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Asymmetric 1,5-diarylpenta-1,4-dien-3-ones: Antiproliferative activity in prostate epithelial cell models and pharmacokinetic studies
- Source :
- European Journal of Medicinal Chemistry. 137:263-279
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones ( 25 – 58 ) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic prostate epithelial cell line. All these asymmetric dienones are sufficiently more potent than curcumin and their corresponding symmetric counterparts. The optimal dienone 58 , with IC 50 values in the range of 0.03–0.12 μM, is 636-, 219-, and 454-fold more potent than curcumin in three prostate cancer cell models. Dienones 28 and 49 emerged as the most promising asymmetric dienones that warrant further preclinical studies. The two lead compounds demonstrated substantially improved potency in cell models and superior bioavailability in rats, while exhibiting no acute toxicity in the animals at the dose of 10 mg/kg. Dienones 28 and 46 can induce PC-3 cell cycle regulation at the G 0 /G 1 phase. However, dienone 28 induces PC-3 cell death in a different way from 46 even though they share the same scaffold, indicating that terminal heteroaromatic rings are critical to the action of mechanism for each specific dienone.
- Subjects :
- Male
0301 basic medicine
Antineoplastic Agents
Apoptosis
Pharmacology
Article
Rats, Sprague-Dawley
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Prostate cancer
Pharmacokinetics
Prostate
Cell Line, Tumor
Drug Discovery
Tumor Cells, Cultured
medicine
Animals
Humans
Potency
Cell Proliferation
Dose-Response Relationship, Drug
Molecular Structure
Cell growth
Chemistry
Cell Cycle
Organic Chemistry
Prostatic Neoplasms
Epithelial Cells
General Medicine
medicine.disease
Rats
Bioavailability
Alkadienes
030104 developmental biology
medicine.anatomical_structure
Microsomes, Liver
Curcumin
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 137
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....63e52718eb0f2ac7efdb8639a36dca0f