Rearrangement of 5-Indolyl-3-pyrrolin-2-ones into Privileged 4-Indolyl-3-pyrrolin-2-ones Leads to Identification of Antiproliferative Compounds Active under Hypoxia

Abstract

Herein, we describe a synthetic route toward privileged 4-indolyl-3,5-diaryl-3-pyrrolin-2-ones based on a previously reported Friedel–Crafts reaction of 5-hydroxy-3,5-diaryl-3-pyrrolin-2-ones with indole. The intermediate 5-indolyl-3,5-diaryl-3-pyrrolin-2-ones are not isolated but further reacted under one-pot conditions, leading to the indole moiety migration from position C5 to position C4 of the 3-pyrrolin-2-one ring. The optimal reaction conditions found involved stirring with 2 equiv of aluminum chloride in 1,4-dioxane to complete the Friedel–Crafts step and then heating at 130 °C for 40 min in a microwave reactor to achieve the rearrangement step. Using the developed chemistry, a variety of compounds were prepared for biological testing, including those oxidized at C5 because 5-hydroxy-3-pyrrolin-2-ones have been reported to possess diverse biological properties as well. The synthesized compounds were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions at a single concentration of 10 μM, and a number of compounds belonging to each of the series were identified to have noteworthy antiproliferative action under both normoxia and hypoxia. Several compounds from each series were further tested against ovarian cancer cells, and compounds from each series were capable of reducing cell viability of chemotherapy-resistant OVCAR-5 cells by as much as 75–80% at a concentration of 5 μM.