Design, synthesis and biological evaluation of phenol-linked uncialamycin antibody-drug conjugates
Design, synthesis and biological evaluation of phenol-linked uncialamycin antibody-drug conjugates
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DOI：
10.1016/j.bmcl.2019.126782
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发表时间：
2020-01-01
影响因子：
2.7
通讯作者：
Gangwar, Sanjeev
中科院分区：
文献类型：
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作者：
Poudel, Yam B.;Rao, Chetana;Gangwar, Sanjeev
Uncialamine是烯二炔类天然产物中结构更简单、更新的成员之一。它对几种类型的细菌和癌细胞表现出高度有效的活性。这里描述了一种使用抗体-药物偶联(ADC)方法将这种细胞毒剂靶向递送到肿瘤的策略。ADC设计的核心是产生有效且化学稳定的信号霉素类似物，以及将可切割的蛋白酶连接物附着到新实现的酚类手柄上，以制备连接物有效载荷。介绍了接头-有效载荷与肿瘤靶向抗体的偶联、体外活性和体内评价。
Uncialamycin is one of the structurally simpler and newer members of enediyne family of natural products. It exhibits highly potent activity against several types of bacteria and cancer cells. Described herein is a strategy for the targeted delivery of this cytotoxic agent to tumors using an antibody-drug conjugate (ADC) approach. Central to the design of ADC were the generation of potent and chemically stable uncialamycin analogues and attachment of protease cleavable linkers to newly realized phenolic handles to prepare linker-payloads. Conjugation of the linker-payloads to tumor targeting antibody, in vitro activity and in vivo evaluation are presented.