Date of Award

7-18-2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Thomas L. Netzel - Chair

Second Advisor

Dabney W. Dixon - Co-Chair

Third Advisor

David Boykin

Fourth Advisor

Jerry Smith

Abstract

Anthraquinone (AQ) has been used in electron transfer studies in DNA. The focus of this dissertation is the synthesis of conjugates between AQ derivatives and 2’-deoxyadenosine (dA), which can be used to induce adenine oxidation in DNA. Different AQ derivatives were attached to dA via ethynyl or ethanyl linkers. If incorporated into DNA, these short linkers should enable regiocontrol for electron transfer from adenine within the DNA duplex structure. The challenge in working with anthraquinone-2’-deoxynucleosides conjugates is that they and their intermediates are insoluble in water and only sparingly soluble in most organic solvents. A strategy used to overcome this problem was the use of either tert-butyldiphenylsilyl (TBDPS) or 4’,4-dimethoxytrityl (DMTr) 5’-protected deoxynucleosides as starting materials. A water-soluble, ethynyl-linked AQ-dA conjugate with a 3’-benzyl hydrogen phosphate was synthesized using DMTr protection. The DMTr group was not stable to the hydrogenation required to make the ethanyl-linked AQ-dA conjugate with 3’-benzyl hydrogen phosphate. Hence the latter was synthesized starting with the TBDPS protecting group. Both of these syntheses were based on the Pd coupling between ethynylanthraquinone and 8-bromodeoxyadenosine derivatives. New conjugates between AQ and A, in which the AQ moieties have been modified with formyl, trifluoroacetyl and methyl ester groups as electron withdrawing substituents were also synthesized. The synthesis of these AQ-dA conjugates was based on Pd coupling between bromoanthraquinone and 8-ethynyldeoxyadenosine derivatives. This route avoided the use of ethynylanthraquinone derivatives that had extremely low solubility and photoinstability. Other anthraquinones with electron withdrawing groups (which should provide enhanced driving force to enable respective AQ derivative to oxidize adenine) were synthesized as models. Cyclic voltammetry showed that the conjugate with the two ester groups and ethynyl linker was the most easily reduced of the derivatives synthesized. Conjugates between AQ and dU were also synthesized. Those conjugates can potentially be used to oxidize guanine or adenine or they can be used as a deep trap for an electron in reduced DNA.

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