Wurtz, Nicholas R. (2002) Sequence specific alkylation of DNA by polyamide-chlorambucil conjugates. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:04262012-150437308
Small molecules that bind selectively to a DNA sequence in the human genome are potentially useful tools for molecular biology and human medicine. Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) are small molecules that bind DNA according to a set of "pairing rules" with affinities and specificities similar to many naturally occurring DNA binding proteins. Two alternate routes of synthesis of polyamides are presented that allowed improved synthesis of commonly used motifs as well as access to polyamides with truncated tails which increase the number of DNA sequences targetable by polyamides with high affinity. Py-Im polyamides may offer a general approach to chemical regulation of gene expression provided inhibition of DNA binding for a variety of transcription factor families can be achieved. Two successful strategies are shown for the inhibition of DNA binding by two such proteins, GCN4 and NF-κB. An alternate method of gene regulation would be inhibition of transcription during the elongation phase by site-specific alkylation in the coding region of genes. A new class of compounds is created by the attachment of a bis (dichloroethylamino)-benzene nonspecific DNA alkylator to polyamides, which alkylate DNA with high yield and specificity. The biological activity and cell permeability of one of these compounds in several systems is studied.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Degree Grantor:||California Institute of Technology|
|Division:||Chemistry and Chemical Engineering|
|Thesis Availability:||Restricted to Caltech community only|
|Defense Date:||27 November 2001|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Dan Anguka|
|Deposited On:||26 Apr 2012 22:40|
|Last Modified:||26 Dec 2012 04:42|
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