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 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. [ABSTRACT FROM AUTHOR]

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