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Structure-activity relationship and pharmacokinetic studies of 3-O-substitutedflavonols as anti-prostate cancer agents
- Source :
- European Journal of Medicinal Chemistry. 157:978-993
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Thirty-eight 3-O-substituted-3′,4′-dimethoxyflavonols and twenty-five 3-O-substituted-3′,4′,7-trimethoxyflavonols have been synthesized for systematic investigation on the structure-activity relationships of 3-O-substituted-3′,4′-dimethoxyflavonols in three human prostate cancer cell models. Our findings indicate that incorporation of an appropriate amino group to 3-OH of 3′,4′-dimethoxyflavonol and 3′,4′,7-trimethoxyflavonol through a 3- to 5-carbon linker can substantially improve the in vitro antiproliferative potency in three human prostate cancer cell models, but not in two non-neoplastic human epithelial cell models (MCF 10A and PWR-1E). 1-Methylpiperazine, pyrrolidine, and dibutylamine are optimal terminal amine groups that, in combination with a 3- to 5-carbon linker, are notably beneficial to the anti-proliferative potency of 3-O-substituted-3′,4′-dimethoxyflavonols. It is worth noting that 3-O-(4-methylpiperazin-1-yl)propyl-3′,4′,7-trimethoxyflavonol (76) induces PC-3 cell death in a completely different way from 3-O-pyrrolidinopentyl-3′,4′,7-trimethoxyflavonol (81) even though they belong to 3-O-substituted-3′,4′,7-trimethoxyflavonols and exhibit similar potency in inhibiting PC-3 cell proliferation, suggesting that the mechanism of action for each specific 3-O-substitutedflavonol varies with different amino moiety. 3-O-(N,N-Dibutylamino)propyl-3′,4′-dimethoxyflavonol (42) emerged as the most promising derivative due to its substantially improved potency in cell models, superior bioavailability in rats, and good selectivity of inhibiting prostate cancer cell proliferation over non-neoplastic human epithelial cell proliferation.
- Subjects :
- Male
0301 basic medicine
Flavonols
Antineoplastic Agents
Article
Pyrrolidine
Rats, Sprague-Dawley
Structure-Activity Relationship
03 medical and health sciences
Prostate cancer
chemistry.chemical_compound
0302 clinical medicine
Drug Discovery
medicine
Animals
Humans
Potency
Structure–activity relationship
Cells, Cultured
Cell Proliferation
Pharmacology
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Organic Chemistry
Prostatic Neoplasms
General Medicine
medicine.disease
Rats
Bioavailability
030104 developmental biology
Mechanism of action
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Drug Screening Assays, Antitumor
medicine.symptom
Linker
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 157
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....4a204bab469cd442edc45946eb903b33