University of Chicago, Department of Chemistry, Chicago, Illinois 60637, USA.
J Am Chem Soc. 2010 Jun 2;132(21):7288-90. doi: 10.1021/ja101811x.
We describe structure-based design and chemical synthesis of a simplified analog of bistramide A, which potently and reversibly binds monomeric actin with a K(d) of 9.0 nM, depolymerizes filamentous actin in vitro and in A549 (nonsmall cell lung cancer) cells, inhibits growth of cancer cell lines in vitro at submicromolar concentrations, and significantly suppresses proliferation of A549 cells in a nude mice tumor xenograft model in terms of both tumor growth delay and average tumor volume. This study provides a conceptual framework for the design and development of new antiproliferative compounds that target cytoskeletal organization of cancer cells in vivo by a combination of reversible G-actin binding and effective F-actin severing.
我们描述了基于结构的设计和化学合成一种双硫仑 A 的简化类似物，该类似物能够强有力且可逆地与单体肌动蛋白结合，其 K(d)值为 9.0 nM，在体外和 A549（非小细胞肺癌）细胞中解聚丝状肌动蛋白，在亚微摩尔浓度下抑制体外癌细胞系的生长，并在裸鼠肿瘤异种移植模型中显著抑制 A549 细胞的增殖，无论是在肿瘤生长延迟还是平均肿瘤体积方面。本研究为设计和开发新的抗增殖化合物提供了一个概念框架，这些化合物通过与 G-肌动蛋白结合的可逆性和有效 F-肌动蛋白的切断，结合在一起，靶向体内癌细胞的细胞骨架组织。
