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, N-acetyl calicheamicin γ1I, 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 (ADC) 已成为有价值的靶向抗癌疗法，至少有 11 种疗法获得批准，并且超过 80 种疗法正在通过临床试验。烯二炔 DNA 损伤有效负载，以该抗肿瘤药物家族的旗舰产品N-乙酰基加利车霉素为代表γ 1我，拥有经过验证的成功记录。然而，它们对连接药物的开发和优化提出了重大的合成挑战。我们最近报道了安西拉霉素（烯二炔类化合物的另一种代表）的简化全合成，具有令人信服的合成可及性。在此，我们报告了具有多种可裂解和不可裂解接头的 uncialamycin ADC 的合成和评估。我们发现uncialamycin ADC具有很强的旁观者杀伤作用，并且在体外和体内具有高度选择性和细胞毒性。