Cleavage of DNA by Polamide-Seco-CB1 Conjugates

Author: Chang, Aileen Yulin

Year: 2001

Degree: Dissertation (Ph.D.)

Advisor: Hoffmann, Michael R.

Committee Members: Goddard, William A., III; Dervan, Peter B.; Rees, Douglas C.; Tirrell, David A.; Hoffmann, Michael R.

Option: Chemistry

DOI: 10.7907/FY0F-DW57

Abstract

Small molecules that bind to any predetermined DNA sequence in the human genome are potentially useful tools for molecular biology and human medicine. Polyamides containing N-methylimidazole (Im) N-methylpyrrole (Py) are cell permeable small molecules that bind DNA according to a set of "pairing rules" with affinities and specificities similar to many naturally occurring DNA binding proteins. Py-Im polyamides offer a general approach to the chemical regulation of gene expression. We demonstrate here that polyamide containing a DNA alkylating moiety seco-CBI can specifically direct sequence specific DNA alkylation. We can also control the strand of DNA that is alkylated, depending on the enantiomer of seco-CBI used and the orientation of the polyamide relative to the alkylation site (Chapter 2). This class of molecules has been applied to a gene repair system in collaboration with the Baltimore group at Caltech (Chapter 3). Also reported are additional seco-CBI polyamide conjugates synthesized to study other systems (HIV-1 and COX-2) (Appendix 1).

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