| 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. |
