Elucidating the biological activity of prodigiosin analogues
LE3 .A278 2009
2009
McFarland, Sherri
Acadia University
Bachelor of Science
Honours
Chemistry
Prodigiosin is a naturally occurring red pigment containing a 4-methoxy,2-2-bipyrrole ring system, produced by terrestrial and marine bacterial strains such as Streptomyces and Serratia, and has been shown to possess anticancer activity. A new series of 13 C-ring functionalized prodigiosenes was examined for their biological activity through DNA cleavage assays, mechanism-based asssays, DNA binding studies, and cellular imaging studies for targeted use in breast cancer thearapy. The results of the copper-mediated DNA cleavage assays show that all prodigiosenes induce single-strand breaks in the presence of copper(II) ions. The β-carbonyl group on the C-ring, as well as the attachment of ester linkages, did not significantly lower the activity of the prodigiosenes. However, there appears to be a critical length for the C-ring carbon tether that greatly inhibits the ability to cleave DNA. Cleavage of the DNA, as determined from mechanism-based assays, was envisioned to occur through reduction of Cu(II) to form Cu(I), followed by reaction with H2O2 to form a Cu-oxo species (and/or hydroxyl radical), which can cause single-stranded breaks in the DNA. DNA binding was characterized though spectroscopic analyses of CT-DNA titrations as well as DNA melting studies, and indicate a definite interaction with DNA. CT-DNA titrations with free prodigiosene showed signs of intercalation into the CT-DNA as well as protonation of the C-ring nitrogen of the prodigiosene, while CT-DNA titrations of Cu(II)-bound prodigiosene demonstrate signs of primarily intercalation. Melting studies also indicate an interaction with DNA as the prodigiosenes increased the melting point of CT-DNA, pointing toward an intercalative binding mode. Cellular imaging assays also revealed that prodigiosene, as well as a prodigiosene-copper mixture can be taken up by HL-60 human leukemia cells. These results, as well as others, are detailed and discussed in this report.
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https://scholar.acadiau.ca/islandora/object/theses:601