靶向CaMKIIγ:cMyc轴用于淋巴瘤治疗的贝萨维宁和小檗胺衍生物的半合成
Semisynthesis of bersavine and berbamine derivatives that target the CaMKIIγ:cMyc axis for lymphoma therapy.
作者信息
Lujan Berkley, Zhang Mingfeng, Cao Yujie, Kacker Arnav, Mai Lina, Wu Shunquan, Alexander Taylor, Huang Wendong, Kou Kevin G M
机构信息
Department of Chemistry, University of California, Riverside, California 92507, USA.
Department of Diabetes Complications & Metabolism Research, City of Hope National Medical Center, Duarte, California 91010, USA.
出版信息
Org Biomol Chem. 2025 May 7;23(18):4403-4408. doi: 10.1039/d5ob00310e.
Berbamine, a bisbenzylisoquinoline alkaloid (bisBIA), is a promising lead for developing novel therapeutics to treat aggressive cancers such as lymphoma, by targeting the CaMKIIγ:cMyc axis. Herein, we report an aza-Friedel-Crafts method for -aminoalkylation of berbamine's phenolic motif, enabling the semisynthesis of the natural product bersavine and analogs that complement current methods focusing on modifying the phenolic oxygen. Several new analogs synthesized by this method exhibit potent cytotoxicity against lymphoma-associated cell line H9 exceeding the naturally occurring berbamine (1) and bersavine (3a). A molecular docking analysis was used to devise a model that rationalizes the structure-activity relationship between the novel bisBIA analogs and CaMKIIγ inhibition.
小檗胺是一种双苄基异喹啉生物碱（bisBIA），通过靶向CaMKIIγ:cMyc轴，它是开发治疗侵袭性癌症（如淋巴瘤）新型疗法的一种有前景的先导化合物。在此，我们报道了一种用于小檗胺酚基序的氮杂傅克法 - 氨基烷基化反应，该方法能够半合成天然产物小檗红碱及其类似物，补充了目前侧重于修饰酚氧的方法。通过该方法合成的几种新类似物对淋巴瘤相关细胞系H9表现出强效细胞毒性，超过了天然存在的小檗胺（1）和小檗红碱（3a）。分子对接分析被用于设计一个模型，该模型能够合理说明新型bisBIA类似物与CaMKIIγ抑制之间的构效关系。
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