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.

中文翻译：

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蒽醌稠合烯二炔的 DNA 相互作用和裂解模式：天赐霉素、杨普霉素及其半合成类似物的研究

自 1989 年发现以来，动力霉素 A 一直是唯一被探索的原型蒽醌融合烯二炔 (AFE)。这项研究研究了新兴 AFE 的独特 DNA 结合和切割机制，以天赐霉素和杨普霉素以及半合成类似物为代表。我们的研究结果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 治疗可以显着抑制乳腺肿瘤生长，且毒性最小。最有效的 AFE 之一，即天西霉素 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，与动力霉素 A 相比，新兴的 AFE 可以更深地嵌入富含 AT 的 DNA 碱基对。重要的是，天西霉素 A 可以在插入模式和嵌入模式之间实现平衡，而无需脱嵌，从而能够选择性切割 T 和 A 碱基。这项研究强调了 AFE 之间细微的结构变化如何显着影响其 DNA 识别和切割，从而促进未来新型 AFE 的设计，作为抗体药物偶联物的有效和选择性有效负载。