López-López Edgar, Medina-Franco José L, Salinas-Arellano Eric, Ardila-Fierro Karen J, Pardo-Novoa Julio C, Del Río Rosa E, Cerda-García-Rojas Carlos M
Departamento de Química y Programa de Posgrado en Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
DIFACQUIM Research Group, Department of Pharmacy, School of Chemistry, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Chem Biol Drug Des. 2025 Sep;106(3):e70165. doi: 10.1111/cbdd.70165.
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.
微管蛋白 - 微管系统抑制剂是治疗各类癌症的有效策略的一部分，对其研究使科学家能够发现并开发新的、更具选择性的分子。卡卡罗尔（1）是一种具有抗癌活性且在乳腺细胞中具有明确选择性的天然产物，但与之相关的分子机制尚未阐明。这项工作的主要目的是提供证据，以帮助解释卡卡罗尔（1）对癌细胞系所报道的抑制和选择性活性，并拓展对其作用机制的认识。使用反应性方法、微管蛋白聚合测定、质谱和分子建模技术研究了卡卡罗尔衍生物，以解码抑制性结合机制。这项工作表明，在高氧化条件下会生成卡卡罗尔的一种氧化形式——亚甲基环己二烯酮2，从而模拟癌细胞中的环境。该物质（2）通过促进与α - 微管蛋白中Cys347的不可逆结合相互作用来抑制微管蛋白聚合。
