Pustilnik, Michael Morris (1995) The construction and application of metal complexes for DNA strand scission. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-10182007-103625
NOTE: Text or symbols not renderable in plain ASCII are indicated by [...]. Abstract is included in .pdf document.
Substitutionally inert transition metal complexes have been constructed which bind to DNA and deliver additional labile metal ions to promote cleavage of the phosphodiester backbone. Both oxidative and hydrolytic DNA cleavage have been explored through the use of different chelates and reactive metal ions.
To explore oxidative chemistry, two complexes, [...] and [...], have been synthesized by tethering two bis(2-picolyl)amine or bis(2-ethylpyridyl)amine chelates to the [...] moiety. Both complexes promote site-selective oxidative DNA cleavage in the presence of CuSO4 and a thiol, with the site-selectivity being governed by the [...] core. Copper-ligand binding affinity, complex-DNA binding mode, and the [...]/[...] redox potential all appear to sensitively influence the cleavage efficiency. Product analysis of the DNA cleavage reaction is consistent with hydrogen abstraction from C1', C3', and C4' of the deoxyribose ring. The [...] core therefore serves as a vehicle to deliver oxidative reactions to DNA. These complexes may be valuable for the design of drugs that cleave DNA in vivo.
The complexes [...], [...], [...], and [...] have also been prepared so as to explore the delivery of secondary metal ions and functionalities to promote DNA hydrolysis. The complexes each have two tethered bis(2-picolyl)amine chelating groups; the latter three complexes also have two 2-dimethylaminoethyl or 3-dimethylaminopropyl groups designed for general acid assistance. DNA hydrolysis has not been established, but [...] promotes efficient DNA cleavage in the presence of [...]. Product analysis of DNA oligonucleotide cleavage by [...] is consistent with a [...] mediated reaction which is remarkably enhanced compared to those of ruthenium complexes lacking the tethered chelates; this reactivity may indicate that [...] promotes abasic site cleavage. [...], which does not sensitize [...] formation, promotes still more efficient DNA cleavage. The mechanism is yet to be established.
|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:||25 July 1994|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Imported from ETD-db|
|Deposited On:||02 Nov 2007|
|Last Modified:||26 Dec 2012 03:06|
- Final Version
Restricted to Caltech community only
See Usage Policy.
Repository Staff Only: item control page