Prodrugs of Butyric Acid from Bench to Bedside: Synthetic Design, Mechanisms of Action, and Clinical Applications

The research from 24 years ago focused on the synthesis, biological activities, and clinical applications of a novel family of butyric acid (BA) prodrugs. These prodrugs were designed to efficiently transport BA into cells, significantly increasing its potency. The prodrugs were studied for their anticancer activity, their ability to induce hemoglobin expression, and their potential to protect hair follicles from damage caused by cytotoxic agents. The most studied member of this family, AN-9, showed anticancer activity in vitro and in animal models and was in phase II clinical trial for non-small cell lung carcinoma patients. Another prodrug, AN-10, was shown to induce hemoglobin expression in erythroleukemic cell lines and fetal hemoglobin expression in sickle cell anemia and β-thalassemia progenitor blood cells. Importantly, AN-10 was also found to protect hair follicles, suggesting potential use for treatment of radio- and chemo-therapy induced alopecia.