The design, synthesis and biological effects of novel steroid prodrugs for treatment of gastrointestinal diseases

Abstract

The aim of the work described in this thesis was to synthesize and test the biological effects of a novel type of prodrug to deliver steroids to the colon for the treatment of gastrointestinal diseases. Glucocorticoids are used as anti-inflammatory agents in the treatment of inflammatory bowel disease. Unfortunately they undergo absorption from the GIT before reaching the colon and, as a consequence, a high number of systemic side effects are caused in patients. The prodrugs reported here are completely novel and are designed to reach the colon and exploit azoreductase and nitroreductase activity of colonic microflora to release the steroid there. Prednisolone and hydrocortisone have hydroxyl groups at positions 11, 17 and 21. Due to the different reactivity of these hydroxyl groups position 21 is favoured to undergo an esterification/lactamization. The proposed compounds have an azo group which is designed to undergo reduction in the colon liberating an anilide poised to undergo cyclization at an adjacent ester releasing the steroid. Chapter 2 describes synthetic studies directed towards candidate compounds and models for kinetic studies. Chapter 3 describes in vitro kinetic studies on the feasibility of the prodrugs and proof of concept studies in a clinically relevant model of colitis.