Phosphate bioisosters : Synthetic access and physicochemical properties

Abstract

Bioisosterism describes groups or molecules, having the chemical and physical similarities, while producing broadly similar biological properties. In lead optimization, the final step of drug discovery, bioisosteric replacements are key. Thereby the exchange of an atom or a group of atoms with an alternative broadly similar atom or group of atoms can comprise property enhancements, such as fewer side effects, decreased toxicity, increased metabolic stability, simplified synthesis and improved selectivity and pharmacokinetics.The phosphate moiety is vital in numerous biological processes and in many enzymes the phosphate group is crucial for triggering the enzyme’s activity. Consequently, proteins that identify phosphate groups have become an important target in drug development.In this thesis we focused on phosphate bioisosters, wheras phosphates display the most challenging functionalities to mimic in therapeutic development, due to high polarity and the charged nature of phosphates at physiological pH. Thereby, we designed a compound library of 42 potential phosphate bioisosters including 16 different functionalities, linked to simple general scaffolds. We enabled the synthesis of 26 library compounds and analyzed all library compounds, regarding their physicochemical properties. Besides the experimental determination of logP, pKa and permeability, in silico predictions of the mentioned properties as well as charge distribution and polar surface area have been done. The purpose was not only to analyze the library compounds in regard of mimicking the phosphate moiety but also to study if understandable trends between physicochemical properties evolve. Additionally, we compared experimental with calculated data in order to evaluate how reliable the applied computational methods are.