含过氧桥组蛋白去乙酰化酶抑制剂的合成及抗肿瘤细胞增殖活性研究

Synthesis and antiproliferative activity of endoperoxide conjugates as histone deacetylase inhibitors

目的设计合成含过氧桥的组蛋白去乙酰化酶(HDAC)抑制剂,并考察化合物的抗肿瘤细胞增殖活性。方法以含过氧桥的胺类化合物或醇类化合物为起始原料,经缩合、水解、缩合、脱保护等4步反应合成目标化合物,同时合成了对应的非过氧桥类似物。采用MTT法测试化合物对肿瘤细胞及正常细胞的IC50值,探讨过氧桥、不同连接键方式、碳链的长度对化合物活性的影响。结果与结论合成了15个未见文献报道的全新化合物,化合物结构经氢谱、碳谱以及高分辨质谱确证;体外抗肿瘤细胞增殖活性评价表明,羟肟酸部分是活性必需基团,碳链缩短会导致活性降低,过氧桥结构对化合物的抗肿瘤细胞增殖活性影响较大,过氧桥取代基的位阻增大有利于提高化合物的活性,化合物对肿瘤细胞的选择性优于正常细胞。

Abnormal epigenetic control is a commonly observed phenomenon at the early stages of tumor progression. Transcription balance disruption was often induced by HDAC overexpression, making HDAC a promising target for cancer treatment. It was demonstrated that HDAC inhibitors, such as SAHA, could sti- mulate ROS generation;Co-incubation of SAHA with anti-oxidants reduced its anticancer activity. More- over,the endoperoxide pharmacophore within RKA182 was reported to be able to release reactive oxygen species（ ROS）, and that was reported to enhance HDAC inhibitor potency. In this research, conjugates bea- ring the endoperoxide pharmacophore and the hydroxamic acid were designed with the hope of discovering more potent HDAC inhibitors. The target compounds were synthesized through the coupling of suberic acid monomethyl ester with endoperoxide amino derivatives,hydrolysis of the methyl ester bond, coupling of in- termediate O-（tetrahydro-2H-pyran-2-yl） hydroxylamine, and the deprotection process. Modifications of the chain length, cap group, connecting unit and replacement of the endoperoxide pharmacophore with the non- peroxide rings were made to investigate their contribution to the activity. Fifteen new compounds were pre- pared and characterized with 1H-NMR, 13 C-NMR and HRMS. The antiproliferative activity results showed that N＇- （ 3,3-adamantyl-1,2,4,5-tetraoxaspiro [ 5.5 1 undecan-9-yl ） -N8-hydroxyoctanediamide （ 4a ） exhibi- ted the most potent antiproliferation activities against A549, MDA-MB-231, HL60 and MCF-7 with IC50 values of 2.9 μmol·L^-1,1.9 μmol·L^-1,2.7 μmol·L^-1, 1.1μmol·L^-1 respectively, which was almost one fold better than SAHA. In addition ,4a had a three times selectivity between MCF-7 and human normal hepa- tocellular cell HL7702. The endoperoxide pharmacophore and hydroxamic acid moiety were all essential to the antitumor activity. This work offered new strategies to discover potent HDAC inhibitors.