Synthesis and Antihemolytic Activity of Disulfates of Bisphenols and Some Carboxylic Acids

Abstract

Activation of the complement system plays a key role in the fight against bacterial infections and in the inflammation process, but it can lead to the loss of intrinsic cells and tissues (e.g., graft rejection, necrosis of heart tissues upon infarction, meningitis-induced brain tissue lesion, diabetic angiopathy, and autoimmune affection of tissues involved in some other disorders) [1, 2]. Although the cytolytic properties of serum were described more than a century ago [3], the pharmaceutical market still cannot offer at least a single drug inhibiting complement [4]. In this context, the search for simple and inexpensive inhibitors of the complement system is a promising direction of research. In the course of our investigation, it was established that substances whose molecules contain anion centers are capable of inhibiting the classical pathway of complement inhibition [5]. An analysis of the antihemolytic properties of a large number of polymers and low-molecular-mass compounds allowed us to formulate structural criteria of a high activity of this type. In particular, a comparative analysis of compounds containing various anion groups (carboxy, phosphate, sulfate) showed that the maximum antihemolytic activity is inherent in sulfates and sulfonic acids. In order to create effective inhibitors of the complement system, it is important to study the role of a molecular fragment occurring between the charged groups so as to determine whether this fragment has to be rigid or flexible, which substituents are necessary, should it be hydrophobic, and what is the optimum distance between the charged groups. Convenient objects for such investigations are bisphenols modified by sulfate groups (I – XII) and dicarboxylic acids with analogous structures (XIV – XXIV). Compounds I – XII were obtained via reactions of the corresponding alcohols with sulfuric acid and acetic anhydride in pyridine. The original method used for the sulfation of alcohols by the SO3 – pyridine complex [6] had some disadvantages leading to low conversion of the initial compound, the presence of a considerable admixture of monosulfate, and difficulties in purification of the target product related to the presence of impurities (probably, polymers) possessing low chromatographic mobility. Apparently, the course of the reaction depends on the quality of involved complexes. However, the salt-like character and the resulting low volatility and poor solubility in all conventional solvents make purification of these complex a very difficult task. The use of chlorosulfonic acid as a sulfating agent led to the complete conversion of the initial alcohol into a disulfate, but the formation of a large amount of polymeric chains still hindered isolation of the target product. A new method developed in this study allows the sulfates of various alcohols to be obtained with better yields using simple and readily available reactants. It was established that effective sulfation of bisphenol A (Ia) can be conducted in a sixfold excess of sulfuric acid and acetic anhydride in pyridine (Scheme 1).