Synthesis and Characterization of Griseofulvin Derivatives as Microtubule-Stabilizing Agents

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-spiro[benzofuran-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.

Automated summary

Griseofulvin derivatives showed activity in breast cancer cells, with the most promising compound characterized as a microtubule-stabilizing agent and also inhibiting proliferation of other cancer cells.