Syntheses of 3-(2-Nitrovinyl)-indoles, Benzo[<i>a</i>]carbazoles, Naphtho[2,1-<i>a</i>]carbazoles, and 1-Hydroxy-β-carbolines Lead to Identification of Antiproliferative Compounds Active under Hypoxia

Herein, we describe a novel reaction between C-2-substituted indoles and 2-nitroacetophenones leading to a variety of indole-containing heterocyclic scaffolds. At 60 °C in AcOH with H₂SO₄ as catalyst, C-2 aryl indoles give 3-(2-nitrovinyl)-indoles with high <i>Z</i> or <i>E</i> geometric selectivity depending on the type of substrate utilized. These compounds undergo an electrocyclization process in a sealed vial in a microwave apparatus in DMF at 250 °C to give benzo[<i>a</i>]carbazoles and naphtho[2,1-<i>a</i>]carbazoles depending on whether the C-2 aromatic moiety is phenyl or naphthyl. Utilization of 2-methylindoles in the reaction with 2-nitroacetophenones and performing the reaction in a sealed vial in a microwave apparatus in AcOH at 200 °C leads to 1-hydroxy-β-carbolines. Selected compounds from each scaffold were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions, and three compounds belonging to the 3-(2-nitrovinyl)-indole and 1-hydroxy-β-carboline series were identified to have single-digit micromolar IC₅₀ values.