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A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models
- Source :
- Bioorganicmedicinal chemistry letters. 26(17)
- Publication Year :
- 2016
-
Abstract
- Flavonoids are a large class of polyphenolic compounds ubiquitously distributed in dietary plants with an array of biological activities. Flavonols are a major sub-class of flavonoids featuring a hydroxyl group at C-3. Certain natural flavonols, such as quercetin and fisetin, have been shown by in vitro cell-based and in vivo animal experiments to be potential anti-prostate cancer agents. However, the Achilles' heel of flavonols as drug candidates is their moderate potency and poor pharmacokinetic profiles. This study aims to explore the substitution effect of 3-OH in flavonols on the in vitro anti-proliferative potency against both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Our first lead flavonol (3',4'-dimethoxyflavonol), eight 3-O-alkyl-3',4'-dimethoxyflavonols, and six 3-O-aminoalkyl-3',4'-dimethoxyflavonols have been synthesized through aldol condensation and the Algar-Flynn-Oyamada (AFO) reaction. The WST-1 cell proliferation assay indicates (i) that all synthesized 3-O-alkyl-3',4'-dimethoxyflavonols and 3-O-aminoalkyl-3',4'-dimethoxyflavonols are more potent than the parent 3',4'-dimethoxyflavonol and the natural flavonol quercetin in suppressing prostate cancer cell proliferation; and (ii) that incorporation of a dibutylamino group to the 3-OH group through a three- to five-carbon linker leads to the optimal derivatives with up to 292-fold enhanced potency as compared with the parent flavonol. Flow cytometry analysis showed that the most potent derivative 22 can activate PC-3 cell cycle arrest at the G2/M phase and induce PC-3 cell apoptosis. No inhibitory ability of 22 up to 50μM concentration was observed against PWR-1E normal human epithelial prostate cells, suggesting its in vitro safety profile. The results indicate that chemical modulation at 3-OH is a vital strategy to optimize flavonols as anti-prostate cancer agents.
- Subjects :
- 0301 basic medicine
Male
Cell cycle checkpoint
Flavonols
Clinical Biochemistry
Cell
Pharmaceutical Science
Antineoplastic Agents
Apoptosis
Biochemistry
Article
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
0302 clinical medicine
In vivo
Cell Line, Tumor
Drug Discovery
medicine
Structure–activity relationship
Humans
Molecular Biology
Cell Proliferation
chemistry.chemical_classification
Flavonoids
Cell growth
Organic Chemistry
Prostatic Neoplasms
G2 Phase Cell Cycle Checkpoints
030104 developmental biology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
Drug Design
Molecular Medicine
M Phase Cell Cycle Checkpoints
Quercetin
Fisetin
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 26
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....0d32f3a47ba3d95f23e3a8d86c473382