title: A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models.
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.
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA. Electronic address: qchen@csufresno.edu.
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry / Q000633:toxicity; D044948:Flavonols / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011794:Quercetin / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D044948:Flavonols; D011794:Quercetin; C017875:fisetin
keywords: 3′,4′-Dimethoxyflavonol; Cell proliferation; Flavonol; Prostate cancer; Quercetin