Discovery of azaisoerianin derivatives as potential antitumors agents

• N-substituted-diarylanilines were synthesized as a novel class of isoCA-4 analogues.
• Compounds 2b and 2m displayed GI50 in a nanomolar range toward various cancer cells.
• 2b and 2m displayed substantial efficacy as potent antivascular agents.
• 2b and 2m showed a binding mode similar to those observed with isoCA-4.

A series of N-methyl-diarylamines 2 was designed and synthesized as a novel class of CA-4 and isoCA-4 analogues. Compounds 2b and 2m showed excellent antiproliferative activity with mean GI50 values at a nanomolar level in a diverse set of human cancer cells. These compounds also inhibited tubulin assembly at a micromolar range, arrested the cellular cycle in the G2/M phase and induced apoptosis at very low concentrations. Preliminary in vitro results revealed that 2b and 2m displayed substantial efficacy as potent antivascular agents. Docking studies indicates that these lead compounds showed a binding mode similar to those observed with isoCA-4 at the colchicine binding site of tubulin.

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