Hydroxamic Acids: Biological Properties and Potential Uses as Therapeutic Agents

Abstract

AbstractHydroxamic acids take their biological properties from the ability to chelate metal ions which are important for a variety of biological processes, as well as for the catalytic activity of a number of metalloenzymes. In particular, the preference for chelation of iron and zinc ions by hydroxamates led to derivatives endowed with high potential as therapeutic agents. As iron chelators, most hydroxamates and retro‐hydroxamates (zileuton, atreleuton) are potent 5‐lipoxygenase inhibitors, useful for treatment of inflammatory diseases, asthma, and cancer, others (deferoxamine) can be used for the molecular control of iron homeostasis during transfusional iron overload, and for the treatment of acute ischemic stroke, thalassemia, and sickle cell anemia. Metal ion complexation by hydroxamates furnished also highly active antibacterial agents, through inhibition of two metal‐containing enzymes (peptide deformylase with iron, and UDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) with zinc) crucial for bacterial growth and viability. The ability of hydroxamates to efficiently complex zinc ion makes them useful compounds for inhibiting matrix metalloproteinases (MMPs) and related enzymes (see for example prinomastat) responsible for cancer and arthritis diseases, and histone deacetylases (HDACs), a family of enzymes involved in gene silencing and loss of tumor suppressor functions (see for example vorinostat and romidepsin, recently approved by FDA for the treatment of cutaneous T‐cell lymphoma).