Selective therapy with minor groove binders

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2011
Thesis identifier
  • T12741
Qualification Level
Qualification Name
Department, School or Faculty
  • Over the past five years, the University of Strathclyde has developed extremely potent anti-bacterial molecules known as minor groove binding agents (MGB) which intrinsic helicity allows binding to the minor groove of DNA. These molecules were effective in vivo, non-toxic and showed activity and selectivity against Gram positive bacteria. Whilst such selectivity is an advantage, an extension of activity of such agents towards Gram negative organisms and eventually targeting cancer cells would be valuable. Since the biological properties of such minor groove bonders are related to the chemical feature, this aim could be achieved by modifying the structure of the tail group only. The MPhil project involved the synthesis of a small number of selected minor groove binders differing in their tail groups (Boc protected, OAc protected, guanidine, cyano alkene, nitro alkene) but bearing the same fluorescent head group ((E)-4-(3-methoxystyryl)benzyl). The yield of the coupling reaction between the head group and the pyrrole-pyrrole core linked with a protected tail group (Boc or OAc) was improved up to two- to five- fold, using propane phosphonic acid anhydride as a mild reagent. These MGBs were then evaluated for anti-bacterial and anti-cancer drug activity in screens available at the Strathclyde Institute of Pharmaceutical and Biological Sciences (SIPBS). They were tested against Gram negative E. coli, against Gram positive Staph. aureus and against the fibroblast hamster cell line V79, in order to evaluate respectively their anti-bacterial activity and their toxicity. The penetration of these synthesized molecules into bacteria and cells was observed under microscopy in order to assess the structural features that could lead to a potential anti-bacterial and/or anti-cancer molecule if nuclear permeation occurs. Almost all MGBs tested permeate into Gram positive bacteria, but not all of them showed an anti-bacterial activity. These results were consistent with earlier experiments. However permeation in Gram negative bacteria was observed for the first time in these kind of MGB, but only one molecule appeared to be toxic towards this family of Gram negative bacteria above 20μg/mL. Furthermore, tested MGBs showed permeation into V79 mammalian cells with or without reaching the nucleus, and only one molecule developed significant toxicity towards the V79 cell line, thus giving an idea of which molecule could potentially bind to DNA and become a potential anti-cancer drug.
Resource Type
Date Created
  • 2011
Former identifier
  • 820797