Dissertation
Synthesis and biological testing of flavonol analogs in plant germination and cell proliferation
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2009
DOI:
https://doi.org/10.7273/000006079
Abstract
Flavonoids are polyphenolic compounds commonly found in fruits and vegetables. In plants, flavonoids have been shown to serve as a messenger molecule in the pollination sequence[1], a signaling molecule between plants and other organisms[2, 3], and to provide UV protection[4, 5]. In animals, flavonoids act as antioxidants[6], enzyme inhibitors[7], and growth regulators[8, 9]. Traditionally, flavonol analogs with varying substituents on the B-ring have been synthesized through a stepwise method.[10, 11] We developed a procedure for synthesizing flavonol analogs from a common intermediate through a palladium catalyzed Suzuki-Miyaura cross-coupling reaction. This common intermediate allowed the synthesis of many flavonol analogs with a variety of properties (hydrophobicity, steric hindrance, and photoaffinity) to be tested on pollen germination in petunia plants and on cell viability of the prostate cells lines DU-145, PC-3, and human infant fetal foreskin (HIFF). In plants, the least hydroxylated flavonols, such as kaempferol, have been found to increase pollen germination.[12, 13] Unfortunately, this trend did not extend to the flavonol analogs. The natural product galangin (H-flavonol) was the only non-hydroxylated compound to activate pollen germination to a similar degree as kaempferol and the 4 -methyl flavonol led to partial activation. The remaining flavonol analogs gave low or minimal activity. Competition assays between these minimally activating flavonols and kaempferol showed that the analogs were only able to weakly inhibit kaempferol from activating the pollination sequence. Thus, the 4 -methyl flavonol was the only analog to act as an agonist and the other minimally activating flavonols acted as weak antagonist. In prostate cancer cells, all of the flavonol analogs synthesized in this study decreased cell viability more than the natural products (quercetin, kaempferol, kaempferide, and galangin). The most potent flavonol analogs were 6.5 fold more active at decreasing the number of viable cells in prostate DU-145 and PC-3 cells than quercetin. Hydrophobic substituents (4 -iodo, and 3 - and 4 -phenyl flavonols) on the B-ring of the flavonol possessed the greatest ability to decrease cell viability in both cancer cell lines. There also appeared to be a steric effect from the 3 - and 4 -positions of the flavonol analogs: in general, the 4 -analogs inhibited cell growth better than the 3 -analogs. Further studies are needed to determine the mechanisms by which flavonols decrease cell viability in prostate cell lines and activate pollen germination in plants.
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Details
- Title
- Synthesis and biological testing of flavonol analogs in plant germination and cell proliferation
- Creators
- Alaina M. Forbes
- Contributors
- G. Patrick Meier (Chair)Robert C Ronald (Committee Member) - Washington State University, Department of ChemistryJeffrey P Jones (Committee Member) - Washington State University, Department of ChemistryGary G Meadows (Committee Member) - Washington State University, Department of Pharmaceutical Sciences
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Chemistry
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 180
- Identifiers
- 99901055025701842
- Language
- English
- Resource Type
- Dissertation