Synthesis and bioactivation of redox-activated quinone prodrugs of guanidine

• Main Author: Martin, Claire Marie
• Published: Bangor University 2012
• Subjects: 615.3
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568210

This thesis describes the preparation of several novel guanidine derivatives (where X= tetrarnethyl, dipiperidine and dimorpholine); three containing a previously described trimethyl-substituted quinone I and three analogous guanidines containing the novel phenyl-substituted quinone H. These conformationally locked derivatives were tested as substrates in a benzoquinone-based drug delivery system which is activated by the enzyme human quinone-oxidoreductase I (hNQOI). Molecular modelling studies were initially performed and demonstrated that all six derivatives were viable substrates of the enzyme hNQOI, as determined by the drug/hNQOI i~teractions. Following their successful preparation, these derivatives were subsequently analysed by high performance liquid chromatography (HPLC). Preliminary findings confirmed their ability to act as substrates for the enzyme hNQOI and showed they followed the intended mechanistic pathway for this drug delivery system. These results also indicated that the rate of reaction with hNQOI was faster for quinone I versus H and the reaction of H did not proceed to completion.