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针对DOT1L和HAT作为抗白血病剂的腺衍生物的设计,合成和生物评估

Bidyadhar Sethy¹, Zih-Yao Yu², Iin Narwanti³

¹School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.

Bioorganic chemistry

|September 19, 2024

概括

新的腺衍生物被合成为破坏端粒沉默1类 (DOT1L) 抑制剂的破坏者. 化合物15通过诱导DNA损伤和亡,表现出强烈的抗白血病活性,为急性髓性白血病 (AML) 治疗提供了潜力.

科学领域:

药用化学医学化学
癌症生物学癌症生物学
分子药理学分子药理学

背景情况:

端粒沉默1类破坏剂 (DOT1L) 是血液恶性瘤的验证治疗标,特别是急性髓性白血病 (AML).
由DOT1L调节的基因组甲基化,在癌症发展中起着关键作用.

研究的目的:

设计和合成新的腺衍生物作为DOT1L抑制剂.
评估这些化合物的抗白血病潜力和作用机制.

主要方法:

用皮佩里丁-4-甲基链接剂合成氨酸/胺醇支架.
在体外酶抑制试验测试以确定与DOT1L相比的IC50值.
细胞测试以评估H3K79me2的抑制,白血病细胞活力,基因素乙化,DNA损伤和亡.
对各种白血病细胞系进行查,包括MLL重新排列和非重新排列.

主要成果:

化合物8,12和13显示出强大的DOT1L酶抑制 (IC50:0.1250.408μM).
化合物12降低了细胞中的H3K79me2水平.
化合物15在多个细胞系中表现出显著的抗白血病活性 (IC50:0.451.66μM),尽管DOT1L抑制弱.
化合物15诱导了DNA损伤,基因素过化和亡,对正常的T淋巴细胞有有限的毒性.

结论:

针对DOT1L的新型腺衍生物成功合成和表征.
化合物15通过独立于直接DOT1L抑制的机制显示出有前途的抗白血病特性.
对AML治疗中的化合物15进行进一步的研究是有必要的.

关键词:

急性髓性白血病癌症癌症腺氨酸衍生品的衍生品这是一种DOT1L抑制剂.皮皮瑞丁-4-甲基基因图案

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