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Title: Structure and binding affinity in DNA minor groove binders
Author: Donoghue, Gavin
ISNI:       0000 0004 2699 3020
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2010
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Minor groove binders are small molecules that bind selectively to the minor groove of DNA. Many synthetic MGBs are analogues of the natural products netropsin and distamycin; these belong to the polyamide class of MGBs. These compounds consist of two and three methylpyrrole monomers linked by amides, with a head and tail group also linked by amides. They bind selectively to AT base pairs in DNA and have potential antiviral, antibiotic, and anti oncolytic properties, however they are also toxic. Much work has been carried out to create analogues of these compounds with similar or improved activity with reduced toxicity. Analogues of these compounds typically consist of a tail group linked to a sequence of heterocycles via amide bonds ending with a larger head group than formyl. This project is concerned with developing analogues of Distamycin and netropsin with increased lipophilicity. The aim is to synthesise molecules with improved ability to cross membranes thus improving bioavailability. This primarily involves the synthesis of MGBs with alternative linking groups to amide, namely alkene and diazo. Using linking groups with varying polarity will allow us to test the hypothesis that hydrophobic binding is a major driving force in DNA binding. Using diazo and alkene linkages also opens up interesting applications in terms of the potential colour and fluorescent nature of the resulting molecules. The second aim of this project is to purposely design a series of molecules that will allow us to explore the link between DNA binding and biological activity. Although it is known that certain groups such as branched alkyl chains produce good biological activity there is still a lot to be learned about how and indeed if these groups actually interact with DNA. The synthetic routes employed to make the various diazo and alkene analogues of existing compound are described. Also the discovery of several active lead compounds plus the synthesis of analogues of these leads designed to probe the effects of various linking groups and head group substituents on antibacterial activity and DNA binding are described. This was done by testing all compounds for biological activity and by investigating the DNA binding of selected compounds by physical methods. Various analytical techniques were employed to do this including NMR, thermal denaturation, ITC, capillary electrophoresis and DNA footprinting. A good correlation between antibacterial activity and DNA binding was found. In general it was found that compounds with amide, alkene and diazo bonds all bound to DNA to a certain extent however it would appear that overall alkene linkages produce better results both in terms of antibacterial activity and evidence of DNA binding.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral