Biological Evaluation of 3‐Aryl‐4‐indolylfuranones as potential anti‐cancer agents

Abstract

The American Cancer Society estimates that this year there will be approximately 1.9 million new cases of cancer and nearly 610,000 cancer‐related deaths. The need for new and innovative anticancer drugs is increasingly crucial. One attractive anti‐cancer target is tubulin, which is involved in many cellular functions including cell shape, mitosis, migration, and movement of organelles. While anti‐tubulin drugs have been used to treat cancer for ~70 years, they tend to be complex molecules (derived from natural products), plus suffer from multi‐drug resistance, low solubility, toxicity issues, and/or the lack of multi‐cancer efficacy. These limitations highlight the continued need for the discovery and development of new and novel drugs to enter the pipeline, especially with the significant increase in understanding of tubulin and the mode of action of inhibitors. Using an interdisciplinary approach with undergraduate researchers, we previously developed a furanone‐containing small molecule, PY‐407‐C. The compound demonstrated strong (sub‐micromolar) anti‐proliferative activity in U937 cancer cells. It was submitted for NCI‐60 (National Cancer Institute) screening, which showed nanomolar activity against a variety of cell lines with tubulin as the potential target. We confirmed that it inhibited tubulin polymerization in vitro. We now report on a suite of compounds that are regioisomers of PY‐407‐C and with various moiety modifications. This work has identified new compounds with strong cytotoxicity and important structure‐function information. Overall, these studies provide basic research on small molecule inhibitors of cancer.