BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005;
BioScience Research Collaborative, Department of Chemistry, Rice University, Houston, TX 77005.
Proc Natl Acad Sci U S A. 2021 Jun 22;118(25). doi: 10.1073/pnas.2107042118.
Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, -acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.
抗体药物偶联物（ADCs）已成为具有至少 11 种已批准疗法和超过 80 种正在进行临床试验的有价值的靶向抗癌治疗药物。以该家族抗肿瘤药物的旗舰药物 calicheamicin γ1I（式见正文）为代表的烯二炔 DNA 损伤有效载荷具有良好的成功记录。然而，它们在连接子药物的开发和优化方面提出了重大的合成挑战。我们最近报道了另一种烯二炔类化合物 uncialamycin 的简化全合成，该化合物具有很强的合成可及性。在这里，我们报告了具有各种可裂解和不可裂解连接子的 uncialamycin ADC 的合成和评价。我们发现 uncialamycin ADC 表现出强烈的旁观者杀伤效应，在体外和体内具有高度选择性和细胞毒性。
