Centro de Investigaciones Biológicas Margarita Salas-CSIC, Ramiro de Maeztu, 9, C.P. 28040 Madrid, Spain.
Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland.
J Med Chem. 2020 Aug 13;63(15):8495-8501. doi: 10.1021/acs.jmedchem.0c00855. Epub 2020 Jul 29.
Noscapine is a natural alkaloid that is used as an antitussive medicine. However, it also acts as a weak anticancer agent in certain models through a mechanism that is largely unknown. Here, we performed structural studies and show that the cytotoxic agent 7A--demethoxy-amino-noscapine (7A-aminonoscapine) binds to the colchicine site of tubulin. We suggest that the 7A-methoxy group of noscapine prevents binding to tubulin due to a steric clash of the compound with the T5-loop of α-tubulin. We further propose that the anticancer activity of noscapine arises from a bioactive metabolite that binds to the colchicine site of tubulin to induce mitotic arrest through a microtubule cytoskeleton-based mechanism.
那可丁是一种天然生物碱，用作镇咳药。然而，在某些模型中，它也作为一种弱抗癌剂发挥作用，其机制在很大程度上尚不清楚。在这里，我们进行了结构研究，表明细胞毒性剂 7A--去甲氧基-氨基那可丁（7A-氨基那可丁）与微管蛋白的秋水仙碱结合位点结合。我们认为那可丁的 7A-甲氧基基团由于化合物与 α-微管蛋白的 T5-环的空间位阻而阻止与微管蛋白结合。我们进一步提出，那可丁的抗癌活性来自于一种生物活性代谢物，该代谢物与微管蛋白的秋水仙碱结合位点结合，通过基于微管细胞骨架的机制诱导有丝分裂停滞。
