<br>用于 DNA 切割的可调节且可光激活的加利车霉素 γ1 模拟物,Journal of the American Chemical Society

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用于 DNA 切割的可调节且可光激活的加利车霉素 γ1 模拟物
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-09-09 , DOI: 10.1021/jacs.4c07754
Benjamin Ben-Zvi ₁ , Christina Lian ₁ , Maureen F Brusco ₁ , Tianning Diao ₁

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加利车霉素 γ ₁和相关天然产物因其 DNA 切割功效而闻名，可作为用于治疗白血病的商业 ADC 的弹头。它们的作用机制涉及芳基自由基的形成，芳基自由基从核酸中夺取氢原子。然而，加利车霉素 γ ₁复杂的应变烯二炔结构在合成中提出了重大挑战，导致生产成本高，并且用于调整治疗窗的结构和活性模块性有限。该报告描述了基于重氮盐的简单分子模拟物的开发，该模拟物的合成步骤少于 3 个步骤，能够在绿光或红光照射下产生芳基自由基。对 30 多种类似物进行的 SAR 研究揭示了 DNA 切割的多种效力，EC ₅₀值范围从低纳摩尔到微摩尔。形成苯环双自由基似乎并不是有效 DNA 切割所必需的；相反，当通过适当的键连接时，可以通过分布在不同芳烃之间的自由基来实现DNA切割。效力受到电子效应、立体化学、轨道方向、多自由基之间的距离以及分子内重氮基序数量的影响。除了提供一种更具成本效益、更高效和模块化的加利车霉素 γ ₁替代方案之外，该技术还提供了通过时空控制增强特异性的潜力。

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Tunable and Photoactivatable Mimics of Calicheamicin γ1 for DNA Cleavage

Calicheamicin γ₁ and related natural products are renowned for their potency in DNA cleavage, serving as the warheads in commercial ADCs used for treating leukemia. Their mechanism of action involves the formation of aryl radicals, which abstract hydrogen atoms from nucleic acids. However, the complex strained enediyne structure of calicheamicin γ₁ presents significant challenges in synthesis, resulting in high production costs and limited structural and activity modularity for tuning the therapeutic window. This report describes the development of simple molecular mimics based on diazonium salts, synthesized in fewer than 3 steps, capable of generating aryl radicals upon green or red light irradiation. SAR studies conducted on over 30 analogues reveal a wide range of potencies in DNA cleavage, with EC₅₀ values ranging from low nanomolar to micromolar. Forming benzenoid diradicals does not appear to be necessary for potent DNA cleavage; instead, DNA cleavage can be achieved with radicals distributed among different arenes when connected with proper linkages. The potency is influenced by electronic effects, stereochemistry, orbital orientations, the distance between multiradicals, and the number of diazonium motifs within the molecule. In addition to providing a more cost-effective, efficient, and modular alternative to calicheamicin γ₁, this technology offers the potential for enhanced specificity through spatiotemporal control.

更新日期：2024-09-09

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