CaltechTHESIS
  A Caltech Library Service

Sequence specific alkylation of DNA by polyamide-chlorambucil conjugates

Citation

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

Abstract

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.))
Subject Keywords:Chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Dervan, Peter B.
Thesis Committee:
  • Grubbs, Robert H.
  • Mayo, Stephen L.
  • MacMillan, David W. C.
Defense Date:27 November 2001
Record Number:CaltechTHESIS:04262012-150437308
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:04262012-150437308
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6982
Collection:CaltechTHESIS
Deposited By: Dan Anguka
Deposited On:26 Apr 2012 22:40
Last Modified:26 Dec 2012 04:42

Thesis Files

[img] PDF - Final Version
Restricted to Caltech community only
See Usage Policy.

7Mb

Repository Staff Only: item control page