Design, Synthesis, and Evaluation of in Vitro and in Vivo Anticancer Activity of 4‑Substituted Coumarins: A Novel Class of Potent Tubulin Polymerization Inhibitors

In
this paper, a series of novel 4-substituted coumarin derivatives
were synthesized. Among these compounds 34, 39, 40, 43, 62, 65, and 67 exhibited significant antiproliferative activity
toward a panel of tumor cell lines at subnanomolar IC50 values. Compound 65 showed potent antiproliferative
ability (IC50 values of 7–47 nM) and retained full
activity in multidrug resistant cancer cells. Compound 65 caused G2/M phase arrest and interacted with the colchicine-binding
site in tubulin, as confirmed by immune-fluorescence staining, microtubule
dynamics assays, and competition assays with N,N′-ethylene-bis­(iodoacetamide). Compound 65 reduced the cell migration and disrupted capillary-like tube formation
in HUVEC cells. Importantly, compound 65 significantly
and dose-dependently reduced tumor growth in four xenografts models
including paclitaxel sensitive and resistant ovarian tumors (A2780s
and A2780/T), adrmicycin sensitive and resistant breast tumors (MCF-7
and MCF-7/ADR), suggesting that compound 65 is a promising
novel antimitotic compound for the potential treatment of cancer.