Synthesis and evaluation of tetrahydropyrrolo[1,2-a]quinolin-1(2H)-ones as new tubulin polymerization inhibitors

Dynamic polymers of tubulin, known as microtubules, are among the most important targets for anti-cancer chemo-therapy. Although several inhibitors of tubulin polymerization are clinically successful, the resistance of cancers to existing drugs urges for the development of novel tubulin-binding substances that can inhibit microtubule dynamics. Here we explored new 1,5-disubstituted pyrrolidin-2-ones 1, 2 and 5-aryl-3,3a,4,5-tetrahydropyrrolo[1,2-a]quinoline-1(2H)-ones 3 as potential binders of the colchicine site of tubulin. We evaluated their effects on microtubules dynamics in vitro and on the proliferation of cultured cancer cell lines. Guided by molecular modeling of the interactions between tubulin and the most active of identified compounds, we designed, synthesized, and tested the 3-hydroxyphenyl-substituted compound 3c, which decreased microtubule growth rate in vitro and arrested cancer cells division in the low micromolar range (IC50 = 6.6 μM). This finding demonstrates that 5-aryltetrahydropyrrolo[1,2-a]quinoline-1(2H)-one is a promising scaffold for the development of novel efficient tubulin polymerization inhibitors.