4-哌嗪喹唑啉苯甲酰胺类化合物的设计、合成及抗肿瘤活性研究

Design,synthesis and evaluation of 4-piperazin-quinazolineylcontaining benzamides derivatives as histone deacetylase inhibitors

目的寻找新型苯甲酰胺类组蛋白去乙酰化酶(HDACs)抑制剂,探讨其初步构效关系。方法以恩替司他(MS-275)为先导结构,对其酶表面识别区、链接区及锌离子结合区进行改造,设计并合成了系列4-哌嗪喹唑啉苯甲酰胺类化合物。以取代4-羟基喹唑啉为原料,经氯代、氨解、水解制备苯甲酸类衍生物,然后与邻苯二胺或4-氟邻苯二胺经缩合反应制备目标化合物7a^7h;经体外组蛋白去乙酰化酶1抑制活性试验及对人结肠癌细胞HCT-116的抗增殖活性试验,进行目标化合物的活性评价。结果与结论共合成8个未见文献报道的新化合物,结构经质谱及核磁共振氢谱确认。体外初步活性试验表明,目标化合物均具有HDAC1酶抑制活性及抗肿瘤细胞增殖活性。与MS-275相比,目标化合物对HDAC1酶抑制活性减弱,但化合物体外对人结肠癌细胞HCT-116的抗增殖活性却优于或相当于MS-275,其中化合物7g对HCT-116抑制作用的IC50值为0.245μmol·L-1,具有进一步研究价值。

To better understand the structure-activity relationships （SAR） and discover novel HDACs inhibitors with high potency and good safety profiles, herein a series of benzamide-based HDACs inhibitors possessing 4-piperazin-quinazolineyl residues were synthesized and evaluated. The target compounds were synthesized by chlorination, amination, hydrolysis and condensation. The final compounds were characterized by 1H-NMR and mass spectroscopy. All the newly synthesized compounds were evaluated for their ability to in- hibit recombinant human HDAC1. In general, most of these compounds showed lower potency than MS-275. However,4-piperazin-quinazolineyl-containing benzamides derivatives had the significant potency on cell proliferation against HCT-116 cells with the low ICs0 values, ranging from 0. 254 μmol .L^-1 （Tg） to 2. 643 μmol.L^-1 （7a）. Among them, compound 7g exhibited good antiproliferative activity against HCT- 116 cells, which was selected for further evaluation.