = 37.00 ± 0.24 nM; HDAC 6, IC 50 = 35.00 ± 0.71 nM) were not only identified as potent dual‐acting HDAC 1 and HDAC 6 inhibitors with over 10‐fold selectivity to the other HDAC s, but also displayed activities in tubulin acetylation and histone H 3 acetylation induction. Importantly, both of them displayed strong antiproliferative activities against various tumor cell lines in vitro with IC 50 values less than 40 nM, especially for hematologic tumors cells (U266 and RPMI 8226, IC 50 < 1 nM), which were even better than 23bb and SAHA . Furthermore, 32c showed a significant tumor growth inhibition (antitumor rate = 63.98%, p < 0.05) in the resistant MCF ‐7/ ADR xenograft model without any obvious body weight changes and abnormal behaviors. Our findings validate that 32c is a potent dual inhibitor of HDAC 1/6 that can be an efficacious treatment for breast cancer with Adriamycin resistance.