Synthesis and Characterization of Griseofulvin Derivatives as Microtubule-Stabilizing Agents

摘要

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 GI(50) values <10 mu M (5.74 to 9.7 mu M) in breast cancer cell line CAL-51. The most promising compound ((2S,6'R)-4'-(benzhydrylamino)-7-chloro-4,6-dimethoxy-6'-methyl-3H-spirobenzofuran-2,1'-cyclohexan-3'-ene-2',3-dione), was characterized as a microtubule-stabilizing agent with a GI(50) value of 5.74 +/- 1.43 mu M compared to 10.79 +/- 3.06 mu M GI(50) for parental griseofulvin. It also inhibited the proliferation of other cancer cell lines, including KB-3-1 and HCT116, with GI(50) values of 1.19 +/- 0.34 mu M and 2.48 +/- 0.40 mu M, 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.