Abstract:
Dynemicin A has been the sole prototypical anthraquinone-fused enediyne (AFE) explored since its discovery in 1989. This study investigates the distinct DNA binding and cleavage mechanisms of emerging AFEs, represented by tiancimycins and yangpumicins, along with semisynthetic analogues. Our findings reveal their potent cytotoxicity against various tumor cell lines, while 18-methoxy tiancimycin A treatment could significantly suppress breast tumor growth with minimal toxicity. One of the most potent AFEs, i.e., tiancimycin A, preferentially targets DNA sequences 5\'-ATT, 5\'-CTT, 5\'-GAA, 5\'-GAT, and 5\'-TTA. Molecular dynamics simulations suggest that emerging AFEs intercalate deeper into AT-rich DNA base pairs compared to dynemicin A. Importantly, tiancimycin A may equilibrate between insertional and intercalative modes without deintercalation, enabling selective cleavage of T and A bases. This study underscores how subtle structural variations among AFEs significantly influence their DNA recognition and cleavage, facilitating future design of novel AFEs as potent and selective payloads for antibody-drug conjugates.
摘要:
自1989年发现以来,DynemicinA一直是唯一的典型蒽醌稠合炔(AFE)。本研究调查了新兴AFE的独特DNA结合和裂解机制,以天西霉素和杨普明为代表,以及半合成类似物。我们的发现揭示了它们对各种肿瘤细胞系的有效细胞毒性,而18-甲氧基天西霉素A治疗可显着抑制乳腺肿瘤生长,毒性最小。最有效的AFE之一,即,天辛霉素A,优先靶向DNA序列5'-ATT,5\'-CTT,5\'-GAA,5\'-GAT,和5'-TTA。分子动力学模拟表明,与dynemicinA相比,新兴的AFE更深地嵌入富含AT的DNA碱基对中。重要的是,tiancimycinA可以在插入和嵌入模式之间平衡,而不会脱出嵌入,能够选择性切割T和A碱基。这项研究强调了AFE之间微妙的结构变化如何显着影响其DNA识别和裂解,促进新型AFE作为抗体-药物缀合物的有效和选择性有效载荷的未来设计。