Structural Basis of Noscapine Activation for Tubulin Binding

Noscapine is a natural
alkaloid that is used as an antitussive
medicine. However, it also acts as a weak anticancer agent in certain in vivo models through a mechanism that is largely unknown.
Here, we performed structural studies and show that the cytotoxic
agent 7A-O-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.