Pyridoacridines as cytotoxic and anti-neoplastic agents

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Title Pyridoacridines as cytotoxic and anti-neoplastic agents
Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Marshall, Kathryn Marie
Date 2004-05
Description Many clinically used anticancer agents are natural products or derivatives of natural products. Many of these agents act through DNA-directed activities such as DNA intercalation, generation of reactive oxygen species (ROS) and the inhibition of DNA metabolizing enzymes. Pyridoacridines are a class of marine natural products that are the main focus of this dissertation. Pyridoacridines have a planar multi-ring structure; in addition, many of them can intercalate DNA and are cytotoxic. However, only a few characterized DNA directed activities have been reported in the literature and these activities are different depending on the pyridoacridine studied. I hypothesized that the pyridoacridines, reported here, would be cytotoxic as a result of DNA-directed activity. However, there are a number of ways that DNA-directed activity can result in cytotoxicity, and I feel that this is dependent on the pyridoacridine pharmacophore. Thus, I further hypothesized that relatively minor alterations on the pharmacophore in a pyridoacridine can produce immense changes in molecular mechanisms of cell killing. I was able to confirm these hypotheses. Work with AK37 analogs (synthetic pyridoacridines) showed that AK37 intercalated DNA and was able to inhibit the DNA topoisomerase enzymes, in addition to stabilizing topoisomerase I cleavable complexes. When 2 atoms are altered on the A" ring of AK37, as was the case with ascididemin, the DNA damaging activity changed to that of ROS generation. AK37 retained its DNA-directed activity when the "D" ring was removed, but it completely lost its activity when the "F" ring was added. Results obtained for the amphimedines also indicated that the hypotheses were correct. Amphimedine did not intercalate into DNA and was not toxic at tested concentrations. Neoamphimedine, the regioisomer of amphimedine, intercalated DNA and possessed a unique topoisomerase II-mediated ability to catenate circular DNA in vitro. No other pyridoacridines have shown this ability. In addition, deoxyamphimedine, a more potent DNA intercalator, damaged DNA via generation of ROS. Pyridoacridines and pyridoacridine derivatives are considered potential anticancer drugs. Their new biological activities that result from alterations in the pyridoacridine pharmacophore may suggest new prototype structures for further development.
Type Text
Publisher University of Utah
Subject Anatomy and Histology; Grwoth and Development
Subject MESH Marine Biology; Pharmacology; Neoplasms; Antineoplastic Agents
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Pyridoacridines as cytotoxic and anti-neoplastic agents." Spencer S. Eccles Health Sciences Library. Print version of "Pyridoacridines as cytotoxic and anti-neoplastic agents." available at J. Willard Marriott Library Special Collection RS43.5 2004 .M37.
Rights Management © Kathryn Marie Marshall.
Format application/pdf
Format Medium application/pdf
Format Extent 8,187,810 bytes
Identifier undthes,4844
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 8,187,873 bytes
ARK ark:/87278/s6348n6d
Setname ir_etd
ID 191179
Reference URL https://collections.lib.utah.edu/ark:/87278/s6348n6d
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