Discovery of furan-trimethoxyphenyl hybrids as novel colchicine-binding site inhibitors that induce mitotic catastrophe with potent anti-acute myeloid leukemia effect.

Acute myelocytic leukemia (AML) is a common leukemia subtype in adults, necessitating novel, potent treatments. Microtubule-targeting agents (MTAs) are key anti-cancer drugs widely used in clinical practice. A series of novel furan-trimethoxyphenyl hybrids as tubulin polymerization inhibitors were designed using a molecular combination strategy and evaluated for their structure-activity relationships (SARs) in AML. SAR studies demonstrated that the trimethoxyphenyl unit and substituents on benzyl units play significant roles for the antiproliferative activity against human AML cells. Compound III-3 exerted the highest antiproliferative effects on human AML MV-4-11 (IC50 = 74.25 nM), HL-60 (IC50 = 87.99 nM), and THP-1 cells (IC50 = 92.20 nM). Compound III-3 could directly bind to β-tubulin at the colchicine-binding site, thereby disrupting the microtubule network structure. Compound III-3 activated the spindle assembly checkpoint (SAC), promoting M-phase arrest and mitotic catastrophe and activating the mitochondrial apoptotic pathway in AML cells. In the xenograft mouse model constructed with MV-4-11 cells, the tumor-inhibitory rate of compound III-3 (20 mg/kg body weight, 71.40%) was higher than that of the positive control Ara-C (50 mg/kg body weight, 58.41%). Thus, furan-trimethoxyphenyl hybrids are a promising class of tubulin inhibitors with potential therapeutic applications in AML.