新型大环Bcl-2抑制剂的设计合成及生物活性评价
Evaluation of design,synthesis and biological activities novel macrocyclic Bcl-2 inhibitors
查永骏 1杨灿 2白海云 3钟利4
作者信息
- 1. 江西中医药大学药学院,南昌 330004;长三角药物高等研究院,江苏 南通 226100
- 2. 长三角药物高等研究院,江苏 南通 226100
- 3. 长三角药物高等研究院,江苏 南通 226100;百极弘烨(南通)医药科技有限公司,江苏 南通 226100
- 4. 江西中医药大学药学院,南昌 330004;长三角药物高等研究院,江苏 南通 226100;百极弘烨(南通)医药科技有限公司,江苏 南通 226100
- 折叠
摘要
目的 为克服Bcl-2的基因突变引起的耐药问题,设计并合成一系列新型Bcl-2抑制剂,并分别评价其对Bcl-2以及G101V、D103Y两种突变的抑制活性,探讨初步构效关系.方法 通过大环化设计,合成了一系列新型Bcl-2抑制剂,并通过 1H NMR和ESI-MS进行结构确证.采用时间分辨荧光共振能量转移技术(TR-FRET)和MTS法测定化合物对激酶和肿瘤细胞的抑制活性.结果 合成了1个阳性化合物和9个新型大环Bcl-2抑制剂.抑酶活性结果表明化合物28c、28d、28e、28f具有较强的抑制Bcl-2以及G101V、D103Y两种突变激酶的活性.结论 合成的新型大环Bcl-2抑制剂中部分化合物(28c、28e、28g和28i)对肿瘤细胞的增殖具有一定的抑制活性.
Abstract
Objective To solve the drug resistance problem caused by Bcl-2 mutations,to design and synthesize a series of novel Bcl-2 inhibitors,and evaluate their inhibitory activities against Bcl-2 and the two mutations of G101V and D103Y to determine the preliminary conformational relationship.Methods A series of novel Bcl-2 inhibitors were synthesized by macrocyclization design and structurally confirmed by 1H NMR and ESI-MS.The inhibitory activities of the compounds on kinases and tumor cells were determined with time-resolved fluorescence resonance energy transfer technique(TR-FRET)and MTS.Results One positive compound and nine novel macrocyclic Bcl-2 inhibitors were synthesized.Compounds 28c,28d,28e,and 28f possessed strong kinase inhibitory activity against Bcl-2,G101V and D103Y mutations.Conclusion Some compounds(28c,28e,28g and 28i)in the synthesized novel macrocyclic Bcl-2 inhibitors have certain inhibitory activities on the proliferation of tumor cells.
关键词
Bcl-2抑制剂/细胞凋亡/抗肿瘤/合成Key words
Bcl-2 inhibitor/apoptosis/antitumor/synthesis引用本文复制引用
出版年
2024
NETL
NSTL
万方数据