Advisor

Kevin Reynolds

Date of Award

Summer 7-24-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry

Department

Chemistry

Physical Description

1 online resource (x, 98 pages)

Subjects

DNA -- Research, DNA-protein interactions -- Chemical warfare, Cancer -- Treatment -- Research

DOI

10.15760/etd.2465

Abstract

Prodigiosins and tambjamines are natural compounds from bacterial and marine sources belonging to a family containing a common 4-methoxy-2,2'-bipyrrole core. These compounds have received a lot of interest due to their promising biological activities. Studies have suggested DNA as a potential therapeutic target for the natural prodigiosin and tambjamine due to their ability to facilitate oxidative DNA cleavage in the presence of Cu2+. Based on this we sought to study the metal binding activity of new prodigiosin and tambjamine analogues. A new prodigiosin analogue was synthesized and complexed with Cu2+. This revealed 1:1 complex formation between the tripyrrole and Cu2+ that was confirmed by mass spectra and NMR spectra analysis. In addition in situ studies also revealed that our new analogues of prodigiosin cannot bind Zn2+ when the methoxy group on ring B is replaced by an alkyl group or when one of the ring nitrogens is methylated.

Our UV-Vis experiments with calf thymus DNA showed that prodigiosins and tambjamines bind DNA mainly through an external mode, suggesting that hydrogen bonding between the pyrrole ring nitrogens and the bases of DNA takes precedence over stacking interactions. For the new Cu2+ complex synthesized however, we observed spectral changes that suggest intercalation into DNA.

DNA cleavage experiments revealed that the prodigiosin-Cu complex is able to convert supercoiled DNA into its linear form. The data from the gel shift assays fit well to a first-order consecutive reaction model. In addition to preformed metal complexes, we showed DNA cleavage by in situ complexation of the ligands in the presence of Cu2+. However, although we showed Zn2+ complex formation with prodigiosin analogues, in situ studies did not show induction of DNA cleavage by Zn2+ complexes under our experimental conditions.

Persistent Identifier

http://archives.pdx.edu/ds/psu/15890

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