Chemical Derivatization Leads to the Discovery Of Novel Analogs of Azotochelin, a Natural Siderophore, as Promising Anticancer Agents

Abstract

Siderophores are structurally unique medicinal natural products and exhibit considerable therapeutic potential. Herein, we report the design and synthesis of azotochelin, a natural siderophore, and an extensive library of azotochelin analogs as a potential anticancer agent. We modified the carboxylic acid and the aromatic ring motifs of azotochelin using various chemical motifs. We tested the compounds against six different cancer cell lines (KB‐3‐1, SNB‐19, MCF‐7, K‐562, SW‐620, and NCI‐H460) and a non‐cancerous cell line (HEK‐293) to assess the cytotoxicity. Among the twenty compounds tested, the IC50 values of eight compounds (14, 32, 35‐40, and 54) were between 0.7 to 2.0 μM against a lung cancer cell line (NCI‐H460). Moreover, several compounds had a good cytotoxicity profile (IC50 < 10 μM) against many tested cancer cell lines. The flow cytometry analysis showed that compounds 36 and 38 induce apoptosis in NCI‐H460 in a dose‐dependent manner. The cell cycle analysis indicated that compounds 36 and 38 significantly arrest the cell cycle at the S phase to block cancer cell proliferation in the NCI‐H460 cell line. The study has produced various novel azotochelin analogs that are potentially effective anticancer agents and leads for further synthetic and medicinal chemistry exploration.