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 HDAC1 and HDAC6 inhibitors. Among them, 32c (HDAC1, IC50 = 31.10 ± 0.37 nM; HDAC6, IC50 = 16.15 ± 0.62 nM) and 32d (HDAC1, IC50 = 37.00 ± 0.24 nM; HDAC6, IC50 = 35.00 ± 0.71 nM) were not only identified as potent dual-acting HDAC1 and HDAC6 inhibitors with over 10-fold selectivity to the other HDACs, but also displayed activities in tubulin acetylation and histone H3 acetylation induction. Importantly, both of them displayed strong antiproliferative activities against various tumor cell lines in vitro with IC50 values less than 40 nM, especially for hematologic tumors cells (U266 and RPMI8226, IC50 < 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 HDAC1/6 that can be an efficacious treatment for breast cancer with Adriamycin resistance.

中文翻译：

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喹唑啉衍生物作为HDAC1和HDAC6双重抑制剂的设计，合成和生物学评估。

基于铅化合物23bb的结构优化，设计并合成了58种基于喹唑啉的化合物，试图寻找更有效的HDAC1和HDAC6双重抑制剂。其中，不仅将32c（HDAC1，IC50 = 31.10±0.37 nM; HDAC6，IC50 = 16.15±0.62 nM）和32d（HDAC1，IC50 = 37.00±0.24 nM; HDAC6，IC50 = 35.00±0.71 nM）确定为有效HDAC1和HDAC6双作用抑制剂对其他HDAC的选择性超过10倍，但在微管蛋白乙酰化和组蛋白H3乙酰化诱导中也表现出活性。重要的是，它们在体外对各种肿瘤细胞系均表现出强大的抗增殖活性，IC50值小于40 nM，尤其是血液系统肿瘤细胞（U266和RPMI8226，IC50 <1 nM），甚至优于23bb和SAHA。此外，32c在抗性MCF-7 / ADR异种移植模型中显示出显着的肿瘤生长抑制作用（抗肿瘤率= 63.98％，p <0.05），而没有任何明显的体重变化和异常行为。我们的发现证实32c是HDAC1 / 6的有效双重抑制剂，可以有效治疗具有阿霉素抗性的乳腺癌。