A Covalent and Modulable Inhibitor of the Tubulin-Microtubule System: Insights Into the Mechanism of Cacalol

IF 3.3 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Edgar López-López, José L. Medina-Franco, Eric Salinas-Arellano, Karen J. Ardila-Fierro, Julio C. Pardo-Novoa, Rosa E. del Río, Carlos M. Cerda-García-Rojas
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Abstract

Inhibitors of the tubulin-microtubule system are part of an effective strategy to treat different kinds of cancer, whose research has allowed scientists to discover and develop new and more selective molecules. Cacalol (1) is a natural product with anti-cancer activity and documented selectivity in breast cells, but with an undescribed molecular mechanism associated with these properties. The main objective of this work is to provide evidence that helps to explain the inhibitory and selective activity reported for cacalol (1) against cancer cell lines and to expand the knowledge about the mechanism of action involved in it. Cacalol derivatives were studied using reactivity approaches, tubulin polymerization assays, mass spectrometry, and molecular modeling techniques to decode the inhibitory binding mechanism. This work demonstrates that an oxidated form of cacalol, the methylenecyclohexadienone 2, is generated in highly oxidant conditions, thus emulating the environment present in cancer cells. This species (2) is responsible for the inhibition of tubulin polymerization by promoting an irreversible binding interaction with the Cys347 in α-tubulin.

Abstract Image

微管-微管系统的共价可调节抑制剂:Cacalol的机制
微管蛋白-微管系统的抑制剂是治疗不同类型癌症的有效策略的一部分,其研究使科学家能够发现和开发新的更具选择性的分子。Cacalol(1)是一种具有抗癌活性的天然产物,在乳腺细胞中具有选择性,但与这些特性相关的分子机制尚未描述。这项工作的主要目的是提供证据,帮助解释cacalol(1)对癌细胞系的抑制和选择活性,并扩大对其作用机制的了解。利用反应性方法、微管蛋白聚合测定、质谱分析和分子建模技术研究了钙酚衍生物,以解码抑制结合机制。这项工作表明,在高度氧化的条件下会产生一种氧化形式的钙酚,即亚甲基环己二烯酮2,从而模拟癌细胞中存在的环境。该物种(2)通过促进与α-微管蛋白中的Cys347的不可逆结合相互作用来抑制微管蛋白聚合。
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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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