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Type of Document	Dissertation
Author	Fechter, Eric James
Author's Email Address	fechter AT caltech.edu
URN	etd-06052005-164552
Persistent URL	http://resolver.caltech.edu/CaltechETD:etd-06052005-164552
Title	Design of sequence-specific DNA intercalators
Degree	PhD
Option	Chemistry
Advisory Committee	Advisor Name Title Douglas C. Rees Committee Chair Dennis A. Dougherty Committee Member Peter B. Dervan Committee Member Robert H. Grubbs Committee Member
Keywords	intercalation polyamide
Date of Defense	2005-05-31
Availability	restricted
Abstract Small molecules that bind specific DNA sequences may have powerful therapeutic applications by influencing the mechanisms of abnormal gene expression. Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) specifically bind the minor groove of DNA and have been shown to inhibit many protein-DNA complexes. However, some major groove-binding proteins can co-occupy the same DNA sequences as polyamides. Presented here are polyamide-intercalator conjugates that specifically bind target regions of DNA and deliver a non-specific intercalator to an adjacent site. The studies detail intercalative unwinding of specific DNA sequences to allosterically inhibit any protein:DNA complex. The evolution of sequence-specific polyamides to bisintercalate DNA and cause larger distortion of the helix is described. The success of hybrid molecules containing mixed DNA binding modes led to the development of a bis-polyamide-intercalator motif, modeled after the natural product actinomycin D, which is capable of specifically binding extended sequences of DNA. Also described is a polyamide-intercalator series which shows large fluorescence enhancement upon specific DNA binding and may be useful in detecting specific DNA sequences within living cells.
Files	Filename       Size       Approximate Download Time (Hours:Minutes:Seconds)     28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access  01Titlepage.pdf 62.94 Kb 00:00:17 00:00:08 00:00:07 00:00:03 < 00:00:01 02Intro.pdf 126.77 Kb 00:00:35 00:00:18 00:00:15 00:00:07 < 00:00:01 03Chapter1.pdf 2.46 Mb 00:11:23 00:05:51 00:05:07 00:02:33 00:00:13 04Chapter2.pdf 4.71 Mb 00:21:48 00:11:12 00:09:48 00:04:54 00:00:25 05Chapter3.pdf 2.00 Mb 00:09:14 00:04:45 00:04:09 00:02:04 00:00:10 06Chapter4.pdf 1.12 Mb 00:05:09 00:02:39 00:02:19 00:01:09 00:00:05 07Chapter5.pdf 2.03 Mb 00:09:22 00:04:49 00:04:13 00:02:06 00:00:10 Appendix.pdf 3.47 Mb 00:16:03 00:08:15 00:07:13 00:03:36 00:00:18 indicates that a file or directory is accessible from the campus network only and must not be distributed to non-campus persons.