Synthesis and Characterization of Griseofulvin Derivatives as Microtubule-Stabilizing Agents

Abstract

Microtubules have been an attractive target of cancer drug discovery due to their highly dynamic nature during mitosis. Griseofulvin, a natural antifungal compound, is known to interfere with microtubule dynamics. In the present study, we prepared and analyzed twenty-seven novel griseofulvin derivatives. Three of these compounds had GI50 values <10 μM (5.74 to 9.7 μM) in breast cancer cell line CAL-51. The most promising compound ((2S,6’R)-4’-(benzhydrylamino)-7-chloro-4,6-dimethoxy-6’-methyl-3H-spiro[benzofuran-2,1’-cyclohexan]-3’-ene-2’,3-dione), was characterized as a microtubule-stabilizing agent with a GI50 value of 5.74±1.43 μM compared to 10.79±3.06 μM GI50 for parental griseofulvin. It also inhibited the proliferation of other cancer cell lines, including KB-3-1 and HCT116, with GI50 values of 1.19±0.34 μM and 2.48±0.40 μM, respectively. Treatment of cancer cells with it resulted in aberrant mitosis causing G2/M arrest. Finally, we show that this compound increased the expression of p53 protein and induced apoptotic cell death.