Development of <em>Ortho</em>-Substituted Aromatic (Thio)ureas and Derived Heterocycles as Modulators of P-Glycoprotein and Multidrug Resistance-Associated Protein 1

Abstract

In this work, different series of <i>ortho</i>-substituted aromatic (thio)ureas and derived heterocycles were synthesized for various biological investigations. The studies included the establishment of new synthetic routes and the analytical characterization of the target compounds.<br /> A panel of 2-alkylsulfanyl-substituted 4-aminothieno[2,3-<i>d</i>]pyrimidines and 4-aminoquinazolines was devised as modulators of the ABC transporter P-glycoprotein. A bidirectional modulation of transport activity could be demonstrated by the combination of different cytostatics and selected compounds in cell viability measurements.<br /> In a second project, a cyclization reaction to 3-(<i>o</i>-cyanoaryl)thiazolidin-4-ones was examined in detail. Atropisomerism in the thiazolidin-4-ones was found to be influenced by the size of the <i>o</i>-cyanoaryl ring. This phenomenon was investigated by means of NMR measurements and X-ray crystallography and further supported by theoretical calculations.<br /> The development of new inhibitors of multidrug resistance-associated protein 1 was another main objective of the dissertation. Four series of aromatic benzoic and thiophenecarboxylic acids with a substituted urea or thiourea moiety at the neighboring position to the carboxyl group were provided. 2-Thioureidobenzo[<i>b</i>]thiophene-3-carboxylic acids were identified as particularly potent inhibitors of the efflux transporter.<br /> Different routes were explored to produce 2-substituted 3,1-benzothiazin-4-ones. In addition to the elucidation of interconversion pathways, biological activities of 3,1-benzothiazin-4-ones were evaluated on a panel of eight proteases and esterases.<br /> Another project focused on the structural characterization of three related salts derived from tetrafluorophthalic acid and isopropylamine. Among them, an anomalous salt with two dibasic acid molecules per cation was identified. Data from X-ray crystallography were employed to describe geometrical arrangements as well as hydrogen-bonding networks of the salts. The compounds were furthermore characterized by means of solution and solid-state NMR spectroscopy.