Design, synthesis and antiproliferative activity of a novel class of indole-2-carboxylate derivatives

• Compounds with indole scaffold were designed based on the structure of PQQ.
• A series of novel indole-2-carboxylate derivatives was synthesized and characterized.
• 6e and 9l showed potent anticancer activity at low micromolar concentration.
• 6e and 9l dose-dependently induced ROS generation in A549 cells.
• 6e and 9l dose-dependently arrested A549 cells at G1 and G2/M phase, respectively.

Based on the chemical structure of Pyrroloquinoline quinone (PQQ), a novel class of indole-2-carboxylate derivatives was designed, synthesized and assayed for antiproliferative activity in cancer cells in vitro. The biological results showed that some derivatives exhibited significant antiproliferative activity against HepG2, A549 and MCF7 cells. Notably, the novel compounds, methyl 6-amino-4-cyclohexylmethoxy-1H-indole-2-carboxylate (6e) and methyl 4-isopropoxy-6-methoxy-1H-indole-2-carboxylate (9l) exhibited more potent antiproliferative activity than the reference drugs PQQ and etoposide in vitro, with IC50 values ranging from 3.78 ± 0.58 to 24.08 ± 1.76 μM. Further biological assay showed that both compounds 6e and 9l increased ROS generation dose-dependently, and induced PARP cleavage in A549 cells. Consequently, 6e and 9l appeared as promising anticancer lead compounds for further optimization.

Compounds 6e and 9l were identified as potent antiproliferative agents inducing ROS generation.Figure optionsDownload as PowerPoint slide